bluuebunny/crossref_metadata_2025 huggingface dataset:
Platelet activating factor, lyso‐platelet activating factor and arachidonic acid release in normal human skin and the influence of topical steroid treatment.
Authors: Barr RM , Lawlor F , Judge MR , Courtney P , Barlow R , Kobza Black A , Mallet AI , Greaves MW
Published: July 2012

1. Previous, in vitro, studies have established the synthesis of platelet activating factor (PAF) by the 're‐modelling' pathways in which the activation of a phospholipase A2 (PLA2) enzyme catalyses the hydrolysis of an ether‐acyl‐phosphocholine to give concomitant release of lyso‐PAF, the immediate precursor of PAF, and arachidonic acid, the precursor of the icosanoids. The aim of this study was to investigate the relationship between PAF and eicosanoid release in human skin, and to study the effect of treatment of skin with a topical steroid, on the release of PAF, lyso‐PAF and arachidonic acid. 2. A novel assay procedure was developed for the simultaneous assay of PAF and lyso‐PAF in skin exudates from abrasions and suction blisters in normal human skin. In addition we assayed arachidonic acid and prostaglandin E2 (PGE2), a representative eicosanoid. 3. The mean amounts of mediator recovered in the first 30 min period following abrasion were PAF 0.43, lyso‐PAF 11.9, PGE2 25.7 and arachidonic acid 760 pmol/sample. The molar ratio of PAF:lyso‐PAF:arachidonic acid in skin exudates from abrasions was 1:30:1800 and in suction blister exudates was 1:90:3660. 4. Time course studies showed a decline in the recoveries of arachidonic acid and lyso‐PAF, of about 50% in 2 h. In contrast, PAF was recovered in exudates at a constant rate over 2 h but PGE2 release decreased by more than 90% after the initial 30 min period. 5. Topical application under occlusion, of 0.05% clobetasol propionate, a potent corticosteroid, significantly reduced lyso‐PAF by 30% in suction blister exudates but did not significantly alter the concentrations of PAF or arachidonic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
Moclobemide treatment causes a substantial rise in the sparteine metabolic ratio. Danish University Antidepressant Group.
Authors: Gram LF , Brosen K
Published: July 2012

A sparteine test was carried out immediately before (n = 37) and during (n = 33) moclobemide treatment (200 mg twice daily) in 37 patients participating in a controlled clinical trial. The sparteine metabolic ratio (MR) did not correlate with the plasma concentration of moclobemide and/or its oxidized metabolite Ro 12‐8095, and four sparteine poor metabolisers (PM, MR > 20) had plasma moclobemide concentrations similar to those in extensive metabolisers (EM, MR < 20). The Ro 12‐8095/moclobemide ratio tended to correlate negatively with the sparteine MR before and during treatment (rs = ‐0.32, ‐0.37). During moclobemide treatment the sparteine MR rose substantially by a factor of 1‐103 (median 4.7), and two EM became phenotypically PM. In the PM subjects as well as in one EM patient on cimetidine during both tests, no change in sparteine MR occurred.
Individual theophylline dosing based on bioelectrical impedance analysis.
Authors: Sidhu JS , Triggs EJ , Charles BG , Smithurst BA
Published: July 2012

The role of bioelectrical impedance (BI) analysis in determining slow‐ release theophylline dosage was evaluated in fifteen healthy subjects given a standard 200 mg dose. Reactance and l/resistance were identified as the most significant predictors of pre‐dose, steady‐state theophylline concentrations (Css, pre). Compared with doses based on body weight (8.8 mg kg‐1 day‐1), theophylline doses determined by BI analysis (9.6 +/‐ 2.4 mg kg‐1 day‐1) resulted in less biased (mean prediction error = 0.6 vs 1.4) though slightly less precise (mean squared error = 7.1 vs 6.3) Css, pre values. These differences were statistically insignificant (P > 0.05).
A comparison of the concentration‐effect relationships of midazolam for EEG‐derived parameters and saccadic peak velocity.
Authors: Van Steveninck AL , Mandema JW , Tuk B , Van Dijk JG , Schoemaker HC , Danhof M , Cohen AF
Published: July 2012

1. Concentration‐effect relationships of midazolam were assessed in an open study in six healthy volunteers. Saccadic eye movements and EEG parameters derived by fast Fourier transform (FFT) and aperiodic analysis (AP) were used to quantify drug effects. 2. Midazolam was infused at a rate of 0.6 mg kg‐1 h‐1 for a maximum of 15 min. Hypnotic effects were avoided by terminating infusions when subjects could no longer perform the eye movement test properly. 3. Wake‐sleep transitions could be recognized through frequent observation of eye movements. The dose needed to reach maximum conscious sedation averaged 0.10 mg kg‐1, ranging from 0.06 to 0.13 mg kg‐1. 4. Sigmoidal concentration‐effect relationships were found for EEG beta‐amplitudes in five of six subjects, with average EC50 values (+/‐ s.d.) of 120 +/‐ 54 ng ml‐1 for FFT and 104 +/‐ 40 ng ml‐1 for AP. For the 'total number of waves' in the beta frequency range (AP) an average (n = 6) EC50 of 63 +/‐ 37 ng ml‐1 was found. Changes in EEG alpha‐amplitudes were found in three subjects, resulting in an average EC50 value of 55 +/‐ 32 ng ml‐1. 5. For saccadic peak velocity (PV) concentration‐effect relationships were linear in five subjects and sigmoidal in one. The maximal measured decrease in PV averaged ‐44 +/‐ 9%. 6. The differences in concentration‐effect relationships for various effect parameters call for further studies with emphasis on the external validity and reproducibility of data. In such studies the dose needed to reach wake‐ sleep transition may be used as a relevant clinical end‐point.
GABA‐ergic control of visual perception in healthy volunteers: effects of midazolam, a benzodiazepine, on spatio‐temporal contrast sensitivity.
Authors: Blin O , Mestre D , Paut O , Vercher JL , Audebert C
Published: July 2012

1. We studied the effects of midazolam (MDZ), a benzodiazepine, on spatio‐temporal contrast sensitivity, choice reaction time, and mood visual analogue scales in healthy volunteers. 2. Eight extensively trained, healthy volunteers were included in a placebo‐controlled cross‐ over double‐blind trial of MDZ (0.15 mg kg‐1). Treatments were injected intramuscularly and evaluations were performed before and 0.5, 1, 2, 3 and 4 h after drug administration. Spatio‐temporal contrast sensitivity was measured using a micro‐computer with appropriate software. Stimuli were vertical gratings with adjustable contrast, with spatial frequencies of 0.25, 1 and 4 cpd. Four conditions of temporal modulation were used: the grating was either static or drifting laterally with temporal frequencies of 1, 3 and 9 Hz. 3. An analysis of variance was performed on the data. As compared with placebo, MDZ induced an increase in choice reaction time and sedation (as assessed on visual analogue scales). From 0.5‐4 h after the injection, MDZ produced an overall decrease in visual sensitivity, as compared with placebo. More specifically, MDZ preferentially affected medium to high spatial frequencies and low temporal frequencies. Several non‐exclusive hypotheses may account for the results: 1) an increase in the size of the receptive fields, 2) a preferential effect on the visual parvocellular pathways which mediate the sensitivity to high spatial and low temporal frequencies.
Creatinine elevation in patients receiving amiodarone correlates with serum amiodarone concentration.
Authors: Pollak PT , Sharma AD , Carruthers SG
Published: July 2012

Serum creatinine and drug concentrations were measured at 0, 1, 2, 3, 6, 9 and 12 months in 30 consecutive patients started on amiodarone. In 28 of these patients with no obvious cause for altered renal function, mean serum creatinine increased to 11% above baseline (P < 0.005). Rising creatinine concentrations correlated with amiodarone concentrations (y = 93.9 + 8.6x, r = 0.51, P < 0.0001). When assessing elevation of serum creatinine in a patient receiving amiodarone, physicians should be aware that it may be related to this drug.
Pharmacokinetics of zidovudine after the initial single dose and during chronic‐dose therapy in HIV‐infected patients.
Authors: Gallicano K , Sahai J , Ormsby E , Cameron DW , Pakuts A , McGilveray I
Published: July 2012

The pharmacokinetics of zidovudine in 10 symptomatic HIV‐infected men were assessed after administration of the initial 200 mg oral dose at the start of therapy (day 1) and on one occasion during non steady‐ state conditions of chronic‐dose therapy (200 mg every 4 h while awake on day 21‐66; 5 doses per day). The following mean (+/‐ s.d.) pharmacokinetic parameters were determined on day 1 and during chronic therapy, respectively: Cmax (4.09 +/‐ 2.54 vs 3.82 +/‐ 1.03 mumol l‐1), oral clearance (40.7 +/‐ 12.9 vs 41.1 +/‐ 8.4 ml min‐1 kg‐1) and terminal half‐life (68.4 +/‐ 29.4 vs 65.1 +/‐ 13.1 min). Mean pharmacokinetic parameters on day 1 were < 10% different (P > 0.34) from those determined during chronic therapy. Differences in means of 21% for clearance and 36% for Cmax could be detected with a power of 80% at the 5% significance level. Intra‐subject coefficients of variation were 17% for clearance and 32% for Cmax, respectively. This study suggests that within a group of patients whose stage of HIV infection and general health are relatively stable, first‐dose pharmacokinetic parameters provide a good estimate of multiple‐dose pharmacokinetic parameters.
Individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism in male nonsmokers.
Authors: Loi CM , Parker BM , Cusack BJ , Vestal R
Published: July 2012

1. The individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism were examined in six young male nonsmokers. 2. Treatment sequence consisted of 7 days each of cimetidine 400 mg p.o. every 12 h. ciprofloxacin 500 mg p.o. every 12 h, and the combination of cimetidine and ciprofloxacin. 3. Studies of theophylline pharmacokinetics were performed at baseline and on the fifth day of each regimen. 4. Individually, cimetidine and ciprofloxacin decreased the clearance of theophylline by 25% and 32%, respectively. Therapy with the combined regimen resulted in a 41% reduction in theophylline clearance, which was greater than that achieved with each drug alone (P < 0.01). 5. Ciprofloxacin, in contrast to cimetidine, inhibited N‐ demethylations of theophylline to a significantly greater extent than the hydroxylation pathway. Combined treatment produced a further decline in formation of 1,3‐dimethyluric acid than each drug alone. 6. These data suggest that coadministration of cimetidine and ciprofloxacin exerts a greater impairment of theophylline biotransformation than each inhibitor alone. The enhanced inhibitory effect from the two inhibitors will occur only when sub‐maximal doses of each individual agent are used.
The influence of orally deposited budesonide on the systemic availability of budesonide after inhalation from a Turbuhaler.
Authors: Pedersen S , Steffensen G , Ohlsson SV
Published: July 2012

1. The aim of this pharmacokinetic study was to evaluate to what extent oropharyngeal deposition of drug contributes to the systemic availability of budesonide inhaled from a dry powder inhaler (Turbuhaler). 2. The design was a randomized cross‐over study in eight children aged 7‐13 years. The plasma concentrations of the two epimers of budesonide (22R and 22S) after inhalation of 1 mg budesonide from a Turbuhaler were compared with the plasma concentrations obtained when the absorption of the drug deposited in the oropharynx was blocked by drinking and rinsing the mouth with charcoal before and after the inhalation. 3. The plasma concentrations of budesonide were significantly reduced by the charcoal treatment (P < 0.01) and the area under the time vs plasma concentration curve 0‐4 h was significantly reduced from 9.5 to 8.0 mmol l‐1 h for 22S (P < 0.01) and from 7.6 to 5.7 mmol l‐1 h for 22R (P < 0.01). 4. The plasma concentrations and the AUCs after both Turbuhaler administrations were markedly higher than those obtained in earlier studies using other inhalers suggesting a higher intrapulmonary deposition of drug after Turbuhaler treatment. 5. It is concluded that oropharyngeal deposition of drug accounts for about 20% of the total systemic availability of budesonide inhaled from Turbuhaler. Thus, the main contribution to the system comes from budesonide absorbed in the airways.
The pharmacokinetics and physiological effects of buprenorphine infusion in premature neonates.
Authors: Barrett DA , Simpson J , Rutter N , Kurihara‐Bergstrom T , Shaw PN , Davis SS
Published: July 2012

1. The pharmacokinetics and physiological effects of buprenorphine were studied in 12 newborn premature neonates (27 to 32 weeks gestational age) who were given a loading dose of 3.0 micrograms kg‐1 of buprenorphine followed by an intravenous infusion of 0.72 micrograms kg‐ 1 h‐1 of buprenorphine. Plasma concentrations of buprenorphine were measured during the infusion, at steady‐state and for 24 h after the cessation of the buprenorphine infusion. 2. The mean steady‐state plasma buprenorphine concentration (+/‐ s.d.) for an infusion rate of 0.72 micrograms kg‐1 h‐1 was 4.3 +/‐ 2.6 ng ml‐1. 3. Buprenorphine clearance was 0.23 +/‐ 0.07 l h‐1 kg‐1, the elimination half‐life was 20 +/‐ 8 h and the volume of distribution was 6.2 +/‐ 2.11 l kg‐1. 4. Small but significant falls were noted in systolic blood pressure at 6 h and heart rate at 1, 6 and 12 h after the administration of buprenorphine, but these did not appear to cause any clinical deterioration. 5. Four of the 12 subjects studied required an increase in the infusion rate of buprenorphine to achieve adequate sedation. 6. The results suggest that this dosing regimen of buprenorphine is safe but may not be as effective as other opioids in producing sedation and analgesia in premature newborns.
Impairment of psychomotor function at modest plasma concentrations of carbamazepine after administration of the liquid suspension to naive subjects.
Authors: Wildin JD , Pleuvry BJ , Mawer GE
Published: July 2012

1. The influence of pharmaceutical formulation on the plasma drug concentration‐time curve and the psychomotor responses to 400 mg carbamazepine has been assessed in 12 healthy male volunteers; three formulations and placebo were compared in a randomised, blind, crossover study. 2. The plasma concentration of carbamazepine rose to a maximum of 3‐7 mg l‐1 by 2‐3 h after administration of the liquid suspension. Conventional and controlled release tablet formulations gave lower peaks at about 8 and 32 h, respectively. From 32 h onwards the plasma concentrations from the three formulations were indistinguishable. 3. Significant impairment of psychomotor function was observed after the liquid suspension only; subjective sedation was significant at 1 and 2 h and the critical flicker fusion frequency threshold was lowered at 1‐8 h. Digit‐symbol substitution, choice reaction time and body sway gave less conclusive evidence of impairment. 4. The results do not support the hypothesis that a psychomotor effect from carbamazepine is a threshold phenomenon with a critical plasma drug concentration at about 8 mg l‐1. 5. A second hypothesis that rate of rise of plasma carbamazepine concentration has an important influence on psychomotor effect fits the observations. This interpretation is tentative since the use of a fixed dose of carbamazepine meant that differences due to rate of rise of drug concentration were confounded with differences due to peak height.
The lipolytic effect of beta 1‐ and beta 2‐adrenoceptor activation in healthy human volunteers.
Authors: Haffner CA , Kendall MJ , Maxwell S. , Hughes B.
Published: July 2012

1. We investigated the effect of activation beta 1‐ and beta 2‐ adrenoceptors on the process of lipolysis in human volunteers. Ten male subjects underwent a single‐blind randomized cross‐over trial using infusions of terbutaline (a specific beta 2‐adrenoceptor agonist), xamoterol (a partial beta 1‐agonist with beta 2‐adrenoceptor blocking activity) and saline (placebo control). The effect of these infusions on plasma potassium, glucose, free fatty acids (FFA) (total and individual) and insulin levels was studied. 2. Terbutaline infusion induced a significant rise in plasma glucose and a fall in plasma potassium in keeping with its beta 2‐adrenoceptor stimulant properties. Xamoterol infusion had no significant effect on these values. Terbutaline infusion caused a greater rise in total and individual FFA than xamoterol, but both effects were significantly different from placebo. 3. The possible reasons for these results and their implications on the beta‐adrenergic control of lipolysis are discussed.
The measurement of a new antimicrobial quinolone in hair as an index of drug exposure.
Authors: Uematsu T. , Nakano M. , Akiyama H. , Nakashima M.
Published: July 2012

1. Scalp hair samples were obtained at 1 month intervals up to 5 months from healthy male volunteers participating in a phase I study of a new antimicrobial quinolone, OPC‐17116. 2. Hair was sectioned into 1 cm lengths from the scalp end. Corresponding portions from five pieces of hair were dissolved in 1 N NaOH and assayed for OPC‐17116 by h.p.l.c. 3. In all subjects taking a single dose (400 mg, n = 5) or repeated doses (400 mg day‐1, twice daily, for 6.5 days, n = 6), the drug was detected in the portions of hair corresponding to the administration period, assuming a hair growth rate of 1 cm/month. 4. OPC‐17116 (300 mg day‐1, three times daily, for 2 days) was given to four healthy male volunteers, from whom hair samples were obtained at 1 month and 3 months. The drug was detected in 1 to 4 consecutive 2.5‐mm long portions of a single hair and there was no significant axial diffusion of the agent along the hair shaft with time. 5. These findings indicate the utility of measuring this quinolone derivative in hair as an index of exposure, and as a time‐marker for the hair analysis of other drugs.
Equipotent inhibition by R(−)−, S(+)‐ and racemic ibuprofen of human polymorphonuclear cell function in vitro.
Authors: Villanueva M. , Heckenberger R. , Strobach H. , Palmer M. , Schror K.
Published: July 2012

1. The effects of racemic (rac) ibuprofen and its S(+)‐ and R(−)− enantiomers on functions of human polymorphonuclear cells (PMN) and platelets were studied in vitro. 2. Rac‐ibuprofen inhibited PMN functions (O2‐ generation, beta‐glucuronidase release, LTB4 formation). Similar IC50 values (40‐100 microM) were obtained for the S(+)‐ and R(‐ )‐enantiomers. 3. All forms of ibuprofen inhibited cyclooxygenase‐ related platelet functions (aggregation, thromboxane formation). The S(+)‐enantiomer was about twice as active as the racemate while the R(‐ )‐enantiomer was at least 10‐fold less active. This demonstrates that the S(+) is the only cyclooxygenase inhibitory component of the racemate. 4. The concentrations of rac‐ibuprofen in PMN and platelets were similar to those in the incubation medium and represented equal concentrations of the enantiomers. This indicates that neither interconversion nor tissue accumulation of the compounds occurred. 5. These data indicate that antineutrophil effects of ibuprofen on human PMN are independent of cyclooxygenase inhibition. Therefore, R(−)− ibuprofen may be superior to the S(+)‐isomer for the treatment of PMN‐ dependent inflammatory diseases. However, effective free drug concentrations may not be obtained in vivo.
Bronchodilating effects of the novel potassium channel opener HOE 234 in human airways in vitro.
Authors: Miura M. , Belvisi MG , Ward JK , Tadjkarimi S. , Yacoub MH , Barnes PJ
Published: July 2012

Bronchodilating effects of the novel potassium channel opener HOE 234 were examined in human bronchi in vitro and compared with those of BRL 38227. HOE 234 produced concentration‐dependent relaxations of spontaneous tone and of tone increased by methacholine (10(‐6) M), with mean EC50 values of 11 nM and 47 nM, respectively (n = 5). The relaxation produced by HOE 234 was 7 and 3.5 fold more potent than that by BRL 38227 on spontaneous and induced tone, respectively, and was inhibited by glibenclamide (10(‐5) M). These results suggest that HOE 234 is a potent bronchodilator which activates ATP‐sensitive potassium channels in human airways.
High clearance of (S)‐warfarin in a warfarin‐resistant subject.
Authors: Hallak HO , Wedlund PJ , Modi MW , Patel IH , Lewis GL , Woodruff B. , Trowbridge AA
Published: July 2012

A 30 year old black male required a 60 mg daily dose of warfarin to elicit a therapeutic anticoagulant response (normal warfarin dose 2.5‐ 10 mg day‐1; maximum 15 mg day‐1). Hereditary warfarin resistance was suspected after compliance, diet, concurrent medication and any gastrointestinal disorder were eliminated as contributory causes. The disposition of vitamin K and vitamin K epoxide was examined in the propositus, his two sisters and 13 control black male subjects. Each subject was given an i.v. bolus dose (5 mg) of vitamin K prior to and after 2 weeks of warfarin therapy (5 mg day‐1). The oral clearances of (S)‐ and (R)‐warfarin were also measured in each subject during the last day of warfarin therapy. The mean (+/‐ s.d.) systemic clearance of vitamin K was similar in all subjects before (114 +/‐ 35 ml min‐1) and after (112 +/‐ 40 ml min‐1) warfarin therapy. The mean (+/‐ s.d.) AUC value for vitamin K epoxide was increased by warfarin treatment (6.5 +/‐ 5.4 micrograms ml‐1 min before and 139 +/‐ 78 micrograms ml‐1 min after) in all subjects. In the propositus, the oral clearance of (S)‐ warfarin (14.5 ml min‐1) and the clearance ratio for (S)/(R)warfarin (2.6) differed by more than 7 standard deviations from the control group (4.3 +/‐ 1.1 ml min‐1 and 1.2 +/‐ 0.2, respectively). In one sister of the propositus, the stereoselective disposition of warfarin was comparable with that of her brother ((S)‐warfarin clearance = 16.2 ml min‐1; and (S)/(R)‐warfarin clearance ratio = 2.7).
The pharmacokinetics and pharmacodynamics of dermatan sulphate MF701 during haemodialysis for chronic renal failure.
Authors: Gianese F. , Nurmohamed MT , Imbimbo BP , Buller HR , Berckmans RJ , Ten Cate JW
Published: July 2012

Single i.v. bolus doses of dermatan sulphate MF701 were administered before the onset of haemodialysis to patients with chronic renal failure, to prevent clotting in the extracorporeal circuit. Six patients received 2 mg kg‐1; six were given 2.5 and 3 mg kg‐1; 13 received 4.5 and 6 mg kg‐1. Plasma MF701 concentrations (chromogenic assay), activated partial thromboplastin time (APTT) and plasma markers of coagulation and platelet activation (TAT and beta‐TG) were measured over 4 or 8 h from the onset of dialysis. The disposition of MF701 was described by a monoexponential function. C(0) and AUC values increased proportionally with dose. Volumes of distribution (approximately 4 l) were dose‐independent. Half‐lives showed a non significant increase with dose (from 2.2 to 3.1 h) and were 2.5‐3 times longer than those reported for healthy subjects. There was a significant correlation between plasma MF701 concentration and its effects in prolonging APTT and suppressing TAT and beta‐TG generation during dialysis.
The effects of indomethacin and naproxen on zidovudine pharmacokinetics.
Authors: Barry M. , Howe J. , Back D. , Breckenridge A. , Brettle R. , Mitchell R. , Beeching NJ , Nye FJ
Published: July 2012

The effects of indomethacin and naproxen on zidovudine (ZDV) pharmacokinetics were studied in six patients with the acquired immunodeficiency syndrome (AIDS), AIDS related complex (ARC) or asymptomatic HIV disease using a placebo‐controlled crossover design. Indomethacin 25 mg twice daily or naproxen 250 mg twice daily did not alter ZDV pharmacokinetics compared with placebo. The mean AUC value for the glucuronidated metabolite, GZDV, was reduced from 26.6 +/‐ 11.7 mumol l‐1 h in the presence of placebo to 20.9 +/‐ 8.3 mumol l‐1 h (95% C.I. of the difference 1.39‐9.98; P < 0.05) following treatment with naproxen 250 mg twice daily for 3 days. The small decrease in plasma GZDV in the naproxen phase reflects an increase in clearance of ZDV to other metabolites and/or a decrease in the formation clearance to GZDV and/or an increase in the clearance of GZDV. A decrease in formation clearance to GZDV would be consistent with the results of in vitro studies reported previously. No significant increase in ZDV concentration in the presence of naproxen may reflect a lower sensitivity of parent drug measurements to selective inhibition of parallel pathways of metabolism. The clinical significance of these findings is unknown but toxicity may be increased if a decreased formation of GZDV is accompanied by shunting of metabolism to 3'‐amino‐ 3'‐deoxythymidine which is alleged to be cytotoxic.
Examination of some factors responsible for a food‐induced increase in absorption of atovaquone.
Authors: Rolan PE , Mercer AJ , Weatherley BC , Holdich T , Meire H , Peck RW , Ridout G , Posner J
Published: July 2012

1. Atovaquone is a potent antiprotozoal slowly and irregularly absorbed after administration as tablets to fasting volunteers. A series of studies was performed to investigate the effects of food, bile and formulation on atovaquone absorption. 2. In 18 healthy male volunteers, a high‐fat breakfast administered 45 min before 500 mg atovaquone as tablets increased AUC by 3.3‐fold (95% CI 2.8‐4.0) and Cmax 5.3‐fold (4.3‐6.6) compared with fasting. 3. The absorption of atovaquone from tablets was examined in 12 healthy male volunteers after an overnight fast, following toast alone, toast with 28 g butter (LOFAT), or toast with 56 g butter (HIFAT). Compared with absorption when fasted, toast had no significant effect but LOFAT increased AUC 3.0‐fold (2.1‐4.2) and Cmax 3.9‐fold (2.6‐5.8). HIFAT increased AUC 3.9‐fold (2.7‐5.5) and Cmax 5.6‐fold (3.8‐8.4). 4. The absorption of atovaquone was examined in nine healthy fasting male volunteers from tablets, an aqueous suspension, and an oily solution/suspension in miglyol (fractionated coconut oil). Compared with tablets, AUC following the aqueous suspension was increased 1.7‐fold (1.0‐2.7) and Cmax 2.4‐fold (1.7‐ 3.5). Following miglyol, AUC was increased to the same extent but Cmax was only increased 1.8‐fold (1.2‐2.6). 5. Atovaquone absorption was examined in eight healthy fasting male volunteers following an i.v. infusion of cholecystokinin octapeptide (CCK‐OP) which decreased gallbladder volume by 82% (73%‐90%) on occasion 1 or saline on occasion 2. AUC(0,12) was increased following CCK‐OP by 1.6‐fold (1.1‐2.4) and Cmax by 1.5‐fold (0.98‐2.4).(ABSTRACT TRUNCATED AT 250 WORDS)
The influence of gender and sex steroid hormones on the plasma binding of propranolol enantiomers.
Authors: Walle UK , Fagan TC , Topmiller MJ , Conradi EC , Walle T
Published: July 2012

1. Plasma binding of tritium‐labelled racemic propranolol (P) was measured by equilibrium dialysis. The unbound enantiomers were separated by h.p.l.c. after chiral derivatization. The binding of (‐)‐P was higher than that of (+)‐P. 2. Contrary to previous suggestions, a sex difference in the plasma binding of the P enantiomers (9 young women, 12 young men) was not observed. The unbound percentage of (‐)‐P was 9.2 +/‐ 1.8 (mean +/‐ s.d.) in women vs 9.1 +/‐ 1.7 in men; for (+)‐ P it was 10.8 +/‐ 1.8 vs 10.8 +/‐ 2.1. 3. In the nine women, the binding did not change with fluctuating plasma oestradiol concentrations during the menstrual cycle. Testosterone cypionate doubled the circulating concentrations of testosterone in eight men but had no effect on P binding. 4. Ethinyl oestradiol (50 micrograms day‐1) alone or together with norethindrone (OCD) in eight of the women produced an increase in the unbound percentage of both (‐)‐P (11.4 +/‐ 2.6 vs 9.5 +/‐ 1.6 for control; P < 0.001) and (+)‐P (13.2 +/‐ 2.5 vs 11.2 +/‐ 1.5 for control; P < 0.001). This was due to a decrease in the plasma concentrations of alpha 1‐acid glycoprotein from 0.54 +/‐ 0.11 mg ml‐1 in control to 0.37 +/‐ 0.08 mg ml‐1 (P < 0.001) during ethinyl oestradiol treatment. 5. Enantioselectivity in the unbound fraction of P increased with increasing total binding from a (‐)/(+)‐ratio of 0.93 at 84% binding to a (‐)/(+)‐ratio of 0.78 at 94% binding (P < 0.001).
Acoustic rhinometry compared with posterior rhinomanometry in the measurement of histamine‐ and bradykinin‐induced changes in nasal airway patency.
Authors: Austin CE , Foreman JC
Published: July 2012

1. Acoustic rhinometry is a relatively new method for objectively assessing nasal airway patency. In this paper we compare acoustic rhinometry with active posterior rhinomanometry. 2. Twenty normal healthy volunteers underwent nasal challenge with either histamine or bradykinin, 100 micrograms to 1000 micrograms, and responses were assessed by acoustic rhinometry. A further 20 subjects received identical nasal challenges and responses were assessed by active posterior rhinomanometry. 3. On a subsequent occasion, the subjects challenged previously with histamine, were given the selective H1‐ receptor antagonist, cetirizine, 10 mg orally, 3 h before repeat nasal challenge with histamine, 100‐1000 micrograms. Again, responses were assessed by active posterior rhinomanometry and acoustic rhinometry. 4. The acoustic reflection measurements and the nasal airway resistance measurements showed comparable, significant dose‐related changes in nasal patency to both histamine and bradykinin. Pretreatment with cetirizine blocked the histamine‐induced change in nasal patency as measured by both methods. 5. We conclude that acoustic rhinometry has a number of advantages over posterior rhinomanometry. It is quick to perform, requires minimal subject co‐operation and gives a reliable objective, measurement of dose‐related changes in nasal airway patency before and after pharmacological treatment.
Colestipol at varying dosage intervals in the treatment of moderate hypercholesterolaemia.
Authors: Lyons D , Webster J , Fowler G , Petrie JC
Published: July 2012

1. Bile acid sequestrants such as colestipol are effective lipid lowering agents but have a poor reputation for tolerability particularly when administered at the originally recommended doses. We have investigated a low dosage regimen with varying dosage intervals in order to assess efficacy and tolerability. 2. This double‐blind, placebo controlled, parallel group study was conducted to investigate the effect of varying administration schedules of colestipol (10 g daily), against placebo in reducing LDL cholesterol levels in patients with moderate hypercholesterolaemia on the American Heart Association step 1 diet. 3. Colestipol or matched placebo, was administered as 5 g twice daily (COL am/pm) or 10 g once daily in the morning (COL am) or evening (COL pm) at fixed times with meals. 4. All 98 patients who entered the initial 16 week dietary phase, subsequently entered the 12 week active treatment phase and were randomised to placebo or active treatment and to one of the three treatment schedules. Fasting lipid profiles were performed every 4 weeks during both phases. 5. All active treatments significantly reduced LDL and total cholesterol compared with placebo (COL am: 17% and 10%, COL pm: 18% and 10%, COL am/pm: 19% and 12% (P = 0.0001)). HDL cholesterol rose significantly with COL am (5% (P = 0.021)) and COL am/pm (7% (P = 0.002)) when compared with placebo while a marginal increase was seen with COL pm (4% (P = 0.063)). Colestipol tended to increase serum triglyceride concentrations but the changes were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Disposition of clozapine in man: lack of association with debrisoquine and S‐mephenytoin hydroxylation polymorphisms.
Authors: Dahl ML , Llerena A , Bondesson U , Lindstrom L , Bertilsson L
Published: July 2012

A large interindividual variability has previously been demonstrated in the bioavailability, steady‐state plasma concentrations and clearance of clozapine, an atypical neuroleptic drug. To evaluate the importance of genetic factors in the metabolism of clozapine, its disposition after a single oral dose of 10 mg was studied in 15 healthy Caucasian volunteers. Five of the subjects were poor metabolisers (PM) of debrisoquine, five were PM of S‐mephenytoin, and the remaining five were extensive metabolisers (EM) of both probe drugs. There was a 10‐ fold interindividual variation in Cmax and a 14‐fold variation in AUC(0, 24) of clozapine among the 15 subjects studied. The mean (s.d.) Cmax was 117 (81) nmol l‐1 and the mean AUC(0,24) value was 890 (711) nmol l‐1 h. The value of t1/2,z varied 3‐fold with a mean (s.d.) of 13.3 (5.0) h. There were no significant differences in the plasma concentrations or any of the pharmacokinetic parameters of clozapine between PM and EM of debrisoquine, or between the two S‐mephenytoin hydroxylation phenotypes. We conclude that neither of the major genetic polymorphisms of oxidative drug metabolism contribute to the large interindividual variability in clozapine pharmacokinetics.
Effects of a thromboxane receptor antagonist on prostaglandin D2 and histamine induced bronchoconstriction in man.
Authors: al Jarad N , Hui KP , Barnes N
Published: July 2012

Many prostanoids including are prostaglandin (PG) F2 alpha and PGD2 are potent bronchoconstrictor agents. There is evidence to suggest that airway thromboxane (TP) receptor may act as a common receptor for their bronchoconstrictor actions. We tested the hypothesis that inhaled prostaglandin (PG) D2‐induced bronchoconstriction is mediated by interacting with the TP receptor antagonist, ICI 192605, on the bronchoconstrictor response to inhaled PGD2 in a double‐blind, placebo‐ controlled and crossed‐over trial in normal subjects. The effect of ICI 192605 on histamine induced bronchoconstriction served as control for non‐specific bronchodilatory actions. The study had two phases; the first consisted of two inhaled PGD2 challenge study days, and the second phase was that of inhaled histamine. Each study day was separated by at least a week. On each study day, the challenge tests were carried out 30 min after ingestion of 100 mg ICI 192605 or placebo. Doubling concentrations of agonist were given till more than 35% fall in post‐diluent specific airway conductance (sGaw) occurred. The concentration needed to cause a fall in a sGaw of 35% post‐diluent value (PC35sGaw) was then determined from linear interpolation of the log dose‐response. Eight male subjects (median age 26, range 20‐35 years) completed the study. ICI 192605 did not change baseline airway calibre 30 min after ingestion on either PGD2 or histamine study days. ICI 192605 significantly shifted the dose‐response curve to inhaled PGD2 to the right by a median of 3.4 fold (Wilcoxon rank sign test, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Clinical pharmacology and therapeutics in undergraduate medical education in the UK: current status.
Authors: Walley T , Bligh J , Orme M , Breckenridge A
Published: July 2012

1. Medical undergraduate education is currently undergoing major changes in the UK in response to calls for the development of a core curriculum. Teaching in clinical pharmacology and therapeutics will also change to meet these demands. A postal survey was conducted to assess the current status of teaching in these subjects. 2. A questionnaire based on previous similar surveys conducted elsewhere was sent to departments or individuals in 27 medical schools in the UK; 22 (81%) replied. 3. Departmental priorities were defined as (in order): clinical research, undergraduate teaching, basic scientific research and clinical service provision. No change in these priorities in the future was foreseen by respondents. 4. Teaching methods were for the most part traditional, with the lecture as the most widely used and important technique. Specific clinical teaching was conducted by some and was considered very important by them. Teaching by problem solving was much less common. 5. Respondents were asked for free text comments; many of the remarks suggested dissatisfaction with the resources and time currently available for teaching in clinical pharmacology and therapeutics. Some expressed significant concerns that their teaching commitment would be reduced further by the development of the core curriculum.
Comparison of the effects of acute fluvoxamine and desipramine administration on melatonin and cortisol production in humans.
Authors: Skene DJ , Bojkowski CJ , Arendt J
Published: July 2012

1. Acute administration of the specific serotonin uptake inhibitor, fluvoxamine (100 mg at 16.00 h), markedly increased nocturnal plasma melatonin concentrations, with high levels extending into the morning hours. 2. Acute administration of the noradrenaline uptake inhibitor, desipramine (DMI) (100 mg at 16.00 h), increased evening plasma melatonin concentrations. 3. Both drug treatments increased the duration of melatonin secretion, fluvoxamine significantly delaying the offset time and DMI significantly advancing the onset time. 4. The stimulatory effect of DMI on plasma melatonin was mirrored by increased urinary 6‐sulphatoxymelatonin (aMT6s) excretion. 5. On the contrary, there was no correlation between plasma melatonin and urinary aMT6s concentrations following fluvoxamine treatment, suggesting that fluvoxamine may inhibit the metabolism of melatonin. 6. Treatment with DMI increased plasma cortisol concentrations in the evening and early morning, treatment with fluvoxamine increased plasma cortisol at 03.00 h, 10.00 h and 11.00 h. 7. The drug treatments affected different aspects of the nocturnal plasma melatonin profile suggesting that the amplitude of the melatonin rhythm may depend upon serotonin availability and/or melatonin metabolism whilst the onset of melatonin production depends upon noradrenaline availability.
Does tachyphylaxis occur to the non‐pulmonary effects of salmeterol?
Authors: Maconochie JG , Minton NA , Chilton JE , Keene ON
Published: July 2012

1. The potential for tachyphylaxis to the non‐pulmonary effects of salmeterol, a long‐acting selective beta 2‐adrenoceptor agonist was investigated in 12 healthy male subjects in a double‐blind two period crossover study design. 2. Subjects received cumulative doses of up to 400 micrograms (50 + 50 + 100 + 100 + 100 micrograms at 45 min intervals) inhaled salmeterol prior to a 13 day dosing schedule of twice‐daily inhaled salmeterol 100 micrograms or placebo. Twelve hours after the last dose of salmeterol or placebo, subjects again received cumulative doses of up to 400 micrograms inhaled salmeterol. 3. Pulse rate, blood pressure, 12‐lead ECG, physiological tremor and peak expiratory flow rate (PEFR) were measured before administration of cumulative doses of salmeterol, at 10, 20, 30 and 40 min after each incremental dose of salmeterol and at 4, 6 and 8 h after the first dose. Blood samples were taken for plasma potassium, magnesium, non‐ esterified fatty acids (NEFA) and blood glucose concentrations at 20 and 40 min after each dose and at 4, 6 and 8 h after the first dose. 4. Eleven subjects completed the study. One subject withdrew due to beta 2‐ adrenoceptor related adverse events. All other adverse events reported were mild in nature. 5. Dose‐related changes to the effects of salmeterol on pulse rate, QTc interval, tremor, PEFR, blood glucose and plasma potassium were seen, but there was no dose‐related effect of salmeterol on blood pressure, plasma magnesium and NEFA. 6. Tachyphylaxis occurred to the effects of salmeterol on tremor, QTc and blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
Interaction between tolbutamide and ketoconazole in healthy subjects.
Authors: Krishnaiah YS , Satyanarayana S , Visweswaram D
Published: July 2012

A possible interaction between tolbutamide and ketoconazole was studied in seven healthy volunteers. Treatment for 1 week with 200 mg oral ketoconazole increased the elimination half‐life (from mean +/‐ s.d. 3.7 +/‐ 0.4 to 12.3 +/‐ 1.9 h) and AUC(0.12 h) of tolbutamide (from 309 +/‐ 27 to 546 +/‐ 20 micrograms ml‐1 h) by 25 +/‐ 64 and 66 +/‐ 15%, respectively. The percentage blood glucose reduction was also increased when tolbutamide and ketoconazole were coadministered.
Dose of midazolam should be reduced during diltiazem and verapamil treatments.
Authors: Backman JT , Olkkola KT , Aranko K , Himberg JJ , Neuvonen PJ
Published: July 2012

1. The effects of diltiazem and verapamil on the pharmacokinetics and pharmacodynamics of midazolam were investigated in a double‐blind randomized cross‐over study of three phases. 2. Nine healthy volunteers were given orally diltiazem (60 mg), verapamil (80 mg) or placebo three times daily for 2 days. On the second day they received a 15 mg oral dose of midazolam, after which plasma samples were collected and performance tests carried out for 17 h. 3. The area under the midazolam concentration‐time curve was increased from 12 +/‐ 1 microgram ml‐1 min to 45 +/‐ 5 micrograms ml‐1 min by diltiazem (P < 0.001) and to 35 +/‐ 5 micrograms ml‐1 min by verapamil (P < 0.001). The peak midazolam concentration was doubled (P < 0.01) and the elimination half‐life of midazolam prolonged (P < 0.05) by both diltiazem and verapamil treatments. 4. These changes in the pharmacokinetics of midazolam were also associated with profound and prolonged sedative effects. 5. If the administration of midazolam cannot be avoided, the dose of midazolam should be reduced during concomitant treatment with diltiazem and verapamil.
Pharmacokinetics of rac‐leucovorin vs [S]‐leucovorin in patients with advanced gastrointestinal cancer.
Authors: Mader RM , Steger GG , Rizovski B , Sieder AE , Locker G , Gnant MF , Jakesz R , Rainer H
Published: July 2012

1. The pharmacokinetics of [R]‐leucovorin ([R]‐LV), [S]‐leucovorin ([S]‐ LV) and the circulating metabolite [S]‐5‐methyltetrahydrofolate ([S]‐5‐ MTHF) were studied after administration of racemic LV and [S]‐LV in 21 subjects. 2. After intravenous infusion of 600 mg m‐2 rac‐LV (group 1, n = 7) or 300 mg m‐2 [S]‐LV (group 3, n = 7), the decay of [S]‐LV in plasma was biexponential with a distribution half‐life of 0.8 to 1 h and an elimination half‐life of 11 to 23 h. When rac‐LV was administered as a 2 h i.v. infusion (400 mg m‐2) following a loading dose of 200 mg m‐2 (group 2, n = 7), the plasma concentrations of [R]‐ LV and [S]‐5‐MTHF decayed monoexponentially with mean (+/‐ s.d.) half‐ lives of 10 +/‐ 3 h and 7 +/‐ 2 h, respectively. 3. The AUC of [S]‐5‐ MTHF was significantly higher after infusion of 300 mg m‐2 [S]‐LV than after infusion of 600 mg m‐2 rac‐LV (83 +/‐ 22 micrograms ml‐1 h vs 53 +/‐ 22 micrograms ml‐1 h; P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Dose finding studies with imidapril—a new ACE inhibitor.
Authors: Vandenburg MJ , Mackay EM , Dews I , Pullan T , Brugier S
Published: July 2012

1. We describe an approach involving a smaller, shorter study, leading onto a longer, larger study in which the antihypertensive effects of ascending doses of imidapril, a new ACE inhibitor, were investigated. Both studies were planned prospectively, assuming a clinically useful fall in BP to be 8 mm Hg (s.d. = 9). The studies included patients with mild to moderate essential hypertension (baseline sitting diastolic blood pressure (SDBP) 95‐115 mm Hg). After a placebo run‐in of 2‐3 weeks patients received either placebo or imidapril 2.5, 5, 10 or 20 mg in the 2 week study (n = 91) or imidapril 5, 10, 20 or 40 mg in the 4 week study (n = 162). 2. The overall mean baseline SDBP was 103.4 mm Hg (s.d. 0.62) in the initial study and 101.5 mm Hg (s.d. 0.41) in the 4 week study. 3. Compared with placebo, imidapril 10, 20 and 40 mg significantly reduced SDBP. There was no significant difference between these doses, suggesting that 10 mg achieved maximal ACE inhibition in most patients. The 2.5 mg dose showed no significant effect. The 5 mg dose gave an intermediate effect. In both studies the overall incidence of adverse events was similar in the imidapril and placebo groups, and was not worrying.
Failure to reproduce the in vitro cardiac electrophysiological effects of naloxone in humans.
Authors: Oldroyd KG , Rankin AC , Gray CE , Harvey K , Borland W , Rae AP , Cobbe SM
Published: July 2012

1. Opioid receptor antagonists such as naloxone have shown antiarrhythmic activity in animal models of coronary artery occlusion. Studies have indicated that these effects are stereospecific but both isomers of naloxone prolong action potential duration and refractoriness in guinea‐pig and rabbit isolated ventricular myocardium (Class III effect). 2. This study was performed to identify whether this Class III effect of naloxone could be reproduced in human myocardium in vivo. Twenty patients with coronary artery disease received intravenous racemic naloxone (1‐40 micrograms kg‐1 min‐1). Surface electrocardiographic parameters were measured and refractory periods were determined during fixed rate pacing by programmed stimulation. 3. The corrected QT interval during sinus rhythm (SR‐QTc) was prolonged by 5(3)% (P = 0.06) at a dose of 20 micrograms kg‐1 min‐1 and by 9(10)% at 40 micrograms kg‐1 min‐1 (P = 0.03). These small changes were lost at higher paced heart rates. No significant effects on atrial, atrioventricular nodal or ventricular refractoriness were seen. 4. Plasma naloxone concentrations well into the micromolar range were achieved with both of the higher doses of naloxone administered. Plasma beta‐endorphin concentrations invariably increased following naloxone infusion. There was no statistical relationship between peak plasma naloxone concentrations and the absolute or percent prolongation of SR‐QTc. 5. It seems unlikely that racemic naloxone would have any clinical utility as an antiarrhythmic agent. Racemic naloxone may enhance cardiac adrenergic nerve activity and this receptor mediated effect may have prevented the demonstration of any nonreceptor mediated prolongation of cardiac refractoriness. Studies with the individual stereoisomers of naloxone would be of interest.
The effect of low dose lofepramine in depressed elderly patients in general medical wards.
Authors: Tan RS , Barlow RJ , Abel C , Reddy S , Palmer AJ , Fletcher AE , Nicholl CG , Pitt BM , Bulpitt CJ
Published: July 2012

A double‐blind randomised controlled trial of the effect of low dose lofepramine (70 mg once daily) against placebo was carried out on depressed elderly inpatients on general medical wards for the elderly, comparing measures of depression and side‐effects between the randomised groups. Patients were identified for the study using the Geriatric Depression Scale (GDS) and the Brief Assessment Schedule Depression Cards (BASDEC). Sixty‐three subjects were randomised: 46 patients completed the entire trial of 28 days treatment. BASDEC and GDS were administered on day 8 post‐admission, and depressed patients were randomised double‐blind to either low dose lofepramine (70 mg daily) (n = 23) or placebo (n = 23). Assessment of changes in depressive states were made using the Montgomery Asberg Depression Rating Scale (MADRS) on days 8, 18 and 36 post‐admission. Both groups improved by a similar amount during the trial. Lofepramine tended to be more effective than placebo in those patients who were more depressed (GDS > or = 18). On the other hand, subjects who were less depressed (i.e. GDS < 18) improved more on placebo than lofepramine. Low dose lofepramine may prove useful in moderately or severely depressed patients treated for only 4 weeks. However, low dose lofepramine is not indicated for mild (GDS 15‐18) depression.