bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac effects of the beta 3‐adrenoceptor agonist BRL35135 in man.
Authors: Wheeldon NM , McDevitt DG , Lipworth BJ
Published: July 2012

The aim of the present study was to evaluate the cardiac effects of the beta 3‐adrenoceptor agonist BRL35135, and determine whether beta 3‐ receptors are involved in mediating chronotropic or inotropic responses in man. Eight normal males received single oral doses of BRL35135 8 mg (BRL) or the selective beta 2‐adrenoceptor agonist salbutamol 8 mg (SAL), after pretreatment with either placebo (PL), bisoprolol 5 mg (B5) as a selective beta 1‐adrenoceptor antagonist, or nadolol 20 mg (N20) to block beta 1‐ and beta 2‐ but not beta 3‐receptors. Both BRL and SAL produced a significant increase in postural finger tremor in keeping with beta 2‐adrenoceptor stimulation, and this response was totally abolished by pretreatment with N20. Significant increases in systolic blood pressure and Doppler stroke distance occurred with BRL and SAL which were unaffected by pretreatment with B5 and completely blocked by N20, in keeping with beta 2‐mediated effects. BRL and SAL produced significant chronotropic and minute distance responses which were unaffected by beta 1‐adrenoceptor blockade. However, whereas N20 blocked these responses to SAL, a small but significant response occurred with BRL in comparison with placebo despite complete blockade of co‐existing beta 2‐mediated effects. Compared with PL, the mean responses to N20/BRL, and the 95% confidence interval for the differences between the means were 7.4 beats min‐1 [3.2 to 11.6] (P = 0.002) for heart rate, and 208.8 cm [38.3 to 379.3] (P = 0.02) for minute distance responses.(ABSTRACT TRUNCATED AT 250 WORDS)
Liver blood flow, antipyrine clearance, and antipyrine metabolite formation clearance in patients with chronic active hepatitis and alcoholic cirrhosis.
Authors: Bauer LA , O'Sullivan T , Reiss WG , Horn JR , Opheim K , Strandness DE , Carithers RL
Published: July 2012

Duplex scanning was used to measure liver blood flow (hepatic artery and main branches of the portal and hepatic veins) in six healthy subjects, five cirrhotic patients, and six hepatitis patients. Antipyrine clearance and formation clearances to its metabolites were also measured. Compared with healthy control subjects, cirrhotic patients had a lower hepatic vein blood flow (‐76%, P < 0.05). This was due primarily to a lower portal vein blood flow (‐36%, NS). A statistically significant difference in liver blood flow between patients with hepatitis and normal subjects was not detected. Antipyrine half‐life, clearance, and the area under the serum drug concentration vs time curve were significantly different in cirrhotic patients compared with the healthy subjects (mean +/‐ s.d.‐healthy controls: t1/2 = 13.7 +/‐ 3.0 h, CL = 30.0 +/‐ 8.6 ml h‐1 kg‐1, AUC = 549 +/‐ 139 mg l‐1 h; cirrhotic patients: t1/2 = 32.4 +/‐ 1.7 h, CL = 12.3 +/‐ 2.1 ml h‐1 kg‐1, AUC = 1061 +/‐ 218 mg l‐1 h; P < 0.008). Antipyrine half‐life, clearance, and the area under the serum drug concentration vs time curve were not significantly different in hepatitis patients compared with the healthy subjects (hepatitis patients: t1/2 = 14.3 +/‐ 3.7 h, CL = 29.3 +/‐ 8.5 ml h‐1 kg‐1, AUC = 498 +/‐ 142 mg l‐1 h). The volume of distribution of antipyrine was similar in all three groups of subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Maprotiline metabolism appears to co‐segregate with the genetically‐ determined CYP2D6 polymorphic hydroxylation of debrisoquine.
Authors: Firkusny L , Gleiter CH
Published: July 2012

The plasma concentrations of the tetracyclic antidepressant maprotiline and its effect on histamine‐induced bronchoconstriction were measured after single (50 mg) and multiple (50 mg twice daily) oral doses in healthy subjects. Histamine‐induced bronchoconstriction was abolished after a single dose of maprotiline and this effect persisted throughout multiple dose treatment. The mean Cmax of maprotiline in six poor metabolisers (PM) of debrisoquine was 2.7‐fold greater than that in six extensive metabolisers (EM) and the mean AUC(0,48 h) was 3.5 times higher. The duration of the pulmonary effect of maprotiline after cessation of multiple dose treatment in EM was less than 3 weeks compared with at least 4 weeks in PM.
Clinical evaluation of pain during subcutaneous injections of low molecular weight heparins in healthy volunteers.
Authors: Billon N , Gloaguen F , Funck‐Brentano C , Jaillon P
Published: July 2012

In order to compare the intensity and the duration of the pain following the subcutaneous injection of low molecular weight heparins, 0.4 ml nadroparin, 0.4 ml enoxaparin and 0.4 ml placebo (NaCl 0.9%) were administered at 1 week intervals to 12 healthy volunteers in a randomised, double‐blind, three‐period study. Pain was assessed by visual analogue and verbal category scales. Based on visual analogue scale scores, nadroparin resulted in significantly less pain than enoxaprin at 1 and 5 min after injection (6.2 +/‐ 2.6 mm vs 21.9 +/‐ 5.9 mm; P < 0.05 and 3.5 + 1.5 mm vs 14.3 +/‐ 4 mm; P < 0.05, respectively, mean +/‐ s.e. mean). Similar results were obtained using verbal category scale. Confidence interval testing for difference between groups showed that nadroparin injection resulted in less pain than enoxaparin at 1 min (‐15.8: ‐31.2 to ‐0.4 mm).
Volunteer models for predicting antiemetic activity of 5‐HT3‐receptor antagonists.
Authors: Minton NA
Published: July 2012

1. Selective 5‐HT3‐receptor antagonists are highly effective in preventing nausea and vomiting associated with chemotherapy, radiotherapy and surgery. Their pharmacological activity may be determined in vitro and in animal models of emesis. However, these methods may not give an accurate indication of the antiemetic dose range of 5‐HT3‐receptor antagonists in patients. Two volunteer models have been used to predict more accurately clinically effective antiemetic doses of 5‐HT3‐receptor antagonists. 2. The flare response to intradermal 5‐HT is thought to be mediated by excitation of 5‐HT3‐ receptors on cutaneous afferents, with release of substance P and subsequent vasodilation. Antagonism of the flare response appears to provide an indication of the effective antiemetic dose of 5‐HT3‐ receptor antagonists but data on duration of action are conflicting. 3. Ipecacuanha‐induced emesis is thought to be mediated through both peripheral and central 5‐HT3‐receptors. Antagonism of this response has demonstrated a close correlation with clinically effective antiemetic doses of the specific 5‐HT3‐receptor antagonist, ondansetron, and has the advantage of being more conceptually relevant than the flare model. 4. Further work, with newer 5‐HT3‐receptor antagonists, will clarify the role of these models as predictive of the use of these drugs in clinical practice.
Mixed linear and non‐linear disposition of lazabemide, a reversible and selective inhibitor of monoamine oxidase B.
Authors: Guentert TW , Holford NH , Pfefen JP , Dingemanse J
Published: July 2012

1. Single oral doses (100‐300 mg) and multiple oral doses (100‐350 mg 12 hourly for 7 days) of lazabemide were administered to 35 young and 40 elderly healthy subjects. Plasma concentrations of unchanged drug were determined to study the dose‐concentration relationship. 2. The elimination phase time course of lazabemide concentrations indicated concentration‐dependent elimination after both single and multiple dosing. Nevertheless, maximum concentrations and areas under concentration‐time curves increased almost proportionally with dose and accumulation after chronic dosing was less than a factor of 2; steady‐ state concentrations were achieved by the third day of dosing. The apparent half‐life determining accumulation was approximately 8‐9 h. 3. Drug absorption commenced rapidly after a dose; two components to the absorption process were detectable in young subjects possibly due to simultaneous administration of multiple tablets at the higher doses. 4. Observations after single and multiple dosing were described with a compartmental model allowing for parallel saturable (population mean +/‐ s.d.: maximum elimination rate Vmax/F: 2.8 +/‐ 1.4 mg h‐1; concentration at half‐maximum elimination Km: 36 +/‐ 19 micrograms l‐1) and first‐order (CL/F 16 +/‐ 3.8 l h‐1) elimination pathways. No important difference between the young and the elderly subjects was noted in absorption or disposition parameters of lazabemide.
Transdermal administration of morphine to healthy subjects.
Authors: Westerling D , Hoglund P , Lundin S , Svedman P
Published: July 2012

1. Twelve healthy subjects received 10 mg morphine HCl delivered transdermally from an occlusive reservoir applied to a small area of skin, painlessly de‐epithelialised by vacuum suction. On a separate occasion, 10 mg morphine HCl was given as an i.v. infusion over 20 min. 2. Venous blood samples were collected serially for 72 h and assayed for morphine, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) by h.p.l.c. Pupil size, salivation, and central nervous effects (nausea, fatigue, headache, feeling of heaviness and dysphoria/euphoria) were also measured. 3. After transdermal application morphine was absorbed by a first‐order process to produce relatively constant plasma drug concentrations over 11 h. The absolute bioavailability of transdermal morphine was 75% (65‐85%; 95% CI). The plasma concentrations of both M6G and M3G were lower after transdermal administration than after i.v. infusion, and a considerable delay (of up to 1 h) was observed before the metabolites were detectable. AUC ratios for M3G and M6G relative to morphine were similar after both modes of administration. 4. Non‐analgesic effects were less pronounced at the lower plasma drug and metabolite concentrations observed after transdermal delivery than after the i.v. infusion of morphine. 5. Transdermal administration of morphine warrants investigation as an alternative route of morphine delivery.
Identification of human liver cytochrome P450 isoforms mediating secondary omeprazole metabolism.
Authors: Andersson T , Miners JO , Veronese ME , Birkett DJ
Published: July 2012

1. The in vitro metabolism of omeprazole was studied in human liver microsomes in order to define the secondary metabolic pathways and identify the cytochrome P450 (CYP) isoforms responsible for the formation of the secondary metabolites of omeprazole. 2. The major secondary omeprazole metabolite was the hydroxysulphone, which was formed during incubation with both hydroxyomeprazole and omeprazole sulphone. A second metabolite, tentatively identified as pyridine‐N‐ oxide omeprazole sulphone, was also formed during incubation with omeprazole sulphone. The formation kinetics of these two metabolites from omeprazole sulphone were biphasic suggesting the involvement of multiple CYP isoforms in each case. In contrast, the formation kinetics of hydroxysulphone from hydroxyomeprazole were linear. 3. Inhibition studies, performed with omeprazole sulphone as substrate at concentrations at which the high affinity activities predominated, with a series of isoform selective inhibitors as well as with an anti‐CYP2C3 antibody suggested a dominant role of S‐mephenytoin hydroxylase in the formation of hydroxysulphone from omeprazole sulphone. By contrast, CYP3A activities were predominant in the formation of hydroxysulphone from hydroxyomeprazole as well as in the formation of pyridine‐N‐oxide omeprazole sulphone from omeprazole sulphone.
Inhibition of CYP2D6 activity by treatment with propranolol and the role of 4‐hydroxy propranolol.
Authors: Rowland K , Yeo WW , Ellis SW , Chadwick IG , Haq I , Lennard MS , Jackson PR , Ramsay LE , Tucker GT
Published: July 2012

1. The 4‐hydroxylation of propranolol by rat and human liver microsomes is associated with formation of a chemically reactive species which binds irreversibly to cytochrome P4502D6 (CYP2D6) destroying its catalytic function. Therefore, the effect of propranolol treatment (80 mg twice daily) on debrisoquine phenotype was examined, to see if it resulted in phenocopying in vivo. The role of 4‐hydroxypropranolol (4OHP) in the inhibition of CYP2D6 activity was also studied using microsomes from yeast expressing CYP2D6 and from human livers; metoprolol was used as the CYP2D6 substrate. 2. Although a significant effect on apparent oxidation phenotype was demonstrated, the absolute change in the urinary debrisoquine/4‐hydroxydebrisoquine ratio (D/4HD) was small, such that no extensive metaboliser who received propranolol treatment was reclassified as a poor metaboliser. The in vitro studies indicated that 4OHP is a potent inhibitor of metoprolol metabolism (Ki approximately 1 microM). This inhibitory effect was enhanced when 4OHP was pre‐incubated in the presence of a NADPH generating system and human liver microsomes. The effect was decreased significantly when reduced glutathione was added to the pre‐incubation mixture. Metabolism of 4OHP occurred when incubated with human liver microsomes in the presence of a NADPH generating system and irrespective of CYP2D6 phenotype; yeast expressing CYP2D6 did not metabolise 4OHP. 3. We conclude that, although treatment with propranolol 80 mg twice daily significantly decreases the catalytic function of CYP2D6, the inhibition is insufficient to result in phenocopying. The reactive intermediate produced by further metabolism of 4OHP is probably scavenged effectively in vivo by glutathione and other nucleophiles.
The effect of enzyme inhibition on the metabolism and activation of tacrine by human liver microsomes.
Authors: Spaldin V , Madden S , Pool WF , Woolf TF , Park BK
Published: July 2012

1. Tacrine (1,2,3,4‐tetrahydro‐9‐aminoacridine‐hydrochloride: THA) underwent metabolism in vitro by a panel (n = 12) of human liver microsomes genotyped for CYP2D6, in the presence of NADPH, to both protein‐reactive and stable metabolites. 2. There was considerable variation in the extent of THA metabolism amongst human livers. Protein‐ reactive metabolite formation showed a 10‐fold variation (0.6 +/‐ 0.1%‐ 5.2 +/‐ 0.8% of incubated radioactivity mg‐1 protein) whilst stable metabolites showed a 3‐fold variation (24.3 +/‐ 1.7%‐78.6 +/‐ 2.6% of incubated radioactivity). 3. Using cytochrome P450 isoform specific inhibitors CYP1A2 was identified as the major enzyme involved in all routes of THA metabolism. 4. There was a high correlation between aromatic and alicyclic hydroxylation (r = 0.92, P < 0.0001) consistent with these biotransformations being catalysed by the same enzymes. 5. Enoxacin (ENOX), cimetidine (CIM) and chloroquine (CQ) inhibited THA metabolism by a preferential decrease in the bioactivation to protein‐ reactive, and hence potentially toxic, species. The inhibitory potency of ENOX and CIM was increased significantly upon pre‐incubation with microsomes and NADPH. 6. Covalent binding correlated with 7‐OH‐THA formation before (r = 0.792, P < 0.0001) and after (r = 0.73, P < 0.0001) inhibition by CIM, consistent with a two‐step mechanism in the formation of protein‐reactive metabolite(s) via a 7‐OH intermediate. 7. The use of enzyme inhibitors may provide a useful tool for examining the relationship between the metabolism and toxicity of THA in vivo.
Lack of interaction between diazepam and nimodipine during chronic oral administration to healthy elderly subjects.
Authors: Heine PR , Weyer G , Breuel HP , Muck W , Schmage N , Kuhlmann J
Published: July 2012

1. Nimodipine (30 mg three times daily) and diazepam (10 mg once daily), were given orally to 24 elderly healthy subjects in a randomized, non‐blinded, threefold‐crossover study. Each of the three treatment periods lasted 5 days separated by 2 week washout phases. 2. Plasma concentrations of nimodipine and diazepam were not affected by the combined treatment. 3. No clinically relevant changes in haemodynamics, ECG recordings, clinical chemistry or haematology were observed after all of the three treatments. The overall frequency of side effects was lowest during monotherapy with nimodipine and highest during diazepam monotherapy. 4. In the test of subjective rating of tiredness (VAS) and the Pauli calculation test, diazepam, alone and with nimodipine co‐medication, produced an increase in tiredness and a clear reduction in performance and endurance. After nimodipine monotherapy an improvement was observed only in the Pauli test. Using the critical flicker fusion frequency test (CFF) significant decrements in performance were found after diazepam monotherapy only. 5. In summary, there was no evidence that either nimodipine or diazepam affected the pharmacokinetics, safety and tolerance of each other. However, the CNS‐effects of diazepam were compensated partially by nimodipine.
Indomethacin and cognitive function in healthy elderly volunteers.
Authors: Bruce‐Jones PN , Crome P , Kalra L
Published: July 2012

1. Cognitive function was studied after single and multiple doses of indomethacin (I) and matched placebo (P) in 20 healthy elderly volunteers using a double‐blind crossover design. 2. Arousal, attention, integration, coordination, memory and mood were investigated using a battery of psychomotor tests and the Hospital Anxiety and Depression Scale. Assessments were performed before and after the first and last doses of a 7 day course of medication. 3. Critical flicker fusion threshold fell by a mean of 1.96% on indomethacin compared with a 1.13% rise on placebo 5 h after the first dose (P = 0.029). A beneficial effect on choice reaction time latency (P = 0.012) was seen both after acute and continuing administration of indomethacin. Performance at the most discriminating level (level 3) of the paired word association test was significantly better following 8 days of treatment with indomethacin in the younger (55‐65 year‐old) age group (P = 0.001). 4. There was no significant difference in performance on the symbol‐digit substitution test and the continuous attention task. No change was seen in hospital anxiety and depression scale scores. 5. These results suggest that performance on tests of sensorimotor coordination and short term memory may improve in healthy volunteers following indomethacin administration, whereas tests of attention and psychomotor speed remain unaffected. However, further controlled studies in rheumatic patients are needed to evaluate fully the psychomotor effects of indomethacin and other NSAIDs in clinical practice.
The effect of angiotensin‐converting enzyme inhibitors on human neutrophil chemotaxis in vitro.
Authors: Clapperton M , McMurray J , Fisher AC , Dargie HJ
Published: July 2012

1. Myocardial 'reperfusion injury' has been partly attributed to the production of free radicals which are cytotoxic towards cells. Neutrophils are recruited by ischaemic tissue and are one source of free radicals. Angiotensin‐converting enzyme (ACE) inhibitors can reduce 'reperfusion injury' and we decided to determine if ACE inhibitors might contribute to this effect by inhibiting neutrophil chemotaxis. 2. The effects of captopril (a thiol containing ACE inhibitor) and enalaprilat (a nonthiol ACE inhibitor) and N‐ mercaptopropionyl glycine (MPG) (a simple thiol) on neutrophil chemotaxis were tested in an in vitro Boyden chamber assay. 3. The chemotactic response of human neutrophils to fMLP was reduced by 27.6% with MPG (n = 8; P < 0.05), by 13.2% with enalaprilat (n = 8; P = 0.075) and by 5.2% with captopril (n = 8; P = 0.66) at 5 microM (therapeutic concentration.) 4. Neutrophil chemotaxis was significantly decreased with 50 microM and 500 microM MPG and enalaprilat and 500 microM captopril. 5. Supratherapeutic concentrations of ACE inhibitors can reduce neutrophil chemotaxis at high concentrations and this effect does not appear to be ‐SH dependent.
Effects of treatment with oral isosorbide dinitrate on platelet function in vivo; a double‐blind placebo‐controlled study in patients with stable angina pectoris.
Authors: Wallen NH , Andersson A , Hjemdahl P
Published: July 2012

1. A randomised double‐blind placebo‐controlled cross‐over study was performed to investigate the effects of oral isosorbide dinitrate (ISDN; 20 mg twice daily for 2 weeks) on various aspects of platelet function in vivo in 20 patients with stable angina pectoris. Measurements were performed at rest and after platelet activation by physical exercise (bicycle ergometry). 2. Compared with placebo, treatment with ISDN significantly decreased systolic blood pressure at rest by 7 (‐14 to ‐1) mm Hg (mean and 95% CI) and tended to increase exercise capacity by 7 (‐1 to 14) W and attenuate perceived chest pain during maximal work. The dosage was high, as judged by side‐effects reported (mainly headache). Compliance was good, as assessed by electronic counter equipped tablet bottles (Medication Event Monitoring System); only one patient had a compliance rate below 60%. 3. Exercise significantly increased platelet aggregability as measured by filtragometry ex vivo; the time taken for platelet aggregates in whole blood drawn directly from an antecubital vein to occlude a microfilter was significantly decreased from 155 to 95 s (antilog of mean log values). Platelet secretion in vivo also increased, as indicated by significant elevations of beta‐thromboglobulin in plasma; from 22 to 35 ng ml‐1 (P = 0.006). 4. ISDN treatment did not inhibit platelet function. Relative to placebo, filtragometry readings (ISDN/placebo ratios; mean and 95% CI) were not altered either at rest (1.05 (0.83 to 1.32)) or immediately after exercise (0.98 (0.80 to 1.20)). Similarly, beta TG in plasma was unaltered by ISDN treatment; 1.09 (0.98 to 1.21) at rest, and 1.04 (0.82 to 1.30) immediately after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetics and ventilatory effects of intravenous oxycodone in postoperative children [see comments]
Authors: Olkkola KT , Hamunen K , Seppala T , Maunuksela EL
Published: July 2012

1. Oxycodone hydrochloride (0.1 mg kg‐1) was given by intravenous bolus to 18 children after ophthalmic surgery. Plasma was sampled for up to 8 h. Blood pressure, heart rate, peripheral arteriolar oxygen saturation, end‐tidal carbon dioxide and halothane concentrations and ventilatory rate were also recorded. 2. Mean (+/‐ s.d.) values of drug clearance and volume of distribution (Vss) were 15.2 +/‐ 4.2 ml min‐1 kg‐1 and 2.1 +/‐ 0.8 l kg‐1. Maximum mean end‐tidal carbon dioxide concentration and minimum mean ventilatory rate occurred 8 min after administration of oxycodone but the minimum mean peripheral arteriolar oxygen saturation occurred at 4 min. 3. Oxycodone (0.1 mg kg‐1) appears to cause greater ventilatory depression than comparable analgesic doses of other opioids.
The effects of lower than conventional doses of oral nadolol on relative beta 1/beta 2‐adrenoceptor blockade.
Authors: Wheeldon NM , McDevitt DG , Lipworth BJ
Published: July 2012

1. The aim of the present study was to evaluate the relative beta 1/beta 2 antagonist selectivity of the beta‐adrenoceptor blocker nadolol, in lower than conventional clinical doses. 2. Eight normal volunteers received single oral doses of either placebo (PL), nadolol 5 mg (N5), 20 mg (N20) or 80 mg (N80) in a single‐blind, randomised crossover design. beta 1‐adrenoceptor antagonism was assessed by attenuation of exercise tachycardia, and beta 2‐adrenoceptor blockade by effects on salbutamol‐induced chronotropic, hypokalaemic and finger tremor responses. The relative percentage attenuation of beta 2 and beta 1‐mediated responses was calculated and expressed as beta 2:beta 1 selectivity ratios. 3. Nadolol produced dose‐related reductions in exercise tachycardia in keeping with increasing beta 1‐adrenoceptor blockade; mean % reduction (95% CI) compared with placebo: N5 10.7 (6.6 to 14.8), N20 21.4 (17.3 to 25.4), N80 38.9 (34.8 to 42.9). However, even the lowest dose of nadolol (5 mg) produced almost complete blunting of beta 2‐mediated effects and significantly increase exercise hyperkalaemia; peak exercise hyperkalaemia (mmol l‐1) (means and 95% CI): PL 4.88 (4.68 to 5.07), N5 5.36 (5.17 to 5.55), N20 5.48 (5.28 to 5.67), N80 5.42 (5.22 to 5.61). beta 2:beta 1 selectivity ratios significantly increased as the dose of nadolol was reduced. 4. These data suggest that whereas in the clinical dose range nadolol behaves as a non‐selective beta‐adrenoceptor antagonist, as the dose is reduced this drug demonstrates an increasing degree of selectivity for the beta 2‐adrenoceptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Diazepam metabolism by human liver microsomes is mediated by both S‐ mephenytoin hydroxylase and CYP3A isoforms.
Authors: Andersson T , Miners JO , Veronese ME , Birkett DJ
Published: July 2012

1. The primary metabolism of diazepam was studied in human liver microsomes in order to investigate the kinetics and to identify the cytochrome P450 (CYP) isoforms responsible for the formation of the main diazepam metabolites, temazepam and N‐desmethyldiazepam. 2. The formation kinetics of both metabolites were atypical and consistent with the occurrence of substrate activation. A sigmoid Vmax model equivalent to the Hill equation was used to fit the data. The degree of sigmoidicity was greater for temazepam formation than for N‐ desmethyldiazepam formation, so that the ratio of desmethyldiazepam:temazepam formation increased as the substrate (diazepam) concentration decreased. 3. alpha‐Naphthoflavone activated both reactions but with a greater effect on temazepam formation than on N‐desmethyldiazepam formation. In the presence of 25 microM alpha‐ naphthoflavone the kinetics for both pathways were approximated by Michaelis‐Menten kinetics. 4. Studies with a series of CYP isoform selective inhibitors and with an inhibitory anti‐CYP2C antibody indicated that temazepam formation was carried out mainly by CYP3A isoforms, whereas the formation of N‐desmethyldiazepam was mediated by both CYP3A isoforms and S‐mephenytoin hydroxylase.
The effects of angiotensin II on circulating levels of natriuretic peptides.
Authors: Cargill RI , Coutie WJ , Lipworth BJ
Published: July 2012

We have evaluated the differential release of A, B and C‐type natriuretic peptides in response to incremental doses of angiotensin II (2, 4 and 6 ng kg‐1 min‐1). Baseline plasma concentrations of ANP (5.99 +/‐ 0.74 pmol 1‐1) were significantly (P < 0.05) higher than BNP (1.53 +/‐ 0.48 pmol 1‐1) or CNP (0.41 +/‐ 0.11 pmol 1‐1). Angiotensin II infusion caused a significant (P < 0.05) increase in plasma ANP to 53.76 +/‐ 17.3 pmol 1‐1 at 6 ng kg‐1 min‐1. Plasma concentrations of BNP and CNP were not significantly affected by angiotensin II. Arterial blood pressures and systemic vascular resistance increased (P < 0.001) in response to angiotensin II infusion. Thus, ANP, unlike BNP or CNP, is released acutely in response to the pressor stimulus of angiotensin II. This may represent a dissociation in release of the natriuretic peptides, in terms of short and long term responses to activation of the renin‐angiotensin system.
Nitric oxide mediated venodilator effects of nebivolol.
Authors: Bowman AJ , Chen CP , Ford GA
Published: July 2012

1. Nebivolol, a selective beta 1‐adrenoceptor antagonist with antihypertensive effects, has haemodynamic effects suggestive of a direct vasodilator action. 2. The dorsal hand vein technique was used to determine whether nebivolol has venodilator action in vivo in man. 3. Nebivolol and atenolol were infused into the phenylephrine preconstricted superficial hand veins of 11 healthy male volunteers. In separate studies L‐NMMA (0.1 microgram min‐1) was pre‐ and co‐infused with nebivolol to determine whether nitric oxide (NO) mediated mechanisms were present. Further studies with prostaglandin F2 alpha (PGF2 alpha) preconstriction were performed to exclude an alpha‐ adrenergic antagonistic effect of nebivolol. Effects of L‐NMMA infusion on nitroglycerin venodilation were also determined. 4. Nebivolol produced a dose dependent venodilation, (72 +/‐ 18% maximum), whereas atenolol produced no significant venodilation. At doses of nebivolol producing plasma concentrations comparable with plasma levels achieved after standard oral dosing (10(‐13)‐10(‐12) mol min‐1) small (14 +/‐ 6% and 23 +/‐ 8%) but significant (P < 0.05) venodilation was observed. 5. The venodilator response to nebivolol was significantly reduced by infusion of L‐NMMA (maximum dilation 18% vs 72%, P < 0.01). Venodilator responses to nitroglycerin were unaffected by L‐NMMA infusion. A venodilator effect to nebivolol was also seen following preconstriction with PgF2 alpha (40 +/‐ 20% maximum). 6. Nebivolol has nitric oxide mediated, venodilator effects in man.
Pharmacokinetic and pharmacodynamic properties of a long‐acting formulation of the new somatostatin analogue, lanreotide, in normal healthy volunteers.
Authors: Kuhn JM , Legrand A , Ruiz JM , Obach R , de Ronzan J , Thomas F
Published: July 2012

1. The aims of the study were to assess the pharmacokinetic parameters and the hormonal effects of the slow‐release formulation of the somatostatin analogue (SR‐L) in normal male volunteers. 2. Eight healthy males were studied. For the determination of basal values blood was sampled before the injection of vehicle and then every other hour for 8 h in order to measure plasma GH, prolactin (PRL), TSH, free thyroxin (fT4), insulin and glucagon levels. Plasma insulin‐like growth factor 1 (IGF‐1) levels were measured on a single sample. On day 1 of the study, 30 mg SR‐L was administered intramuscularly. Blood was drawn just before injection and then every other hour for a period of 8 h. Thereafter, blood was sampled three times a week for 3 weeks in order to measure lanreotide, IGF‐1, TSH, fT4 and PRL concentrations. Plasma GH was determined on days 6 and 11 of the study. 3. Plasma lanreotide concentrations rose to 38.3 +/‐ 4.1 ng ml‐1 2 h following injection. The levels then progressively decreased, remaining above 1.5 ng ml‐1 until day 11 and reaching 0.92 +/‐ 0.28 ng ml‐1 2 weeks after injection. The apparent plasma half‐life and mean residence time were 4.52 +/‐ 0.50 and 5.48 +/‐ 0.51 days respectively. 4. By comparison with the control day, plasma insulin concentrations only decreased 2 h following injection, whereas plasma glucagon did not change at any time. 5. Plasma TSH concentrations were significantly (P < 0.01) reduced from 2 h to day 4 following SR‐L injection.2+ '
Effects of dideoxyinosine and dideoxycytidine on the intracellular phosphorylation of zidovudine in human mononuclear cells.
Authors: Veal GJ , Wild MJ , Barry MG , Back DJ
Published: July 2012

1. Zidovudine (3'‐azido‐2',3'‐dideoxythymidine; AZT; ZDV) is a dideoxynucleoside analogue active against human immunodeficiency virus (HIV). We are currently investigating the intracellular metabolism of ZDV to its putative active triphosphate form (ZDV triphosphate) in peripheral blood mononuclear cells and a lymphoblastoid cell line (h1A2v2). 2. Optimal conditions for intracellular phosphate formation in peripheral blood mononuclear cells occurred following a 72 h preincubation with the mitogen phytohaemagglutinin at a concentration of 10 micrograms ml‐1. ZDV was metabolized predominantly to the monophosphate with smaller amounts of the di‐ and triphosphate anabolites. There was considerable inter‐ and intraindividual variability in phosphate formation in peripheral blood mononuclear cells. A similar pattern of phosphorylation was seen with the h1A2v2 lymphoblastoid cell line with ZDV monophosphate being the major metabolite. 3. With increasing interest in combination nucleoside analogue therapy in HIV‐positive patients it is important to know if an interaction occurs at the level of phosphorylation. Neither dideoxyinosine (ddI) or dideoxycytidine (ddC) significantly reduced the intracellular phosphorylation of ZDV in either peripheral blood mononuclear cells or h1A2v2 cells. In contrast thymidine always gave marked inhibition (e.g. at 2.0 microM, 89% inhibition of total phosphate formation in peripheral blood mononuclear cells and 79% in h1A2v2 cells). It is, therefore, unlikely that in vivo either ddI or ddC will perturb ZDV phosphorylation.
Responses to low dose intravenous perindoprilat infusion in salt deplete/salt replete normotensive volunteers.
Authors: MacFadyen RJ , Lees KR , Reid JL
Published: July 2012

1. Intravenous ACE inhibitor therapy appears to have a role in the treatment of acute heart failure and early after myocardial infarction. Practical experience with intravenous administration with activation of renin is limited. We report responses to perindoprilat (Pt, 0.67 mg) or placebo (P) infused over 4 h in normotensive male volunteers (n = 12, 19‐28 years, 53‐77 kg) with double‐blind, placebo controlled salt depletion (SD) or salt repletion (SR) as a model of the activated renin system. 2. Salt depletion caused no significant fall in serum sodium (P, 139.4 +/‐ 2.4; Pt, 138.3 +/‐ 1.9) compared with salt replete preparation (P, 139.9 +/‐ 1.2; Pt, 139.7 +/‐ 0.9) but elevation of plasma renin activity 2‐3‐fold. Pretreatment baseline systolic blood pressure following salt depletion (P, 121 +/‐ 9.3/71 +/‐ 7.9; Pt, 121.5 +/‐ 9.6/69 +/‐ 8.1) was higher than following salt replete preparation (P, 114 +/‐ 9.5/61 +/‐ 7.2; Pt, 116.9 +/‐ 6.9/67 +/‐ 7.2). 3. Baseline corrected supine SBP fell significantly and to a similar extent following active treatment regardless of activation of the renin system (SD, ‐14.6 +/‐ 9.5/‐9.4 +/‐ 6.4; SR, ‐12 +/‐ 14/‐10.1 +/‐ 6.6) compared with placebo (SD, ‐6.1 +/‐ 6/‐3.7 +/‐ 5.6; SR, ‐4.7 +/‐ 10/‐1.3 +/‐ 6.5). Heart rate was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone.
Authors: Aranko K , Luurila H , Backman JT , Neuvonen PJ , Olkkola KT
Published: July 2012

1. The effect of erythromycin on the pharmacokinetics and pharmacodynamics of oral zopiclone, a non‐benzodiazepine hypnotic, was investigated in a double‐blind, cross‐over study. 2. Ten healthy volunteers were given placebo or 500 mg erythromycin orally three times a day for 6 days followed by an oral dose of 7.5 mg zopiclone. 3. Erythromycin increased plasma zopiclone concentration by 4‐fold at 0.5 h (P < 0.05) and by 2‐fold at 1 h (P < 0.05). There were increases of 3‐ and 2‐fold in the AUC(0,1 h) and AUC(0,2 h) values (P < 0.05). The total AUC of zopiclone increased by 80% (P < 0.05) but the peak concentration by only 40% (P < 0.05). The peak time of zopiclone concentration was reduced from 2 to 1 h (P < 0.001). 4. Significant pharmacodynamic differences between the treatments were observed from 0.5 h to 2 h with respect to saccadic latency and digit symbol substitution tests. 5. The interaction between erythromycin and zopiclone resulted mainly in accelerated absorption which may lead to a faster hypnotic effect in patients.
Reduced sensitivity to beta‐adrenoceptor stimulation and blockade in insulin dependent diabetic patients with hypoglycaemia unawareness.
Authors: Trovik TS , Jaeger R , Jorde R , Sager G
Published: July 2012

Nine IDDM‐patients with hypoglycaemia unawareness, seven IDDM‐patients with hypoglycemia awareness and a control group of nine healthy persons were included in this study. The patients were recruited from the medical out‐patients' department of the University Hospital of Tromso. The pathophysiological changes which cause hypoglycaemia unawareness are today not clear. Reduced peripheral tissue sensitivity to catecholamines is suggested as one of several mechanisms which may contribute. For further investigation of beta‐adrenergic sensitivity an isoprenaline/metoprolol sensitivity test was performed. Isoprenaline and metoprolol were administered intravenously, and the effects on heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and plasma levels of adrenaline (ADR) and noradrenaline (NA) were measured. All subjects were given the same doses of isoprenaline (0.25‐8 micrograms) and metoprolol (0.5‐8 mg). Metoprolol was given together with the dose of isoprenaline which increased heart rate by 25 beats min‐1. The dose/response curves of both isoprenaline/HR and metoprolol/HR were significantly shifted to the right in IDDM‐patients with hypoglycaemia unawareness compared with controls and IDDM‐patients with hypoglycaemia awareness (P < 0.05). Reduced sensitivity of isoprenaline stimulation has also been shown before, whereas reduced sensitivity of a blocking agent has not earlier been shown. These findings support the hypothesis of reduced beta‐ adrenergic sensitivity as one pathophysiological component in hypoglycaemia unawareness.
Reliability of hormonal levels for assessing the hypothalamic‐pituitary‐ adrenocortical system in clinical pharmacology.
Authors: Coste J , Strauch G , Letrait M , Bertagna X
Published: July 2012

Few data are available on the reliability of measurements of adrenocortical and corticotroph hormones for use in clinical pharmacology. Two placebo controlled cross‐over trials in 20 normal healthy male subjects offered the opportunity to perform three repeat samplings of adrenocortical and corticotroph hormones at 1 to 5 week intervals during the placebo periods. Measurements of baseline levels of plasma, salivary and urinary cortisol, plasma adrenocorticotroph hormone (ACTH), lipotrophic hormone (LPH), beta‐endorphin, post tetracosactrin levels of plasma and salivary cortisol, post corticotrophin releasing hormone (CRH)‐lysine vasopressine (LVP) levels of plasma cortisol, ACTH and LPH; and post metyrapone levels of plasma cortisol and 11‐deoxycortisol (compound S), ACTH, LPH, beta‐endorphin were performed in the same laboratory. The reliability of the measurements was estimated by computing the intraclass correlation coefficient (R) and by using Altman‐Bland graphical method. The Rs of baseline parameters varied from 0.18 (for 08.00 h salivary cortisol) to 0.55 (for 08.00 h plasma cortisol and nocturnal urinary cortisol). In contrast, parameters obtained after direct stimulation or inhibition of the producing targets were much more reliable: Rs were above 0.80 for post tetracosactrin levels of plasma and salivary cortisol, post CRH‐ LVP levels of plasma ACTH and LPH. The Rs were below 0.50 for post metyrapone levels of plasma 11‐deoxycortisol, ACTH, LPH and beta‐ endorphin. The interval between sampling did not affect R estimates. These data show that peak levels of plasma cortisol and ACTH after direct stimulation are highly reliable whereas baseline and main post‐ metyrapone levels are not.(ABSTRACT TRUNCATED AT 250 WORDS)
Interaction between endothelin and vasodilators in the human internal mammary artery.
Authors: He GW , Yang CQ , Mack MJ , Acuff TE , Ryan WH , Starr A
Published: July 2012

1. The internal mammary artery (IMA) is the primary choice as an arterial graft for coronary artery bypass surgery. Endothelin (ET) has been recently measured with an increased release after cardiopulmonary bypass for coronary artery bypass grafting. Threshold concentrations of ET‐1 have been found to amplify specifically contractions induced by noradrenaline and serotonin. This study was designed to investigate the effect of glyceryl trinitrate (GTN) and calcium antagonists on ET‐1 contraction in the human IMA. 2. Human IMA segments taken from 21 patients undergoing IMA‐coronary artery bypass grafting were mounted in an organ bath under the physiological pressure determined from their own length‐tension curves. Four ring segments were allocated into four groups. One served as a control and the others were treated with GTN (10, 100 nM, or 30 microM) for 5 min or nifedipine (20 or 200 nM, or 30 microM) for 25 min before concentration‐contraction curves to ET‐1 were established. In separate experiments, the concentration‐relaxation curves to GTN or nifedipine were established in the IMA rings precontracted with ET‐1 (10 nM). 3. Pretreatment of IMA with GTN for 5 min did not alter the ET‐1‐induced contraction. Pretreatment with 20 or 200 nM of nifedipine slightly but not significantly, altered the maximum contraction induced by ET‐1. Higher concentrations (30 microM) significantly reduced the maximum contraction force (P = 0.008). On the other hand, GTN caused 76.44 +/‐ 6.35% relaxation in ET‐1‐precontracted IMA. In contrast, the nifedipine‐induced relaxation was difficult to establish due to unsustained contraction to ET‐1.(ABSTRACT TRUNCATED AT 250 WORDS)
Analgesics and ENT surgery. A clinical comparison of the intraoperative, recovery and postoperative effects of buprenorphine, diclofenac, fentanyl, morphine, nalbuphine, pethidine and placebo given intravenously with induction of anaesthesia.
Authors: Van den Berg AA , Honjol NM , Prabhu NV , Datta S , Rozario CJ , Muraleedaran R , Savva D
Published: July 2012

1. Vomiting and restlessness following ENT and eye surgery are undesirable, and may be related to the emetic and analgesic effects of any analgesic given to augment anaesthesia during surgery. 2. To rationalise the choice of analgesic for routine ENT surgery we examined the intraoperative, recovery and postoperative effects following the administration of either buprenorphine (3.0 to 4.5 micrograms kg‐1), diclofenac (1 mg kg‐1), fentanyl (1.5 to 2.0 micrograms kg‐1), morphine (0.1 to 0.15 mg kg‐1), nalbuphine (0.1 to 0.15 mg kg‐1), pethidine (1.0 to 1.5 mg kg‐1) or saline (as control) given with the induction of anaesthesia in 374 patients. A standardised anaesthetic technique with controlled ventilation using 0.6‐0.8% isoflurane in nitrous oxide and oxygen was employed. The study population constituted 7 similar groups of patients. 3. Intraoperatively, their effects on heart rate and blood pressure, airway pressure and intraocular pressure, were similar. This implies, most surprisingly, that neither their analgesic nor their histamine releasing effects were clinically evident during surgery. By prolonging the time to extubation at the end of anaesthesia, only buprenorphine, fentanyl, morphine and pethidine provided evidence of intraoperative respiratory depression. 4. Postoperatively, buprenorphine was associated with severe respiratory depression, prolonged somnolence, profound analgesia and the highest emesis rate. Diclofenac exhibited no sedative, analgesic, analgesic sparing, emetic or antipyretic effects. Fentanyl provided no sedative or analgesic effects, but was mildly emetic. Morphine provided poor sedation and analgesia, delayed the requirement for re‐medication and was highly emetic. Nalbuphine and pethidine produced sedation with analgesia during recovery, a prolonged time to re‐medication and a mild emetic effect. None provided evidence, from analysis of postoperative re‐ medication times and analgesic consumption, of any pre‐emptive analgesic effect. 5. We conclude that nalbuphine (mean dose 0.13 mg kg‐ 1) and pethidine (mean dose 1.35 mg kg‐1), given individually as a single i.v. bolus during induction of anaesthesia, are the most efficacious analgesics for routine in‐patient ENT surgery.
Measurement of blood concentrations of FK506 (tacrolimus) and its metabolites in seven liver graft patients after the first dose by h.p.l.c.‐MS and microparticle enzyme immunoassay (MEIA).
Authors: Gonschior AK , Christians U , Braun F , Winkler M , Linck A , Baumann J , Sewing KF
Published: July 2012

1. Blood and urine concentrations of the macrolide immunosuppressant FK506 and its metabolites were measured in seven orthotopic liver transplant patients after the first oral dose of FK506 (0.04 +/‐ 0.02 mg kg‐1) used as primary immunosuppressant. A specific h.p.l.c.‐MS assay was used, allowing the measurement of parent drug and eight metabolites. Results were compared with those obtained using a microparticle enzyme immunoassay (MEIA). 2. Blood drug concentrations were described by an open two compartment model with first‐order absorption giving the following mean data: tmax: 1.9 (h), Cmax: 17.4 (microgram l‐1), AUC: 328.1 (microgram l‐1 h), t1/2,1: 0.74 (h). The terminal elimination half‐life was estimated at about 26 h using the h.p.l.c.‐MS assay. 3. The metabolites found in blood were demethyl‐ FK506 and demethyl‐hydroxy‐FK506, while in urine FK506 and eight of its metabolites were detected.
Inhibition of caffeine metabolism by ciprofloxacin in children with cystic fibrosis as measured by the caffeine breath test.
Authors: Parker AC , Preston T , Heaf D , Kitteringham NR , Choonara I
Published: July 2012

The caffeine breath test was carried out in six children with cystic fibrosis, before and during a course of ciprofloxacin. There was a significant decrease in the 2 h cumulative labelled CO2 exhaled during ciprofloxacin treatment, mean difference (s.d.) ‐5.2(3.3)%, P < 0.02. The results suggest an inhibition of 3‐N‐demethylation of caffeine (CYP1A2 enzyme activity) by ciprofloxacin. Ciprofloxacin may cause significant drug interactions in children with cystic fibrosis. The caffeine breath test can be used to study drug interactions involving CYP1A2 in children.
Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in patients with the acquired immunodeficiency syndrome.
Authors: Barry M. , Howe JL , Ormesher S. , Back DJ , Breckenridge AM , Bergin C. , Mulcahy F. , Beeching N. , Nye F.
Published: July 2012

1. Zidovudine (ZDV) has proved unsuccessful in controlling disease progression over extended periods of time in patients with AIDS. Combination of ZDV with another reverse transcriptase inhibitor, dideoxyinosine (ddI) may improve the duration of effectiveness of antiretroviral therapy. The aim of this study was to investigate the possibility of a pharmacokinetic drug interaction between ZDV and ddI. 2. The pharmacokinetics of ZDV and ddI were determined in eight patients with AIDS who were randomised to receive ZDV 250 mg orally, ddI 250 mg orally or a combination of ZDV 250 mg plus ddI 250 mg orally on 3 study days separated by 1 week. 3. The administration of ZDV did not significantly alter ddI pharmacokinetics. The mean AUC was 6.8 +/‐ 2.0 s.d. and 7.6 +/‐ 2.5 s.d. mumol l‐1 h and oral clearance was 2766 +/‐ 686 and 2660 +/‐ 1297 ml min‐1 in the presence and absence of ZDV, respectively. 4. In the presence of ddI the elimination half‐life of ZDV was increased significantly by 18% from 1.1 +/‐ 0.3 to 1.3 +/‐ 0.3 h (P < 0.05) and the mean AUC increased significantly by 35% from 4.8 +/‐ 1.5 to 6.5 +/‐ 1.5 mumol l‐1 h (P < 0.05). The clearance was decreased by 29% from 3518 +/‐ 1123 to 2505 +/‐ 575 ml min‐1, but this difference was not significant. The renal clearance of ZDV was not altered by ddI. 5. Administration of ddI also resulted in a significant 22% increase in the AUC of GZDV, from 28.5 +/‐ 15.7 to 34.9 +/‐ 12.8 mumol l‐1 h (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Between‐subject and within‐subject variations in the pharmacokinetics of ethanol.
Authors: Jones AW , Jonsson KA
Published: July 2012

1. Twelve healthy men drank 0.80 g ethanol kg‐1 body weight on four occasions spread over several weeks. Ethanol was given as 96% v/v solvent which was diluted with orange juice to make a cocktail (20‐25% v/v). This drink was ingested in exactly 30 min at 08.00 h after an overnight (10 h) fast. 2. Samples of venous blood were obtained at exactly timed intervals of 0, 10, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 min after the start of drinking. The concentrations of ethanol in whole blood were determined by headspace gas chromatography. 3. Summary measures were used to evaluate the concentration‐time profiles of ethanol for each subject. The between‐ subject and within‐subject components of variation for the pharmacokinetics of ethanol were derived by one‐way analysis of variance (ANOVA). 4. The variation between different subjects dominated the total variance for all of the pharmacokinetic parameters studied except the rate of disappearance of ethanol from blood (ko). For this latter parameter, 42% and 58% of the total variation arose from variations between‐ and within‐subjects respectively. These results might be important to consider when experiments on the clinical pharmacokinetics of ethanol are being planned.