bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of acute beta‐adrenoceptor blockade with metoprolol on the renal response to dopamine in normal humans.
Authors: Olsen NV , Lang‐Jensen T , Hansen JM , Plum I , Thomsen JK , Strandgaard S , Leyssac PP
Published: July 2012

The present study investigated the contribution of adrenergic beta 1‐ receptor stimulation to the cardiovascular and renal effects of low‐ dose dopamine in eight normal, water‐loaded humans. Metoprolol (100 mg) or placebo was administered orally at 08.00 h in a randomized, double‐ blind fashion on two different days. Renal clearance studies were performed during a 1 h baseline period, two 1 h periods with dopamine infusion (3 micrograms kg‐1 min‐1), and a 1 h recovery period. Cardiac output was measured by an ultrasonic Doppler method, and lithium clearance (CLLi) was used to estimate proximal tubular outflow. Baseline values of heart rate, systolic pressure and mean arterial pressure decreased with metoprolol compared with placebo, but cardiac output, effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were not significantly changed. Metoprolol significantly decreased baseline CLLi and sodium clearance (CLNa) by 19% (P < 0.01) and 34% (P < 0.01), respectively. Metoprolol blunted the dopamine‐ induced increases in heart rate and systolic pressure, but cardiac output increased to the same extent on both study days by 26% (placebo, P < 0.05) and by 31% (metoprolol, P < 0.01), respectively. With and without metoprolol, dopamine did not significantly change GFR, and the percentage increases in ERPF were similar on the two study days (40% (P < 0.001) and 42% (P < 0.001), respectively). Dopamine increased CLLi and CLNa by 31% (P < 0.01) and 114% (P < 0.01), respectively, with placebo, and by 36% (P < 0.01) and 114% (P < 0.01), respectively, with metoprolol. Values during infusion remained significantly lower with metoprolol compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)
The pharmacokinetics of ondansetron after intravenous injection in healthy volunteers phenotyped as poor or extensive metabolisers of debrisoquine.
Authors: Ashforth EI , Palmer JL , Bye A , Bedding A
Published: July 2012

The pharmacokinetics of the 5‐HT3 receptor antagonist ondansetron following an 8 mg i.v. dose were investigated in 12 subjects previously phenotyped with debrisoquine. Six subjects were poor metabolisers (debrisoquine metabolic ratios 29‐131) and six were extensive metabolisers (debrisoquine metabolic ratios 0.45‐3.4). There was no significant difference in AUC, Cmax, CL or t1/2 between the poor and extensive metabolisers. It is concluded that ondansetron clearance is not mediated exclusively by cytochrome P‐450 2D6.
Concurrent use of more than one major psychotropic drug (polypsychopharmacy) in out‐patients—a prescription database study.
Authors: Rosholm JU , Hallas J , Gram LF
Published: July 2012

1. In order to assess the prevalence of concurrent use of more than one major psychotropic drug (polypsychopharmacy) in out‐patients, a prescription database study was conducted in the Odense area for a period of 2 years. 2. During the index period 5.12% of the inhabitants purchased major psychotropic drugs. Of these, 14% had a period of polypsychopharmacy recorded. The age‐specific prevalence of users increased with age, the prevalence for over 90 years of age was 18%. Sixty‐seven per cent of the psychotropic drug users were women. 3. For neuroleptic and antidepressant users, about 20% were subject to polypsychopharmacy, for lithium 61%. The most prevalent combination was neuroleptics‐neuroleptics. In none of the 10 most prevalent combinations were the mean daily doses significantly lower on polypsychopharmacy compared with single drug regimens, in two they were higher. 4. Polypsychopharmacy with psychotropic drugs was frequent in out‐patients. In polypsychopharmacy daily doses were not lowered in order to limit side effects.
Effects of zolpidem on sleep architecture, night time ventilation, daytime vigilance and performance in heavy snorers.
Authors: Quera‐Salva MA , McCann C , Boudet J , Frisk M , Borderies P , Meyer P
Published: July 2012

1. In a double‐blind, crossover, placebo controlled trial, zolpidem 10 mg, a new imidazopyridine hypnotic drug, was administered in a single dose to 10 healthy non‐obese heavy snorers. 2. Nocturnal polysomnography showed that zolpidem increased total sleep time, sleep efficiency and the percentage of stage 2. 3. Respiratory monitoring showed that zolpidem did not modify the percentage of total sleep time spent snoring. The percentages of total sleep time with a SaO2 < 4% of the baseline value and with a SaO2 < 90% and the mean SaO2 were also unchanged with zolpidem. The respiratory disturbance index was modestly increased by zolpidem although in all but one subject it remained < 5 with both treatments. 4. Zolpidem intake did not impair daytime vigilance and performance evaluated the day after.
Pharmacodynamics of lazabemide, a reversible and selective inhibitor of monoamine oxidase B.
Authors: Holford NH , Guentert TW , Dingemanse J , Kettler R
Published: July 2012

1. The inhibition of monoamine oxidase B (MAO‐B) by lazabemide was measured in platelets collected from 35 young (19‐36 years) and 40 older (60‐78 years) healthy volunteers after single (100‐300 mg) and multiple (100‐350 mg twice daily) oral doses respectively. 2. The relationship of the effect with plasma concentrations of the MAO‐B inhibitor was defined by a sigmoid Imax‐model using either a parametric or semi‐parametric method for predicting plasma drug concentrations. Population parameter estimates were obtained by the expectation maximization method and a standard two‐stage method. 3. At the lowest dose platelet MAO‐B activity was almost completely inhibited for around 20 h. No time delay between plasma drug concentration and resulting inhibition of platelet MAO‐B occurred. Low concentrations of the inhibitor produced 50% of maximum inhibition (IC50, estimates for population mean +/‐ s.d.: 0.48 +/‐ 0.89 microgram l‐1 for young and 1.5 +/‐ 2.3 micrograms l‐1 for elderly subjects). The maximum extent of enzyme inhibition attributable to lazabemide (Imax) was 94 +/‐ 5.1% and 96 +/‐ 4.5% in the young and older populations. There was no correlation between age and either Imax or IC50. 4. Model parameters describing the interaction of lazabemide with the enzyme did not change over the treatment period of 7 days.
Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac‐warfarin [see comments]
Authors: Chan E , McLachlan AJ , Pegg M , MacKay AD , Cole RB , Rowland M
Published: July 2012

1. The disposition of warfarin enantiomers and metabolites has been studied in 36 patients receiving chronic rac‐warfarin therapy, titrated to approximately the same anticoagulant response. 2. A stereoselective h.p.l.c. assay was employed to determine the concentrations of (R)‐ and (S)‐warfarin, (R,S)‐warfarin alcohol and (S)‐7‐hydroxywarfarin in plasma and 24 h urine samples. The concentrations of (R)‐7‐ hydroxywarfarin, (S,S)‐warfarin alcohol and (R)‐6‐ and (S)‐6‐ hydroxywarfarin were also determined in urine samples. The fractions unbound of warfarin enantiomers were determined using equilibrium dialysis. 3. Wide variability was observed in daily dose requirements (mean 6.1 mg; range: 2.5‐12 mg), in plasma concentrations of (S)‐ warfarin (0.48 mg l(‐1); 0.11‐1.02 mg l(‐1)), (R)‐warfarin (0.87 mg l(‐ 1); 0.29‐1.82 mg l(‐1)), (R,S)‐warfarin alcohol (0.31 mg l(‐1); 0.02‐ 0.72 mg l(‐1)) and (S)‐7‐hydroxywarfarin (0.25 mg l(‐1); 0.07‐0.37 mg l(‐1)) and the percentage unbound of (S)‐warfarin (0.53%; 0.29%‐0.82%) and (R)‐warfarin (0.54%; 0.26%‐0.96%). 4. The mean plasma clearances of warfarin enantiomers were 7.5 1 day‐1 per 70 kg (2.5‐22.1) for (S)‐ warfarin and 3.6 1 day‐1 per 70 kg (1.6‐8.8) for (R)‐warfarin. There was a significant correlation between the estimated formation clearance of (S)‐7‐hydroxywarfarin and the clearance of (S)‐warfarin, which accounted for much of the variability in the latter.(ABSTRACT TRUNCATED AT 250 WORDS)
Lymphocyte microsomal epoxide hydrolase in patients on carbamazepine therapy.
Authors: Pirmohamed M , Allott R , Green VJ , Kitteringham NR , Chadwick D , Park BK
Published: July 2012

1. In order to determine whether carbamazepine is an inducer of lymphocyte microsomal epoxide hydrolase, the activity of the enzyme has been measured in the lymphocytes of 40 patients on continuous drug therapy using [3H]‐cis stilbene oxide as a substrate. 2. Induction of the cytochrome P450 isoform, CYP3A, has been assessed in the same patients by measurement of the 24 h urinary excretion of 6 beta‐ hydroxycortisol by radioimmunoassay. The urinary concentrations of carbamazepine and its two metabolites, the 10,11‐epoxide and trans‐ dihydrodiol, have also been measured by h.p.l.c. 3. The 24 h urinary 6 beta‐hydroxycortisol excretion in the patients increased with the dose of carbamazepine (r = 0.57, P < 0.001) indicating induction of CYP3A. 4. The total amount of trans‐dihydrodiol excreted in the urine increased with the dose of carbamazepine, and it was the most abundant urinary metabolite in all patients and at all dose‐levels. There was no relationship between the dose of carbamazepine and the diol to epoxide ratio (r = 0.01, NS). 5. Lymphocyte microsomal epoxide hydrolase activity was marginally, but significantly (P = 0.02) higher in the patients (28.4 pmol diol min‐1 mg‐1 protein) than in drug‐free controls (23.4 pmol diol min‐1 mg‐1 protein (95% CI for difference ‐9 to ‐0.8)). 6. The results indicate that at concentrations of carbamazepine which produce marked induction of hepatic CYP3A, an enzyme involved in the metabolism and bioactivation of carbamazepine, there is only a slight increase in lymphocyte microsomal epoxide hydrolase.
Intestinal drug absorption during induced net water absorption in man; a mechanistic study using antipyrine, atenolol and enalaprilat.
Authors: Lennernas H , Ahrenstedt O , Ungell AL
Published: July 2012

1. The effect of induced water absorption on the intestinal permeability of antipyrine, atenolol and enalaprilat in the proximal jejunum was studied in eight healthy subjects with a regional intestinal perfusion technique. 2. The mean (+/‐ s.d.) net water flux changed from a secretory status of 1.2 +/‐ 1.2 ml h‐1 cm‐1 to an absorptive status of ‐3.7 +/‐ 3.5 ml h‐1 cm‐1 (P < 0.0025) on the introduction of a hypo‐osmolar glucose‐containing electrolyte solution. 3. The mean permeability values for the three drugs in the eight subjects were unchanged despite the increase in net water absorption (5.7 +/‐ 3.0 to 7.0 +/‐ 3.6 × 10(‐4) cm s‐1 for antipyrine, 0.1 +/‐ 0.2 to 0.2 +/‐ 0.2 × 10(‐4) cm s‐1 for atenolol and 0.3 +/‐ 0.3 to 0.1 +/‐ 0.2 × 10(‐4) cm s‐1 for enalaprilat). One subject showed a large change in the permeability for antipyrine and atenolol in parallel with a large increase in water absorption, but enalaprilat was unaffected. 4. The luminal recovery of PEG 4000 was similar before (100 +/‐ 4%) and during (101 +/‐ 7%) induction of water absorption, which indicates that the barrier function of the intestine appears to be maintained during glucose‐stimulated fluid absorption in man. 5. We conclude that induced net water absorption in man does not influence the paracellular permeability of hydrophilic drugs or drugs with high molecular weight to any significant extent.(ABSTRACT TRUNCATED AT 250 WORDS)
Frequency of human CYP2D6 mutant alleles in a normal Chinese population.
Authors: Lee EJ , Jeyaseelan K
Published: July 2012

Substantial differences in the pharmacogenetics of debrisoquine hydroxylation exist between Caucasians and Chinese populations. Among Chinese, not only is the frequency of the poor metabolizer phenotype low, the contribution of the 29B mutation in the CYP2D6 gene is insignificant. By contrast the frequency of D6‐J is very common (approximately 0.6) and is clearly related to the activity of debrisoquine hydroxylase. Its presence however, does not predict the poor metabolizer phenotype. The D6‐C mutation was also not detectable in our population.
Paracetamol absorption from different sites in the human small intestine.
Authors: Gramatte T , Richter K
Published: July 2012

Site‐specificity in the small intestinal absorption of paracetamol was investigated using a segmental intestinal steady state perfusion technique (triple‐lumen tubing system) combined with simultaneous measurements of serum drug concentrations. Dissolved paracetamol was perfused over 160 min into different parts of the small intestine (65‐ 210 cm beyond the teeth). Each of the four healthy subjects was studied twice with a proximal and a more distal site of perfusion. Serum drug concentrations were similar after proximal and distal perfusions. Mean drug absorption rates calculated from intestinal aspirate concentrations were similar in both parts of the intestine—proximal: 869 micrograms 30 cm‐1 min‐1 (95% CI: 659‐1079) vs distal: 941 micrograms 30 cm‐1 min‐1 (794‐1088). The absorption rate was related directly to the amount of paracetamol perfused per unit time as well as to the rate of transmucosal water fluxes.
Thiopurine methyltransferase activity in a French population: h.p.l.c. assay conditions and effects of drugs and inhibitors.
Authors: Jacqz‐Aigrain E , Bessa E , Medard Y , Mircheva Y , Vilmer E
Published: July 2012

1. Thiopurine methyltransferase (TPMT) is a cytosolic enzyme involved in the catabolism of thiopurine drugs, which are used to treat cancer patients and organ transplant recipients. Because TPMT activity is polymorphic and under genetic control, large interindividual variations in the immunosuppressive activity and toxicity of these drugs may, at least in part, be inherited. 2. We have developed a specific h.p.l.c. method for measuring 6‐methyl mercaptopurine formed from 6‐ mercaptopurine (6‐MP) in red blood cell lysates during the TPMT assay procedure. In blinded assays of 55 samples from adult blood donors, the results of the h.p.l.c. method correlated with those of the radiochemical reference method (r = 0.83, P < 0.001). 3. Using this h.p.l.c. assay, we tested the effect of known inhibitors of TPMT activity (syringic acid, p‐anisic acid and tropolone) in vitro and showed that they were highly inhibitory. We also found that drugs often administered concomitantly with 6‐MP (prednisone, prednisolone, 6‐ methylprednisolone, cyclophosphamide, methotrexate, and trimethoprim‐ sulphamethoxazole) had little or no effect on TPMT activity in vitro. 4. In a group of 300 French individuals, TMPT activity was highly variable, ranging from 4.7 to 35.3 nmol h‐1 ml‐1 of packed red blood cells (nmol h‐1 ml‐1 PRBC) with a mean value of 19.3 +/‐ 4.9. TMPT activity was not influenced by sex. 5. This sensitive and reproducible h.p.l.c. assay for TPMT activity in red blood cells may prove useful for prospective clinical studies designed to optimise dosage regimens of thiopurine drugs (detection limit for 6‐methyl mercaptopurine is 5 ng ml‐1, intra‐ and inter‐assay variations are 6.8 and 8.2%, respectively).
Inhibitors of alprazolam metabolism in vitro: effect of serotonin‐ reuptake‐inhibitor antidepressants, ketoconazole and quinidine.
Authors: von Moltke LL , Greenblatt DJ , Cotreau‐Bibbo MM , Harmatz JS , Shader RI
Published: July 2012

1. The biotransformation of the triazolobenzodiazepine alprazolam (ALP) to its hydroxylated metabolites (4‐OH‐ALP and alpha‐OH‐ALP) was evaluated in human, monkey, rat, and mouse liver microsomes. 2. In all species 4‐OH‐ALP was the principal metabolite, accounting for 84% of clearance in human microsomes compared with 16% for alpha‐OH‐ALP. 3. Among the serotonin‐specific reuptake inhibitors fluoxetine (FLU) and sertraline (SERT), and their respective demethylated metabolites norfluoxetine (NOR) and desmethylsertraline (DES), NOR was the most potent inhibitor (mean Ki for 4‐OH‐ALP formation in humans: 11 microM), FLU the weakest (Ki = 83 microM), with SERT and DES falling in between (Ki = 24 and 20 microM). 4. The in vitro data predict 29% inhibition of ALP clearance at mean FLU and NOR plasma concentrations of 77 ng ml‐1 and 72 ng ml‐1, respectively, after correction for liver:water partition ratios in the range of 12‐14. The observed mean degree of inhibition in a previous in vivo study was 21%. 5. Ketoconazole was a potent inhibitor of ALP metabolism in vitro (Ki = 0.046 microM), suggesting that ALP hydroxylation is mediated by the cytochrome P450‐3A sub‐family. Quinidine was a weak inhibitor (Ki = 626 microM).
Pharmacological effects of the non‐competitive NMDA antagonist CNS 1102 in normal volunteers.
Authors: Muir KW , Grosset DG , Gamzu E , Lees KR
Published: July 2012

1. Non‐competitive antagonists at the glutamatergic N‐methyl D‐ aspartate receptor significantly reduce the volume of ischaemic cerebral infarction in animals and are potential agents for the treatment of acute stroke in humans. 2. CNS 1102, a novel non‐ competitive NMDA antagonist, was administered as a 15 min intravenous infusion to healthy male volunteers in a double‐blind, placebo‐ controlled, dose‐ranging study. This was the first administration to man. 3. Clinically significant sedation, increased mean arterial pressure and pulse rate were seen at doses of 30 micrograms kg‐1 and above. Symptoms of sedation and central nervous excitation became unacceptable for conscious individuals at doses of 45 micrograms kg‐1 and above. 4. Rapid onset of central nervous system effects after administration is in keeping with rapid distribution of CNS 1102 to brain. Steady state volume of distribution was large (444 l) and terminal elimination half‐life from plasma was approximately 4 h. 5. Pharmacokinetic properties are favourable for a potential neuroprotective therapy. The maximum tolerated dose for conscious individuals was 30 micrograms kg‐1 given intravenously over 15 min. Further assessment of CNS 1102 should seek methods of drug administration which maximise administered dose with minimal side effects.
The pharmacokinetics of fluconazole after a single intravenous dose in AIDS patients.
Authors: Yeates RA , Ruhnke M , Pfaff G , Hartmann A , Trautmann M , Sarnow E
Published: July 2012

The pharmacokinetics of fluconazole after a single 100 mg i.v. dose were studied in 10 healthy subjects (5 M; 5 F) and 10 HIV‐positive patients (8 M; 2 F). The mean value of plasma clearance was 25% lower in the patient groups (17 +/‐ 6 (s.d.) vs 23 +/‐ 4 ml min‐1; 95% CI of difference ‐11 to ‐0.7; P < 0.05). This difference may have been related to slightly reduced kidney function in the patient group (mean creatinine clearance ‐18%) but is unlikely to be clinically significant. Therefore, no adjustment of the dose of intravenously administered fluconazole appears to be necessary in AIDS patients without clinical signs of enteropathy.
Time‐dependent inhibition by glyceryl trinitrate of platelet aggregation caused by U46619 (a thromboxane/endoperoxide receptor agonist).
Authors: Kampf G , Ritter JM
Published: July 2012

Glyceryl trinitrate is a weak inhibitor of platelet aggregation in vitro. Its effect on platelet aggregation in response to U46619 (a thromboxane/endoperoxide receptor agonist) was studied turbidometrically in platelet‐rich plasma from healthy volunteers. The object was to determine whether inhibition was influenced by a period of preincubation between preparation of platelet‐rich plasma and addition of glyceryl trinitrate. Incubation was performed at 37 degrees C and 22 degrees C. Samples were removed at intervals and transferred to an aggregometer cuvette at 37 degrees C. Glyceryl trinitrate (100 microM) or an equal volume of distilled water was added 5 min before U46619 (2 microM), and aggregation recorded as change in light transmission. Inhibition by glyceryl trinitrate was markedly time and temperature dependent, with a progressive increase in inhibitory potency between 120 and 300 min preincubation at 37 degrees C but not at 22 degrees C. The explanation of this is unknown but the effect was not influenced by lipopolysaccharide or by cycloheximide, so it does not appear to be due to exposure to endotoxin or to enzyme induction in vitro.
Haemodynamic response and pharmacokinetics after the first dose of quinapril in patients with congestive heart failure.
Authors: Squire IB , Macfadyen RJ , Lees KR , Hillis WS , Reid JL
Published: July 2012

1. Twenty‐four elderly patients with stable, chronic congestive heart failure, NYHA II‐IV, requiring addition of an ACE inhibitor to their existing therapy were randomised to receive double‐blind a single dose of quinapril 2.5 mg p.o. or matching placebo after 24‐48 h supervised diuretic withdrawal. 2. The effect of treatment on resting supine blood pressure, heart rate, plasma angiotensin converting enzyme (ACE) and circulating plasma renin activity was compared between groups over the first 24 h after dosing. The pharmacokinetic profiles of quinapril and the active metabolite quinaprilat were determined. 3. Compared with placebo, quinapril caused a statistically significant but modest fall in blood pressure from 3 to 10 h post dose. The maximum fall of 12 mm Hg (95% C.I. 5.4‐18.5) was seen at approximately 5 h. Circulating ACE activity was 40% inhibited within 1 h. Maximum ACE inhibition (83.6%, 95% C.I. 76.7‐90.5) was observed at 3 h. ACE remained 60% inhibited at 24 h post dose. tmax for quinapril was seen at 2.6 +/‐ 1.2 h. while tmax for quinaprilat was at 3.6, +/‐ 0.8 h. 4. Treatment with quinapril was associated with a significant rise in plasma renin activity (PRA) of 8.83 ng AI ml‐1 h‐1 (95% C.I. 0.30‐17.96) compared with placebo. 5. Compared with placebo, quinapril 2.5 mg inhibits plasma ACE by over 60% for 24 h and reduces blood pressure for at least 10 h in patients with stable, chronic congestive heart failure. The blood pressure fall, although moderate and well tolerated, is more sustained than previously described for quinapril in heart failure.
Pharmacokinetics of the enantiomers of bupivacaine following intravenous administration of the racemate.
Authors: Burm AG , Van der Meer AD , Van Kleef JW , Zeijlmans PW , Groen K
Published: July 2012

1. The pharmacokinetics of R(+)‐bupivacaine and S(‐)‐bupivacaine were investigated following a 10 min intravenous infusion of the racemate (dose 30 mg) in 10 healthy males. 2. The fractions unbound of R(+)‐ and S(‐)‐bupivacaine in pre‐dose plasma were determined for each subject after in vitro addition of rac‐bupivacaine (concentration of each enantiomer: approximately 300 ng ml‐1). 3. The total plasma clearance of R(+)‐bupivacaine (mean +/‐ s.d.: 0.395 +/‐ 0.076 l min‐1) was greater (P < 0.0001) than that of S(‐)‐bupivacaine (0.317 +/‐ 0.067 l min‐1). The volumes of distribution of R(+)‐bupivacaine at steady state (84 +/‐ 29 l) and during the terminal log‐linear phase (117 +/‐ 47 l) were larger (P < 0.0002) than those of S(‐)‐bupivacaine (54 +/‐ 20 l and 71 +/‐ 34 l, respectively). The terminal half‐life (210 +/‐ 95 min) and mean residence time (215 +/‐ 74 min) of R(+)‐bupivacaine were longer than those of S(‐)‐bupivacaine (157 +/‐ 77 min, P < 0.01, and 172 +/‐ 55 min, P < 0.02, respectively). 4. The free percentage of R(+)‐ bupivacaine (6.6 +/‐ 3.0 %) was greater (P < 0.0002) than that of S(‐)‐ bupivacaine (4.5 +/‐ 2.1 %). 5. The plasma clearance of unbound R(+)‐ bupivacaine (7.26 +/‐ 3.60 1 min‐1) was smaller (P < 0.01) than that of S(‐)‐bupivacaine (8.71 +/‐ 4.27 l min‐1). Volumes of distribution based on unbound R(+)‐bupivacaine concentrations (Vuss: 1576 +/‐ 934 l; Vu: 2233 +/‐ 1442 l) did not differ from those of S(‐)‐bupivacaine (Vuss: 1498 +/‐ 892 l; Vu: 1978 +/‐ 1302 l). 6. The enantioselective systemic disposition of bupivacaine can to a large extent be attributed to differences in the degree of plasma binding of the enantiomers.
The stereoselective disposition of the enantiomers of ibuprofen in blood, blister and synovial fluid.
Authors: Seideman P , Lohrer F , Graham GG , Duncan MW , Williams KM , Day RO
Published: July 2012

1. A sensitive, stereospecific assay using gas chromatography‐mass spectrometry (GC/MS) was established to measure the concentrations of the enantiomers of ibuprofen in small volumes (50 microliters) of blister fluid. 2. The concentrations of the enantiomers in blister fluid, assessed in eight patients, were similar to those in synovial fluid, both fluids behaving as peripheral compartments with respect to plasma. 3. The mean rate constants of transfer of R‐ibuprofen into (0.14 +/‐ 0.06 h‐1) and out of (0.20 +/‐ 0.04 h‐1) blister fluid were not significantly different from those for synovial fluid (0.19 +/‐ 0.12 h‐1, 0.34 +/‐ 0.11 h‐1, respectively). Similarly, the mean rate constants of transfer of S‐ibuprofen into (0.22 +/‐ 0.07 h‐1) and out of (0.27 +/‐ 0.08 h‐1) blister fluid were not significantly different from those for synovial fluid (0.29 +/‐ 0.10, 0.36 +/‐ 0.11 h‐1). However, the correlations were poor between the transfer constants for each of the enantiomers between plasma, and both blister and synovial fluid (P > 0.2). 4. The complex rate constant of transfer of S‐ ibuprofen into blister fluid (0.22 +/‐ 0.07 h‐1) was greater than that of R‐ibuprofen (0.14 +/‐ 0.07 h‐1), which may be explained by the lesser protein binding of the S‐enantiomer.(ABSTRACT TRUNCATED AT 250 WORDS)
Inability to detect plasma etretinate and acitretin is a poor predictor of the absence of these teratogens in tissue after stopping acitretin treatment.
Authors: Sturkenboom MC , de Jong‐Van Den Berg LT , Van Voorst‐Vader PC , Cornel MC , Stricker BH , Wesseling H
Published: July 2012

1. Concentrations of etretinate, acitretin and its main metabolite 13‐ cis‐acitretin were measured in plasma and subcutaneous fat samples from 37 women of childbearing age exposed to acitretin before November 1990. Twenty of the women still used acitretin and 17 had stopped therapy for a period ranging from 1 to 29 months. 2. The prevalences of detectable etretinate concentrations were 45% and 83% in plasma and subcutaneous tissue, respectively, among current acitretin users and 18% and 86% among those who had stopped acitretin therapy. Thus, inability to detect plasma etretinate is a poor predictor of the absence of etretinate in fat. 3. Acitretin and/or etretinate were detectable in fat and in some cases in plasma from women who had ceased acitretin therapy for up to 29 months. 4. We suggest that (cis)‐acitretin and etretinate should be monitored in subcutaneous tissue when plasma measurements are negative. The recommended contraception period of 2 years after cessation of acitretin therapy should be reconsidered to avoid the risk of teratogenicity.
Transfer of dideoxyinosine across the human isolated placenta.
Authors: Henderson GI , Perez AB , Yang Y , Hamby RL , Schenken RS , Schenker S
Published: July 2012

1. Dideoxyinosine (ddI) has recently been approved for the treatment of patients with HIV infection. As increasing numbers of such patients are pregnant, we wished to define the rate and mechanism(s) of ddI transfer by the placenta to the foetus. Using isolated single perfused human term placental cotyledons, the drug was shown to cross the placenta from mother to foetus at a rate of 25% that of a freely diffusible marker, antipyrine, and at about half the rate of zidovudine (AZT). The transfer of ddI was similar in both directions (maternal to foetal and the reverse), equal to that of L‐glucose, a passively transported sugar, and was not inhibited by excess inosine or uric acid (structural analogues of ddI). ddI did not cross to the foetus against a concentration gradient. The transport process appeared to be passive and it was not altered by AZT. 2. ddI was not metabolized in the Krebs Ringer buffer/albumin perfusate, and placental homogenates converted only 4% of ddI to hypoxanthine over the 4 h incubation. However, when maternal term or cord blood was incubated with ddI for 3 h, 50% of the drug was converted to hypoxanthine in maternal blood and to hypoxanthine and uric acid in cord blood. 3. Thus, ddI metabolism in maternal blood should decrease its net transfer to the foetus in vivo. In the foetal circulation, ddI will be further metabolized by erythrocytes to hypoxanthine and possibly to uric acid. Hence, the fraction of administered ddI delivered to foetal tissues should be much lower than that of AZT.
Central effects of the diuretic, bendrofluazide.
Authors: McDevitt DG , Currie D , Nicholson AN , Wright NA , Zetlein MB
Published: July 2012

1. Central effects of the diuretic, bendrofluazide (2.5, 5 and 10 mg) were studied in 12 healthy volunteers. Two placebos and an active control drug, oxazepam (15 mg), were included. Single doses were administered double‐blind at 10.00 h. The effects of drugs on performance and subjective feelings were assessed before and from 1.5‐ 2.5 and 3.5‐4.5 h after ingestion, and recording of the electrical activity of the brain (EEG) and body sway carried out. 2. Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short‐term memory, together with critical flicker fusion and two flash fusion. Subjects assessed their mood and well‐being on a series of 12 visual analogue scales. The EEG was recorded with eyes open while the subjects carried out a mental arithmetic task, and with eyes closed, when they were required to relax. Body sway was recorded with eyes open and with eyes closed. 3. Bendrofluazide (10 mg) increased the number of errors at letter cancellation and reduced the rate of finger tapping (P < 0.05), while oxazepam increased the number of errors and reduced accuracy at continuous attention (P < 0.01), and increased the number of involuntary rest pauses during tapping (P < 0.05). 4. There were no effects of drugs on subjective assessment of mood. 5. No changes in the electrical activity of the brain were observed with bendrofluazide. In recordings with eyes open, oxazepam reduced delta (0.5‐3 Hz), theta (3.5‐7 Hz) and alpha 2 (10.5‐13 Hz) while increasing beta 1 (13.5‐21 Hz) activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Efficacy of a low dose‐range of fluvastatin (XU 62‐320) in the treatment of primary hypercholesterolaemia. A dose‐response study in 431 patients. The French‐Dutch Fluvastatin Study Group.
Authors: Jacotot B , Banga JD , Pfister P , Mehra M
Published: July 2012

1. In this randomised, double‐blind, placebo‐controlled study, the efficacy of four dosages of fluvastatin (2.5, 5, 10 and 20 mg day‐1) were assessed in 431 patients with primary hypercholesterolaemia recruited in 17 centres. 2. Following an 8‐week dietary stabilisation phase and a 6‐week placebo phase, the patients were randomised to receive placebo or fluvastatin 2.5, 5, 10 or 20 mg once daily at night for a period of 6 weeks. 3. Total cholesterol, beta‐quant LDL‐C, and the beta‐quant LDL‐C/HDL‐C ratio were significantly reduced by all doses of fluvastatin, and HDL‐C was significantly increased by the 10 mg and 20 mg doses. Fluvastatin 20 mg day‐1 also significantly decreased TG and Lp(a):B levels. 4. Fluvastatin was well tolerated during the study, and relatively few biochemical or haematological abnormalities occurred. 5. Of the dosages tested, 20 mg fluvastatin day‐ 1 is the optimal hypolipidaemic dose.
Morphine and morphine‐glucuronide concentrations in plasma and CSF during long‐term administration of oral morphine.
Authors: Van Dongen RT , Crul BJ , Koopman‐Kimenai PM , Vree TB
Published: July 2012

Concentrations of morphine, morphine‐3‐glucuronide (M3G) and morphine‐6‐ glucuronide (M6G) were measured by h.p.l.c. in plasma and cerebrospinal fluid (CSF) samples from 16 patients with cancer receiving oral (controlled‐release) morphine. There was a close correlation between plasma and CSF morphine concentrations (r = 0.94, P = 0.0001) and both correlated with drug dosage (r = 0.61, P = 0.013 and r = 0.74, P = 0.0001, respectively). M3G and M6G in plasma and CSF were correlated (r = 0.81 and r = 0.82, both P = 0.0001). No relationship was apparent between M plus M6G concentrations in the CSF and pain scores.
Determination of dose‐dependent absorption of amoxycillin from urinary excretion data in healthy subjects.
Authors: Chulavatnatol S , Charles BG
Published: July 2012

Measurement of unchanged drug in urine was used to study the rate and extent of amoxycillin absorption after administration of amoxycillin sodium solution to six healthy subjects in a Latin‐Square crossover design. The mean (95% CI) fraction of the dose excreted as unchanged amoxycillin decreased (P < 0.05) from 0.50 (0.44‐0.56) after 97 mg amoxycillin sodium (= 0.25 mmol amoxycillin) to 0.23 (0.19‐0.27) after 3103 mg (8 mmol), while the mean residence time determined from urinary excretion rate data increased (P < 0.05) from 1.54 (1.32‐1.76) h to 2.16 (2.01‐2.41) h. Plots of total urinary excretion and initial (0‐30 min) excretion of unchanged drug vs dose indicated significant non‐ linearity above 776 mg doses. Michaelis‐Menten parameters describing this relationship with respect to amount absorbed were 3.02 mmol for maximum amount absorbed and 1.93 mmol for amount absorbed at half maximum for 0‐30 min. These results support a saturable absorption mechanism for amoxycillin which had clinical implications for high oral amoxycillin doses, and for competition with other drugs having capacity‐ limited absorption.
Anti‐emetic effect of high‐dose metoclopramide vs alizapride—a randomised crossover study.
Authors: Seng KT , Tiong CE , Hiang TC
Published: July 2012

A randomised double‐blind crossover study was undertaken to compare the anti‐emetic efficacy of alizapride against high dose metoclopramide. A total of 32 patients on cisplatin were randomised to receive either high dose metoclopramide (7 mg kg‐1 day‐1) or alizapride (5 mg kg‐1 day‐ 1). Anti‐emetic responses in terms of control of vomiting episodes were similar in both regimens (59%). However, patients showed a statistically significant preference for high dose metoclopramide (P = 0.02). Side effects of both regimens were minimal. We conclude that alizapride is not superior to high dose metoclopramide in controlling cisplatin induced vomiting.
Preliminary study of the efficacy of xamoterol in bradycardia‐ tachycardia syndrome.
Authors: Mizutani N , Kobayashi T , Watanabe T
Published: July 2012

Following 4 weeks on placebo, eighteen patients with bradycardia‐ tachycardia syndrome (BTS) were treated with 100 mg xamoterol twice daily for 2‐4 weeks. Ambulatory 24 h Holter electrocardiogram recordings showed that xamoterol decreased maximum heart rate from 140 +/‐ 5.1 to 107 +/‐ 6 beats min‐1 (P < 0.001) during exercise, increased minimum heart rate from 43 +/‐ 1.7 to 51 +/‐ 2.4 beats min‐1 (P < 0.005) at night and shortened maximum duration of sinus arrest from 3438 +/‐ 484 to 1767 +/‐ 202 ms (P < 0.005) in BTS. Symptomatically, patients reported that palpitations were improved and syncopal attacks disappeared. Although the study has the limitation of an open design, effects of treatment were objectively evaluated using Holter monitoring by investigators who reviewed the recordings in a blinded manner. The findings suggest that xamoterol may be useful in the treatment of BTS. Further studies are needed to evaluate fully its therapeutic potential in this condition.
Local L‐NG‐monomethyl‐arginine attenuates the vasodilator action of bradykinin in the human forearm.
Authors: O'Kane KP , Webb DJ , Collier JG , Vallance PJ
Published: July 2012

1. Studies in animals indicate that bradykinin relaxes blood vessels directly through an action on smooth muscle and indirectly through the release of endothelium‐derived mediators. Its precise mechanism of action in the human arterial circulation is not yet known. 2. In this study the effects of a specific inhibitor of nitric oxide synthase, L‐ NG‐monomethyl‐arginine (L‐NMMA) and noradrenaline on the vasodilator responses to bradykinin were examined in the forearm arterial bed of healthy volunteers. Noradrenaline was used as a control for vasoconstriction by L‐NMMA; glyceryl trinitrate (GTN) as a control vasodilator acting independently of the NO synthase enzyme. 3. L‐NMMA (4 mumol min‐1; 5 min) alone reduced resting forearm blood flow by 44% (P < 0.01; n = 6) confirming that nitric oxide plays an important role in regulating vascular tone. 4. Bradykinin (10 and 100 pmol min‐1; 3 min each dose) and GTN (2 and 5 nmol min‐1; 3 min each dose) increased forearm blood flow in a dose‐dependent manner (percentage changes 171 +/‐ 17% and 398 +/‐ 35%, and 176 +/‐ 21% and 268 +/‐ 42%, respectively; n = 6). 5. The response to bradykinin, but not that to GTN, was attenuated by L‐NMMA compared with noradrenaline (P < 0.05; n = 6), suggesting that bradykinin‐induced vasodilatation in the forearm is mediated, at least in part, by stimulating release of nitric oxide.
Clinical response to non‐steroidal anti‐inflammatory drugs in urate‐ crystal induced inflammation: a simultaneous study of intersubject and intrasubject variability.
Authors: Walker JS , Nguyen TV , Day RO
Published: July 2012

1. It is well known that an individual subject often responds preferentially to a particular nonsteroidal anti‐inflammatory drug (NSAID) and clinical response to these drugs is characterised by considerable variability between individuals. Variability in response has often been attributed to the episodic nature of musculoskeletal disease. Few studies have studied intrasubject variability in response to these drugs using a multiple crossover design. A major difficulty has been the lack of objective, validated measures of inflammation sensitive to NSAIDs. The primary aim of the present study was to test the utility of urate‐crystal induced inflammation as a tool to predict NSAID response in humans. 2. An inflammatory reaction was established in twenty‐five healthy subjects with intradermal injection of urate crystals on four separate occasions separated by 1 week. Each subject was randomly assigned to receive either ibuprofen on two of these occasions (800 mg four times over 36 h) or matched placebo on the other two occasions using a double‐blind, cross‐over design. Decrease in the area under the wheal size‐time curve was used to indicate anti‐ inflammatory response. 3. Peak inflammatory response was observed at about 32 h and had dissipated by 56 h post‐urate injection. The logarithmic mean wheal area was significantly lower after ibuprofen (mean +/‐ s.e. mean; 6.74 +/‐ 0.09) compared with placebo (6.96 +/‐ 0.07 mm h); a difference of 20% (95% confidence interval for difference: 1 to 35%; P < 0.05). 4. There was marked intra‐ and intersubject variability in response to ibuprofen over the four treatment periods.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetics and effects on intracranial pressure of sufentanil in head trauma patients.
Authors: Scholz J , Bause H , Schulz M , Klotz U , Krishna DR , Pohl S , Schulte am Esch J
Published: July 2012

Ten patients with head trauma received an intravenous bolus of sufentanil (2 micrograms kg‐1) followed at 30 min by infusion of sufentanil (median 150 micrograms h‐1) and midazolam (median 9.0 mg h‐ 1) over 48 h. Median (range) values of pharmacokinetic parameters for sufentanil were: t1/2,z = 16 (7‐49) h; CL = 1215 (519‐2550) ml min‐1; CLR = 7 (2‐38) ml min‐1; Vss = 10.0 (6.8‐24.2) 1 kg‐1. Decreases in intracranial pressure (ICP) (from 16.1 +/‐ 1.7 to 10.8 +/‐ 1.3 mm Hg; P < 0.05) and mean arterial blood pressure (MAP) (from 85.5 +/‐ 3.9 to 80.2 +/‐ 4.9 mm Hg; P < 0.05) were observed within 15 min of the bolus injection of sufentanil and remained unchanged thereafter. Thus, cerebral perfusion pressure (CPP = MAP‐ICP) was stable.
Pharmacokinetics of co‐administered didanosine and stavudine in HIV‐ seropositive male patients.
Authors: Seifert RD , Stewart MB , Sramek JJ , Conrad J , Kaul S , Cutler NR
Published: July 2012

The pharmacokinetics of single and co‐administered didanosine and stavudine were evaluated in 10 HIV‐seropositive subjects in an open, within subject design in which each subject received each of three treatments. Single doses of didanosine 100 mg were alternated randomly with single doses of stavudine 40 mg on days 1 and 2. Beginning on day 3, subjects received the same doses of both drugs simultaneously every 12 h for nine doses. Serial blood and urine samples were obtained on single dose days 1 and 2, first simultaneous dose day 3, and last simultaneous dose day 7. The average maximum plasma concentrations of didanosine and stavudine before and after simultaneous administration were 422 +/‐ 184 (s.d.) ng ml‐1 and 603 +/‐ 160 (s.d.) ng ml‐1, and 419 +/‐ 153 (s.d.) ng ml‐1 and 726 +/‐ 188 (s.d.) ng ml‐1, respectively. Didanosine and stavudine AUC values before and after simultaneous administration were 615 +/‐ 170 (s.d.) ng ml‐1 h and 1246 +/‐ 230 (s.d.) ng ml‐1 h, 637 +/‐ 155 (s.d.) ng ml‐1 h and 1326 +/‐ 267 (s.d.) ng ml‐1 h, respectively. No significant changes in maximum plasma concentration, AUC elimination half‐life, or renal clearance of didanosine and stavudine were observed when the drugs were administered simultaneously. Co‐administration of didanosine 100 mg and stavudine 40 mg is well tolerated and the drugs do not interact pharmacokinetically.
Angiotensin converting enzyme inhibition does not affect the response to exogenous angiotensin II in the human forearm.
Authors: Lyons D , Stewart D , Webster J , Benjamin N
Published: July 2012

Suppression of endogenous levels of angiotensin II by angiotensin converting enzyme inhibition, may result in up‐regulation of vascular AT1 receptors. We have evaluated the effects of orally administered enalapril on angiotensin II induced vasoconstriction in the human forearm. Subjects received in random order, enalapril (20 mg) or matched placebo daily for 2 weeks. Forearm blood flow response to increasing doses of angiotensin II was measured using venous occlusion plethysmography at the beginning of the study and at the end of each 2 week treatment period. Treatment with enalapril significantly reduced plasma angiotensin II levels and supine blood pressure compared with placebo. The percentage reductions in forearm blood flow in the infused arm, in response to the maximum dose of angiotensin II (50,000 fmol min‐ 1) were 48.1 +/‐ 3.6% at baseline, 57.5 +/‐ 3.6% on placebo and 54.5 +/‐ 4.2% on enalapril. The differences were not significantly different. This demonstrates that suppression of plasma angiotensin II for a 14 day period does not enhance the response to exogenous intra‐arterial angiotensin II in the human forearm of healthy salt replete subjects.
Effect of short‐term treatment with fluticasone propionate nasal spray on the response to nasal allergen challenge.
Authors: Scadding GK , Darby YC , Austin CE
Published: July 2012

The aim of the study was to investigate the effect of short‐term treatment with fluticasone propionate on the response to nasal allergen challenge in patients with allergic rhinitis. Responses to nasal allergen challenge were assessed subjectively by recording symptom scores on visual analogue scales, and objectively by measuring histamine, PGD2 and LTC4 in nasal lavage and by measuring nasal inspiratory peak flow following challenge. Nasal allergen challenge resulted in an increase in all symptom scores (P < 0.05); an increase in histamine and PGD2 (P < 0.05), and a decrease in nasal inspiratory peak flow at 1 h, 5 h and 7 h following challenge (P < 0.05). The allergen‐induced changes in symptom scores, mediator levels and nasal inspiratory peak flow were attenuated by treatment with fluticasone propionate (P < 0.05 for all parameters measured). Post‐challenge nasal obstruction was decreased by 45%; sneezing, itching and rhinorrhoea by 73, 78 and 80% respectively in the group as a whole comparing scores whilst on fluticasone propionate with those on no therapy. Fluticasone propionate, 200 micrograms twice daily for 2 weeks is effective in reducing significantly the early and late response to nasal allergen challenge.
S‐mephenytoin, sparteine and debrisoquine oxidation: genetic polymorphisms in a Turkish population.
Authors: Basci NE , Brosen K , Bozkurt A , Isimer A , Sayal A , Kayaalp SO
Published: July 2012

A mephenytoin test was carried out in 106 unrelated healthy Turkish volunteers. Racemic mephenytoin was coadministered with either debrisoquine or sparteine. The S/R mephenytoin ratio ranged from < 0.1 to 0.73 in 105 subjects, accordingly phenotyped as extensive metabolisers. One subject had an S/R mephenytoin ratio of 1.02, showing that he was a poor metaboliser of mephenytoin (0.94%, confidence interval 0.25% and 13.65%). In 48 subjects, the metabolic ratios of debrisoquine and sparteine were correlated significantly (rs = 0.61, P < 0.001).
The use of nitrates, calcium channel blockers and ACE inhibitors in primary care in the Northern Region: a pharmacoepidemiological study.
Authors: Roberts SJ , Bateman DN
Published: July 2012

1. Prescribing rates for cardiovascular drugs have substantial local variation. The objectives of this study were to determine the prescribing prevalence of nitrates, calcium channel blockers and angiotensin‐converting enzyme inhibitors in general practice, to examine the indications recorded for these prescriptions, and to identify which therapeutic areas contribute to the variation in prescribing. 2. Anonymised patient‐specific prescription data were taken from computerised records in 41 VAMP research practices in the Northern Region (total population 330,749). All patients who received any prescription for calcium channel blockers, nitrates or angiotensin‐ converting enzyme (ACE) inhibitors during a 12 month period were included. Prescribing rates were determined in terms of patients per 1,000 population within age, sex and diagnostic groups. 3. Overall, 4.3% of the study population were prescribed one or more of the drugs. There was virtually no prescribing for patients under the age of 35 years, but thereafter the prevalences rose steeply to peak at ages 65‐ 74 years for calcium channel blockers (91 per 1,000 population) and ACE inhibitors (34 per 1,000), and at ages 75‐84 years for nitrates (100 per 1,000). Prescribing prevalence amongst the over 85's was less than half the peak rate for each drug group. Rates for men and women were comparable, except for nitrates where men had higher rates. 4. Recorded indication rates for patients with ischaemic heart disease and treated with any of these drugs reached 112 per 1,000 population in the 75‐84 age group, and were higher in men than women, at all ages. Hypertension indication rates were substantially higher in women over 65; across the genders the peak rate was 88 per 1,000 for those aged 65‐74 years.(ABSTRACT TRUNCATED AT 250 WORDS)
An assessment of the systemic activity of single doses of inhaled fluticasone propionate in healthy volunteers [see comments]
Authors: Grahnen A , Eckernas SA , Brundin RM , Ling‐Andersson A
Published: July 2012

1. The systemic effects of inhaled fluticasone propionate (FP), administered via Diskhaler, on the hypothalamo‐pituitary‐adrenal (HPA) axis were assessed primarily by measuring plasma cortisol at frequent intervals for 20 h after drug administration. 2. FP showed a dose‐ related suppression of plasma cortisol measured as area under the plasma cortisol vs time curve (AUC 0‐20). The cortisol suppression (expressed as % fall from placebo) was 8, 19, and 28% for single doses of 250 micrograms FP, 500 micrograms FP and 1000 micrograms FP, respectively. A single dose of budesonide, 800 micrograms (via Turbuhaler), resulted in a 16% cortisol suppression. The cortisol suppression for all three single doses of FP, and for the single dose of budesonide, was statistically significantly different from placebo. 3. Repeated dosing of FP (1000 micrograms twice daily for 3.5 days) resulted in a more marked plasma cortisol suppression; a fall of 65% from placebo (AUC FP 1000 mg twice daily vs AUC placebo, P < 0.001). 4. In a well‐controlled study in healthy volunteers, inhaled FP, in therapeutic doses, was shown to exhibit systemic effects which appear to be more pronounced after repeated dosing.