bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stereoselective interaction between piroxicam and acenocoumarol
Authors: BONNABRY P. , DESMEULES J. , RUDAZ S. , LEEMANN T. , VEUTHEY J.‐L. , DAYER P. 
Published: October 2003

1An open‐label study was performed to assess the effect of piroxicam on the pharmacokinetics of acenocoumarol enantiomers. 2Eight healthy male volunteers received an oral dose of 4 mg rac‐acenocoumarol on days 1 and 8, plus 40 mg piroxicam orally 2 h before the anticoagulant on day 8. R‐ and S‐acenocoumarol, piroxicam and their metabolites were measured in plasma over a 24 h interval. 3The pharmacokinetics of R‐acenocoumarol were markedly modified by piroxicam: Cmax+28.0% (s.d.23.8), P<0.05; AUC(0, 24 h)+47.2% (21.5), P<0.005; and t1/2+38.0% (34.5), P<0.01. A concomitant decrease of CL/F was observed: −30.8% (10.0), P<0.0001. A similar, but statistically non‐significant trend, was observed on the S‐enantiomer: Cmax: +9.5% (s.d.36.6), AUC(0, 24 h): +15.4% (23.4), t1/2: +19.9% (42.0), and CL/F: −9.8% (20.5). V/F remained unchanged for both enantiomers. 4Piroxicam plasma AUC(0, 24 h) correlated closely with R‐ and Sacenocoumarol AUCs on day 1 (r=0.901, P<0.005 and r=0.797, P<0.05, respectively), as well as with the difference of AUC between days 1 and 8 for R‐acenocoumarol (r=0.903, P<0.001) and S‐acenocoumarol (r=0.711, P<0.05). 5Piroxicam markedly reduced acenocoumarol enantiomer clearance, with a greater effect on the more active R‐isomer. This interaction, which occurs in addition to the well documented pharmacodynamic one (effect on platelets), is expected to result in increased anticoagulant effect.
Effects of food and antacid on the pharmacokinetics of single doses of mycophenolate mofetil in rheumatoid arthritis patients
Authors: BULLINGHAM R. , SHAH J. , GOLDBLUM R. , SCHIFF M. 
Published: October 2003

1Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is being developed for the prevention of rejection following solid organ transplantation. This crossover study investigated the effect of food and antacid (Maalox® TC) on the plasma pharmacokinetics of MPA and its inactive glucuronide metabolite MPAG after giving single 2 g MMF doses orally to rheumatoid arthritis patients. 2With food, the AUC of MPA in plasma was equivalent to that following an overnight fast. MPA tmax was slightly delayed and Cmax was lowered about 25%, consistent with delay in gastric emptying in the fed state. MPAG Cmax and AUC were higher in the fed relative to the fasting state, suggesting more complex processes involving changes in glucuronidation may also be occurring with food. 3With antacid, AUC of MPA was lowered about 15% compared with fasting and Cmax was decreased 37%. Plasma MPAG parameters were similarly reduced. These parallel changes in MPA and MPAG are consistent with reduced absorption. 4The changes in MPA with both food and antacid are small in comparison with the interpatient variability and are not likely to have clinically major effects; the changes in MPAG are of mechanistic interest.
The asthma death problem revisited
Authors: FULLER R. W. 
Published: October 2003

1Asthma is a potentially dangerous disease. Asthma deaths occur at varying degrees throughout the world and there is evidence for epidemics occurring in different populations at different times. Such epidemics have been noted as early as last century. Much investigation has been made into the role of inhaled β‐adrenoceptor agonists in these epidemics and indeed there is some evidence fenoterol is implicated. However, evidence for other β‐adrenoceptor agonists is not substantiated. 2It is also noted that asthma deaths are not all the same, there being at least two types: deaths occurring in chronic severe asthmatics related to disease severity and sudden deaths of an anaphylactic nature that can occur in asthmatics of any disease severity. 3The important next step in the study of asthma deaths is to concentrate on other important factors rather than the role of therapy which cannot explain all the epidemics and the background instance of asthma death.
Pharmacokinetics and tolerance of intravenous and intramuscular phylloquinone(vitamin K1) mixed micelles formulation
Authors: SOEDIRMAN J. R. , DE BRUIJN E. A. , MAES R. A. A. , HANCK A. , GRÜTER J. 
Published: October 2003

1The pharmacokinetics and tolerance of phylloquinone(vitamin K1) mixed micelles formulation (Konakion® MM) were evaluated, in normal human adult volunteers (n=30) using an open randomized crossover design protocol following a 10 mg intravenous or intramuscular injection. 2Blood samples were collected for up to 12 h after the intravenous and up to 72 h after the intramuscular injections and the phylloquinone(vitamin K1) levels determined by reversed phase h.p.l.c. with fluorometric detection after post‐column electrochemical reduction. 3Konakion® MM was well tolerated after either route of administration. Pharmacokinetic analysis of plasma phylloquinone(vitamin K1) concentration vs time profiles revealed that in one‐fifth of the subjects systemic availability of intramuscular phylloquinone(vitamin K1) was below 65%. 4Our data suggest that due to sustained, but irregular and unpredictable absorption of the phylloquinone(vitamin K1) from the depot site, the intramuscular route of Konakion® MM administration is not suitable and thus not recommended. 5Konakion® MM i.v. is indicated to be well tolerated and effective in antagonizing coumarin‐type‐anticoagulants like Marcoumar®
A study of 5 day fractionated ifosfamide pharmacokinetics in consecutive treatment cycles
Authors: LEWIS LIONEL D. 
Published: October 2003

1Ifosfamide demonstrates increased clearance with time when administered daily for 5 days. The objectives of this study were to define whether the increased ifosfamide clearance was sustained between treatment cycles and whether it was reproducible in consecutive treatment cycles.2Seven patients with inoperable cancer received 1.5 g m−2 ifosfamide infused intravenously over 0.5 h, each day for 5 days, for two consecutive cycles. Urine and appropriately timed blood samples were collected for up to 24 h post ifosfamide infusion on day 1 and day 5. Plasma ifosfamide concentrations were assayed by gas liquid chromatography and pharmacokinetic parameters were imputed using non‐compartmental analysis.3The difference in the mean (n=7) total ifosfamide plasma clearance between day 5 and day 1 of Cycle I was an increase of 56.8 ml min−1 (99.8% CIs +22.6→+91.4). The difference in the mean (n=7) total ifosfamide plasma clearance between day 1 of Cycle II and day 5 was a decrease of 61.9 ml min−1 (99.8% CIs−111.2→−12.6). The magnitude of the mean increase in total ifosfamide plasma clearance in Cycle II and Cycle I was similar because the difference between these means (0.9 ml min−1; 99.8% CIs−63.7→+65.3) was not statistically significant. There was no change in the apparent volume of distribution of ifosfamide between the two study days in either of Cycle I or II, or between cycles.4The difference in the mean (n=7) ifosfamide renal clearance between day 5 and day 1 of Cycle I was minus 0.4 ml min−1 (99.8% CIs−8.5→+8.6); the means±s.d. were 6.3±2.6 ml min−1 and 6.7±3.2 ml min−1 respectively. The difference in the mean (n=4) ifosfamide renal clearance between day 5 and day 1 of Cycle II was −0.2 ml min−1 (99.8% CIs −5.7→+5.2); the means±s.d. were 7.8±6.1 ml min−1 and 8.0±6.2 ml min−1 respectively.5These data suggest that the increase in total ifosfamide plasma clearance with time in a 5 day fractionated regimen was due to an increase in ifosfamide metabolism which was not sustained over the 21 days between cycles, but was reproducible and of a similar magnitude in the two consecutive treatment cycles studied.
Intestinal absorption of strontium chloride in healthy volunteers: pharmacokinetics and reproducibility
Authors: SIPS A. J. A. M. , Van Der VIJGH W. J. F. , BARTO R. , NETELENBOS J. C. 
Published: October 2003

1The absorption kinetics of orally administered strontium chloride and its reproducibility were investigated in healthy volunteers after administering strontium either under fasting conditions (study I, n=8) or in combination with a standardized meal (study II, n=8). Each subject received strontium orally at day 0, 14, and 28 and intravenously at day 42. The study was performed as part of a project in which a simple clinical test for measuring intestinal calcium absorption is being developed, based on the use of stable strontium as a marker. 2Plasma strontium concentration–time curves were analysed by noncompartment analysis and a four compartment disposition model. Within a volunteer each oral curve was fitted simultaneously with the intravenous curve, by which means a two segment model for absorption was revealed. 3Mean absolute bioavailability of strontium was 25% without a meal and 19% with a meal, whereas the intraindividual variation was 24% and 20%, respectively. 4Various limited sampling absorption parameters were determined in order to select a potential test parameter for measuring intestinal calcium absorption using strontium as a marker. Fractional absorption at 4 h (Fc240), obtained after co‐ingestion of strontium with a meal, appeared to be the best test parameter, because it represented bioavailability well (r=0.90).
Dissecting the function of cytochrome P450
Authors: BOOBIS ALAN R. , EDWARDS ROBERT J. , ADAMS DELYTH A. , DAVIES DONALD S. 
Published: October 2003

1The role that P450 plays in the metabolism of drugs and other chemicals is often pivotal in determining the duration and magnitude of their biological effects, so that it is important to identify the specific forms of the enzyme involved. 2The similarity between different forms of P450 is such that polyclonal antibodies raised by conventional means, even against a homogeneous preparation of the enzyme will often react with several different P450s. 3Whilst monoclonal antibodies are often more specific, their selectivity cannot be determined prior to their use. 4The use of short sequences of amino acids (4–7 residues) predicted to occur in surface loop regions of the protein as immunogens, affords a means of targeting antibodies to specific forms of P450. 5The terminal amino acid of a peptide, here the C‐terminal residue, is very immunodominant in determining the specificity of the resultant antibody. Hence, antibodies against the C‐terminal residues of P450 have a high affinity and, in most cases, will be specific. 6Application of anti‐peptide antibodies to the major forms of P450 in human liver revealed the anticipated interindividual variation. However, evidence was found that the polymorphism in CYP3A5 expression is quantitative rather than qualitative. 7A putative pro‐inhibitory region on the surface of mammalian P450, possibly involved in intramolecular electron transport, has been identified, using a combination of directed anti‐peptide antibodies and sequence alignment based on secondary structure. 8Antibodies directed against defined regions of P450 enzymes are proving invaluable in exploring the regulation, specificity and function of these key enzymes.
Pharmacokinetics, pharmacodynamics, long‐term efficacy and safety of oral 1‐deamino‐8‐d‐arginine vasopressin in adult patients with central diabetes insipidus
Authors: LAM K. S. L. , WAT M. S. , CHOI K. L. , IP T. P. , PANG R. W. C. , KUMANA C. R. 
Published: October 2003

1The pharmacokinetics and pharmacodynamics of intranasal (IN) and oral 1‐deamino‐8‐d‐arginine vasopressin (DDAVP) were compared in 10 Chinese adults with central diabetes insipidus previously controlled on IN DDAVP. This was followed by comparison of the acute pharmacodynamics of commonly used oral preparations (containing 100, 200 and 400 μg per tablet) and a 1 year prospective evaluation of the long‐term safety and efficacy of oral DDAVP. 2Following 20 μg IN and 200 μg orally, respective plasma DDAVP concentrations peaked after 45.6±7.3 and 93.3±3.3 (mean±s.e.mean) min, reaching 24.1±4.7 and 15.1±3.2 pmol l−1 and respective terminal half‐lives were 2.2±0.1 and 2.0±0.1 h. Based on the area under the concentration‐time‐curve, the bioequivalent IN/oral ratio was 1:16. 3As judged by changes in urine flow rate and osmolality after IN or oral (100, 200 or 400 μg) DDAVP, antidiuretic activity increased rapidly during the second hour and peaked at 4 h. The antidiuresis duration and magnitude correlated with the oral dose (P<0.001 and <0.05 respectively), and was least following 100 μg (P<0.01 vs 200 or 400 μg). Increasing the dose from 200 to 400 μg did not increase maximal antidiuretic activity significantly, but there was a trend towards a longer duration of action (P=0.076). 4During the 1‐year prospective study with oral DDAVP 300–600 μg per day in two to three doses, stable and satisfactory antidiuresis (comparable with that on previous IN therapy) was maintained; tablets were well‐tolerated and no side‐effect warranted drug withdrawal. 5These findings suggest that the 100 and 200 μg preparations of oral DDAVP are adequate for the long‐term control of central diabetes insipidus in our population, and that the 400 μg preparation may have a role if the frequency of administration is to be reduced.
γ‐l‐glutamyl‐5‐hydroxy‐l‐tryptophan, but not γ‐l‐glutamyl‐l‐tryptophan, causes sodium retention in normal man
Authors: LI KAM WA T. C. , FREESTONE S. , SAMSON R. R. , JOHNSON N. R. , LEE M. R. 
Published: October 2003

1This randomized, placebo‐controlled, cross‐over study compared the relative effectiveness of γ‐l‐glutamyl‐5‐hydroxy‐l‐tryptophan (glu‐5‐HTP) and γ‐l‐glutamyl‐l‐tryptophan (glu‐TRP) in terms of their ability to act as substrates for renal 5‐hydroxytryptamine (5‐HT) synthesis and their actions on urinary sodium excretion. 2Urinary excretion of 5‐HT and sodium were determined before, during and after 1 h intravenous infusion of an equimolar amount (45 nmol kg−1 min−1) of glu‐5‐HTP or glu‐TRP or placebo in nine healthy male subjects. 3Cumulative urinary 5‐HT excretion over the 4 h after the start of glu‐5‐HTP infusion was 350‐fold greater than that after placebo, and this was associated with a reduction in the urinary excretion of sodium. 4In contrast, the urinary excretion values of 5‐HT and sodium after administration of glu‐TRP were not significantly different from those observed on the placebo day. 5The marked increase in urinary 5‐HT excretion and the retention of sodium after administration of glu‐5‐HTP have been demonstrated in previous studies and result from increased intrarenal generation of 5‐HT. The absence of a rise in urinary excretion of 5‐HT after glu‐TRP infusion suggests that there was no significant conversion of this glutamyl compound to 5‐HT within the kidney. As a result, there was no effect on urinary sodium excretion.
An investigation into variability in microvascular skin blood flow and the responses to transdermal delivery of acetylcholine at different sites in the forearm and hand
Authors: Gardner‐Medwin Janet M. , Taylor J. Y. , Macdonald I. A. , Powell R. J. 
Published: October 2003

Aims Transdermal iontophoresis in combination with laser Doppler fluxmetry (LDF) are useful techniques for examining dermal microcirculatory responses to different vasodilators. Differences in skin and microcirculation structure could influence the recorded baseline flux, and the observed vasodilatation. To examine this we compared baseline flux and the response of microvascular blood flow to a single vasodilator, acetylcholine, at sites in the forearm and hand.
Methods Baseline microcirculation flow was recorded by LDF in a temperature controlled laboratory. The change in flux with iontophoresis of identical doses of acetylcholine, 150 μA for 40 s, was recorded at 12 different sites in the forearm and hand in 10 female and 3 male subjects.
Results Baseline flux patterns and the vasodilatation to identical periods of iontophoresis of acetylcholine were site dependent. Palmar sites showed a higher baseline flux, but no vasodilatation to iontophoresis of acetylcholine. In contrast the volar forearm, dorsal hand and finger sites showed lower site‐dependent baseline flux, but did vasodilate.
Conclusions Patterns of baseline flux are specific to sites on the hand and forearm reflecting differences in underlying microvascular structure. The vasodilatation to transdermal delivery of acetylcholine is also site dependent, but differences in skin structure may be more important than the underlying microvasculature in determining the response.
Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers
Authors: Mordi M. N. , Mansor S. M. , Navaratnam V. , Wernsdorfer W. H. 
Published: October 2003

Aims To determine the pharmacokinetics of artemether (ARM) and its principal active metabolite, dihydroartemisinin (DHA) in healthy volunteers.
Methods Six healthy male Malaysian subjects were given a single oral dose of 200 mg artemether. Blood samples were collected to 72 h. Plasma concentrations of the two compounds were measured simultaneously by reversed‐phase h.p.l.c. with electrochemical detection in the reductive mode.
Results Mean (± s.d.) maximum concentrations of ARM, 310±153 μg l−1, were reached 1.88±0.21 h after drug intake. The mean elimination half‐life was 2.00±0.59 h, and the mean AUC 671±271 μg l−1 h. The mean C
max of DHA, 273±64 μg l−1, was observed at 1.92±0.13 h. The mean AUC of DHA was 753±233 μg h l−1. ARM and DHA were stable at ≤−20° C for at least 4 months in plasma samples.
Conclusions The relatively short half‐life of ARM may be one of the factors responsible for the poor radical cure rate of falciparum malaria with regimens employing daily dosing. In view of the rapid loss of DHA in plasma samples held at room temperature (26° C) it is recommended to store them at a temperature of ≤−20° C as early as possible after sample collection.
Concentrations and effects of zopiclone are greatly reduced by rifampicin
Authors: Villikka K. , Kivistö K. T. , Lamberg T. S. , Kantola T. , Neuvonen P. J. 
Published: October 2003

Aims  The effects of rifampicin on the pharmacokinetics and pharmacodynamics of zopiclone, a non‐benzodiazepine hypnotic, were studied. Methods  In a randomized, placebo‐controlled cross‐over study with two phases, eight young healthy volunteers took either 600 mg rifampicin or placebo once daily for 5 days. On the 6th day, 10 mg zopiclone was administered orally. Plasma zopiclone concentrations and effects of zopiclone were measured for 10 h. Results
The total area under the plasma zopiclone concentration‐time curve after rifampicin was 18.0% (95% CI 13.5–22.5%) of that after placebo (86.1±34.5 ng ml−1 h vs 473±114 ng ml−1 h (mean±s.d.); P<0.001). Rifampicin decreased the peak plasma concentration of zopiclone from 76.9±27.2 ng ml−1 to 22.5±6.0 ng ml−1 (P<0.001) and the half‐life from 3.8±0.6 h to 2.3±0.9 h (P<0.005). A significant (P<0.02) reduction in the effects of zopiclone was seen in three of the five psychomotor tests used (digit symbol substitution test, critical flicker fusion test and Maddox wing test) after rifampicin pretreatment. Conclusions  The strong interaction of rifampicin with zopiclone is due to enhanced metabolism of zopiclone. Zopiclone may show a reduced hypnotic effect when used concomitantly with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.
A comparative population pharmacokinetic analysis for methylprednisolone following multiple dosing of two prodrugs in patients with acute asthma
Authors: J Parker T. , Daley‐Yates P. T. , Wood S. A. 
Published: October 2003

Aims To conduct a randomized, parallel group comparison of the population pharmacokinetics of the two methylprednisolone (MP) prodrugs Promedrol (MP suleptanate) and Solu‐Medrol (MP succinate) in patients hospitalized with acute asthma.Methods Ninety volunteers were included in the pharmacokinetic analysis. Each volunteer received a dosage regimen of 40 mg (MP equivalents) i.v. 6 hourly for 48 h. The bio‐conversion and disposition of a 40 mg (MP equivalent) i.v. dose of either MP suleptanate or MP succinate to MP was modelled as a first order input, and a mono‐exponential elimination phase.Results Population modelling indicated that the only difference in MP pharmacokinetics between MP suleptanate and MP succinate was in the input rate constant (66.0 h−1vs 5.5 h−1 respectively). Based on individual Bayesian estimates, the exposure of patients to MP was marginally lower for MP suleptanate although the parameter estimates were not significantly different for half‐life (2.7 h vs 3.0 h), steady‐state AUC (2007.0 ng ml−1 h vs 2321.0 ng ml−1 h) and steady‐state Cmax (698.4 ng ml−1vs 647.8 ng ml−1 ) for MP suleptanate and MP succinate respectively.Conclusions It was concluded that for the multiple dosage regimen used in patients with acute asthma the systemic exposure to MP following dosing with MP suleptanate is similar to that arising from MP succinate. In addition the differences in the pharmacokinetics for the prodrugs resulted in only a small difference in the relative bioavailability of MP for MP suleptanate (0.94) compared with MP succinate.
Pharmacokinetics of β‐adrenoceptor blockers in obese and normal volunteers
Authors: Cheymol Georges , Poirier Jean‐Marie , Carrupt Pierre‐Alain , Testa Bernard , Weissenburger Jacques , Levron Jean‐Claude , Snoeck Eric 
Published: October 2003

Aims Obesity can modify the pharmacokinetics of lipophilic drugs. As β‐adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic β‐adrenoceptor blockers in obese and control subjects.Methods Nine obese (157±24% of ideal body weight (IBW) mean±s.d.) and nine non‐obese healthy volunteers (98±10% IBW), aged 32±9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic β‐adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of β‐adrenoceptor blockers were assessed.Results The pharmacokinetic data for the three drugs were qualitatively similar. There was a trend towards a greater total distribution volume (Vss ) in obese patients than in controls. However, Vss expressed per kg body weight was slightly smaller in obese patients. The relationship between Vss and lipophilicity of five β‐adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The Vss of the five drugs was positively and well‐correlated (r2=0.90; P<0.01) with their distribution coefficient at pH 7.4 (log D7.4 ), but not with their partition coefficients. The linear regression coefficients for lean and obese subjects were very similar.Conclusions Lipophilic β‐adrenoceptor blockers seem to diffuse less into adipose than into lean tissues. All electrical forms of the drugs (i.e. cations, neutral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects.Their tissue distribution in obese patients could be restricted by the sum of hydrophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.