bluuebunny/crossref_metadata_2025 huggingface dataset:
Involvement of CYP2D6 but not CYP2C19 in nicergoline metabolism in humans
Authors: BÖTTIGER Y. , DOSTERT P. , STROLIN BENEDETTI M. , BANI M. , FIORENTINI F. , CASATI M. , POGGESTI I. , ALM C. , ALVAN G. , BERTILSSON L.
Published: October 2003

1Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia.

2Nicergoline is rapidly hydrolysed to an alcohol derivative, 1‐methyl‐10‐α‐methoxy‐9,10‐dihydrolysergol (MMDL), which is further N‐demethylated to form 10‐α‐methoxy‐9,10‐dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by their diminished capacity to form the MDL metabolite. The aim of this study was to determine whether defective nicergoline metabolism is associated with the debrisoquine and/or the S‐mephenytoin hydroxylation polymorphisms.

3After a single, oral 30 mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, divided into three groups with respect to their debrisoquine and S‐mephenytoin hydroxylation phenotypes.

4The pharmacokinetic parameters of MMDL and MDL were similar in the ten subjects who were extensive metabolisers of debrisoquine (five of whom were poor metabolisers of S‐mephenytoin) (mean MMDL Cmax 59 nmol l−1 and AUC (0, th) 144 nmol l−1h, mean MDL Cmax 183 nmol l−1 and AUC 2627 nmol l−1h) but were markedly different from the five subjects who were poor metabolisers of debrisoquine (mean MMDL Cmax 356 nmol l−1 and AUC 10512 nmol l−1h, MDL concentrations below limit of quantitation).

5We conclude that the formation of MDL from MMDL in the metabolism of nicergoline is catalysed to a major extent by CYP2D6 and that the observed interindividual variation in the metabolic pattern of the drug is related to the debrisoquine hydroxylation polymorphism.
Characterization and validation of a pharmacokinetic model for controlled‐release oxycodone
Authors: MANDEMA JAAP W. , KAIKO ROBERT F. , OSHLACK BENJAMIN , REDER ROBERT F. , STANSKI DONALD R.
Published: October 2003

1Oxycodone is a strong opioid agonist that is currently available in immediate‐release (IR) formulations for the treatment of moderate to severe pain. Recently, controlled‐release (CR) oxycodone tablets were developed to provide the benefits of twice‐a‐day dosing to patients treated with oxycodone. The purpose of this investigation was to develop and validate a pharmacokinetic model for CR oxycodone tablets in comparison with IR oxycodone solution.

2Twenty‐four normal male volunteers were enrolled in a single‐dose, randomized, analytically blinded, two‐way crossover study designed to compare the pharmacokinetics of two 10 mg CR oxycodone tablets with 20 mg IR oxycodone oral solution. Pharmacokinetic models describing the oxycodone plasma concentration vs time profiles of CR tablets and IR solution were derived using NONMEM version IV. The predictive performance of the models was assessed by comparison of predicted oxycodone plasma concentrations with actual oxycodone plasma concentrations observed in a separate group of 21 volunteers who received repeated doses of IR and CR oxycodone for 4 days.

3The unit impulse disposition function of oxycodone was best described by a one‐compartment model. Absorption rate of the IR solution was best described by a mono‐exponential model with a lag time, whereas absorption rate of the CR tablet was best described using a bi‐exponential model. The absorption profile of the CR tablets was characterized by a rapid absorption component (t1/2abs=37 min) accounting for 38% of the available dose and a slow absorption phase (t1/2abs=6.2 h) accounting for 62% of the available dose. Two 10 mg tablets of oral CR oxycodone hydrochloride were 102.7% bioavailable relative to 20 mg of IR oxycodone hydrochloride oral solution. The population model derived after administration of a single dose accurately predicted both the mean and range of oxycodone concentrations observed during 4 days of repeated dosing. The mean prediction error was 2.7% with a coefficient of variation of 54%.

4The absorption characteristics of CR oxycodone tablets should allow effective plasma concentrations of oxycodone to be reached quickly and for effective concentrations to be maintained for a longer period after dosing compared with the IR oral solution. The CR dosage form has pharmacokinetic characteristics that permit 12 hourly dosing.
A novel mutant variant of the CYP2D6 gene (CYP2D617) common in a black African population: association with diminished debrisoquine hydroxylase activity
Authors: MASIMIREMBWA COLLEN , PERSSON IRENE , BERTILSSON LEIF , HASLER JULIA , INGELMAN‐SUNDBERG MAGNUS
Published: October 2003

1The debrisoquine hydroxylase (CYP2D6) is polymorphically distributed. Not only are there differences in the proportions of extensive metabolisers to poor metabolisers in various ethnic groups, but there are also pronounced variations in the metabolic capacity among those classified as extensive metabolisers.

2The mean debrisoquine metabolic ratio of Caucasian extensive metabolisers is lower than that for a number of African populations. In the present study, we have searched for novel CYP2D6 mutations to explain the diminished enzyme activity in African populations.

3Three Zimbabwean Shona subjects with EM phenotypes (metabolic ratios for debrisoquine of 0.4, 1.5 and 10.5 respectively) were selected and the open reading frame of the CYP2D6 gene of each was sequenced.

4The subject with metabolic ratio of 10.5 was found to be homozygous for an allele with a nucleotide exchange in exon 2, 1111C→T causing a 107Thr→Ile amino acid exchange in a conserved region of the enzyme. In addition, he was homozygous for the 2938C→T and 4268G→C mutations causing 296Arg→Ser and 486Ser→Thr amino acid substitution found in the CYP2D6*2 allele.

5Seventy‐six Zimbabwean Shona subjects were subsequently genotyped for the 1111C→T mutation and for the intron 1 gene conversion present in the CYP2D6*2 gene. The 1111C→T mutation was found at an allele frequency of 34% and was only present in alleles carrying the gene conversion in intron 1 indicative for the CYP2D6*2 gene.

6This allele (CYP2D6*17), containing the 1111C→T, 2938C→T and 4268G→C mutations, was found to be strongly associated with lower capacity for debrisoquine hydroxylation. We therefore postulate that the CYP2D6*17 allele might contribute to the molecular basis of the previously established diminished debrisoquine hydroxylase activity in African Bantu populations.
Effect of food on the absorption of frusemide and bumetanide in man
Authors: McCRINDLE J. L. , LI KAM WA T. C. , BARRON W. , PRESCOTT L. F.
Published: October 2003

1The influence of food on the absorption of frusemide and bumetanide was compared in two separate randomized crossover studies. 2On three separate occasions frusemide 40 mg was administered to eight healthy male volunteers intravenously, orally in the fasting state and orally after a standard breakfast. Blood and urine were collected at intervals over 8 h and urine alone for a further 16 h. The study was then repeated in nine healthy volunteers using intravenous and oral bumetanide 2 mg. 3Breakfast significantly reduced the peak plasma concentration of frusemide from 2.35±0.49 to 0.51±0.19 mg l−1 (95% confidence intervals (95% CI)=1.39 to 2.28 mg l−1) and delayed the time to peak concentration from 0.69±0.21 to 1.91±0.93 h (95% CI=0.41 to 2.03 h). The oral bioavailability of frusemide was significantly reduced by approximately 30% (75.6±10.6 to 43.2±16.8%; 95% CI=13.5 to 51.4%). 4With bumetanide, the meal also significantly reduced the peak concentration from 0.097±0.015 to 0.036±0.012 mg l−1 (95% CI=0.048 to 0.073 mg l−1) and delayed the time to peak from 0.53±0.08 to 1.36±0.72 h (95% CI=0.23 to 1.44 h). However, food had no statistically significant effect on the bioavailability and urinary recovery of bumetanide. 5In this study, the absorption of bumetanide was affected less than frusemide by food.
Pharmacokinetics of fluconazole in people with HIV infection: a population analysis
Authors: McLACHLAN A.J. , TETT S.E.
Published: October 2003

1 The population pharmacokinetics of fluconazole have been investigated in 113 male subjects with HIV infection and AIDS. Plasma concentration–time data (between 1 and 17 observations per dose) were collected from individuals as part of a pharmacokinetic investigation (13 subjects) or during routine fluconazole therapy (100 subjects) for the treatment or prophylaxis of fungal infection.

2 A one‐compartment pharmacokinetic model was used to describe the disposition of fluconazole after oral and intravenous infusion doses. Population pharmacokinetic parameters were generated using the NONMEM and P‐PHARM computer programs.

3 The population estimates (calculated using NONMEM) of fluconazole clearance and volume of distribution were 0.78 l h−1 and 47.6 l, respectively. The intersubject variability for these parameters was 41% and 8%, respectively. The model‐dependent estimate of the extent of absorption was 0.99 with an intersubject variability of 6%. Mean population estimates generated by NONMEM and P‐PHARM were in close agreement.

4 Examination of the relationship between patient covariates and pharmacokinetic parameters indicated that intersubject variability in fluconazole clearance could in part be explained by the severity of disease (as indicated by CD4+T‐lymphocyte count) and renal function (indicated by estimated creatinine clearance). Other pharmacokinetic parameters were unaffected by these covariates.

5 Fluconazole clearance (estimated using NONMEM) in subjects with a CD4+T‐lymphocyte count less than and greater than 200 cells mm3 was 0.73 l h−1 (95% CI ; 0.64–0.82 l h−1) and 0.99 l h−1 (95% CI ; 0.86–1.12 l h−1), respectively. The regression model for fluconazole clearance that accounted for changes in renal function and disease severity was CL (l h−1)=0.25 (33%)+0.0057 (32%)×CLcr (in ml min−1)+0.00068 (10%)×CD4 cell count (in cells mm−3) where intersubject variability (expressed as %CV) is shown in brackets.

6 Based on pharmacokinetic considerations a reduction in the dose of fluconazole would appear to be warranted in people with HIV infection who are seriously ill or who have compromised renal function. However, the emergence of resistance to fluconazole must also be considered when thinking of dosage adjustments.
Pharmacodynamics of oxypurinol after administration of allopurinol to healthy subjects
Authors: GRAHAM S. , DAY R. O. , WONG H. , McLACHLAN A. J. , BERGENDAL L. , MINERS J. O. , BIRKETT D. J.
Published: October 2003

1 Eight healthy subjects received 50, 100, 300, 600 and 900 mg allopurinol daily for 1 week each, in random order with 1 week separating each treatment period. The pre‐dose plasma concentration of oxypurinol, the extent of inhibition of xanthine oxidase, plasma urate concentration and urine urate excretion rate were assessed on the last 2 days of each treatment week.

2 The ratio of 1‐methyluric acid (1MU) over 1‐methylxanthine (1MX) in the urine, following a dose of 50 mg 1MX infused intravenously over 20 min, was used to measure the inhibition of xanthine oxidase.

3 The steady‐state plasma concentration of oxypurinol increased linearly with increasing dose of allopurinol between 50 mg to 600 mg day−1, with a weak indication of saturation at the higher 900 mg day−1 dose rate.

4 The relationships between plasma oxypurinol concentration and xanthine oxidase inhibition (1MU/1MX ratio), plasma urate concentration and urine urate excretion rate were fitted to an inhibition sigmoid Emax model and the C50 values for oxypurinol were 26.38±4.87, (mean±s.d.) 36.58±8.36 and 24.61±9.08 μm, respectively.

5 1MU/1MX ratio appeared to be a reliable index of xanthine oxidase activity in vivo as the C50 for oxypurinol observed for 1MU/1MX ratio, plasma urate concentration and urine urate excretion rate were similar.

6 The concentration of oxypurinol required for inhibition of xanthine oxidase, as indicated by C50, was lower than those often observed in clinical practice.
Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism
Authors: VARHE ANU , OLKKOLA KLAUS T. , NEUVONEN PERTTI J
Published: October 2003

1 The interaction between triazolam and two antifungal agents, fluconazole and terbinafine, was investigated in a double‐blind, randomized crossover study of three phases.

2 Twelve healthy young volunteers received 100 mg fluconazole, 250 mg terbinafine or placebo orally once a day for 4 days. On day 4 they took a single 0.25 mg dose of triazolam. Plasma samples were collected and pharmacodynamic effects were measured up to 17 h after the intake of triazolam.

3 Fluconazole increased the area under the triazolam concentration time‐curve more than twofold (P<0.001) and prolonged the elimination half‐life of triazolam nearly twofold (P<0.001). The peak concentration of triazolam was also increased significantly (P<0.05) by fluconazole.

4 During the fluconazole phase pharmacodynamic effects of triazolam (e.g. digit symbol substitution test, body sway and drowsiness) were enhanced significantly (P<0.05) when compared with the placebo phase.

5 Terbinafine did not change significantly the pharmacokinetics or pharmacodynamics of triazolam.

6 Care should be taken when triazolam is prescribed to patients using fluconazole. Although the interaction is not as strong as that of triazolam with ketoconazole or itraconazole, it is clinically significant. Triazolam and probably other drugs metabolized by CYP3A4 can be used in normal doses with terbinafine.
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).
All‐trans‐retinoic acid 4‐hydroxylation in human liver microsomes: in vitro modulation by therapeuticretinoids
Authors: NADIN LOUISE , MURRAY MICHAEL
Published: October 2003

All‐trans retinoic acid (ATRA) induces remission in patients with acute promyelocytic leukaemia. Other retinoids, including 9‐cis‐ and 13‐cis‐retinoic acid (9‐cis‐ and 13‐cis‐RA), are now being evaluated for their therapeutic potential. The elimination of ATRA is partially dependent on cytochrome P450 (P450)‐mediated 4‐hydroxylation, but the interaction of other retinoids with P450 has not yet been assessed. In the present study 9‐cis‐ and 13‐cis‐RAs, as well as all‐trans‐retinol and three isomeric retinals were found to inhibit ATRA 4‐hydroxylation in human hepatic microsomes, but the arotinoids acitretin and etretinate were not inhibitors. 9‐cis‐ and 13‐cis‐RA were competitive inhibitors of ATRA 4‐hydroxylation (Ki:Km ratios 3.5±0.8 and 6.3±0.5, respectively) suggesting that these retinoids are alternate, but inferior, substrates for the P450 enzyme(s) that mediate the activity. The biotransformation of therapeutic retinoids containing the β‐ionone ring system is likely to involve the microsomal ATRA 4‐hydroxylase P450.
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.
Lipoproteins and cardiovascular reactivity
Authors: Howes Laurence G. , Abbott Denise , Straznicky Nora E.
Published: October 2003

The observation that relatively short periods of cholesterol lowering therapy can reduce the incidence of coronary artery disease events has prompted interest in the short term effects of lipoproteins on cardiovascular responsiveness. Numerous studies in animals and humans have demonstrated that oxidized LDL‐cholesterol can impair endothelial dependent vasodilation in coronary arteries and peripheral resistance vessels. Reduction of plasma LDL‐cholesterol levels in hypercholesterolaemic patients improves nitric oxide mediated vasodilator responses in the coronary and peripheral circulation. LDL‐cholesterol also potentiates responses to vasoconstrictors such as noradrenaline and endothelin‐1 in the absence of endothelium, possibly by enhancing calcium influx into vascular smooth muscle cells. Pharmacological reduction of plasma LDL‐cholesterol levels has been shown to reduce blood pressure responses to intravenous infusions of pressor hormones and to stress. However, the relative contribution of changes in endothelial dependent vasodilation and vasoconstrictor or inotropic responses remains to be established. Short term changes in LDL‐cholesterol produce changes in cardiovascular responsiveness that may influence the development of ischaemic events.
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.
Picumeterol: dissociation of improvement in lung function and reduction of airways hyperresponsiveness in asthmatics
Authors: Weersink E. J. M. , Postma D. S. , Koëter G. H. , Man Y. , Nials A. T. , Coleman R. A.
Published: October 2003

Aims The new potent and selective β2‐adrenoceptor agonist, GR 114297A (picumeterol) is the R‐enantiomer of the racemic form, GR 63411B. Picumeterol has been shown to produce long‐lasting relaxation of airways smooth muscle both in vitro and in vivo. We assessed the intrinsic activity of picumeterol by increasing intracellular levels of c‐AMP and compared this with isoprenaline and salbutamol.

Methods In human atopic asthmatics, we have investigated the duration of action and efficacy of picumeterol and GR 63411B with regard to improvement in resting lung function (i.e. FEV1 ) and airways responsiveness (i.e. PC20 ) to methacholine (MCh). The study design consists of two clinical parts each for one drug. Different asthmatics participated in the two studies, seven in the first part and eight in the second part. In human bronchial smooth muscle cells in vitro, we have investigated the intrinsic activity of picumeterol in increasing intracellular levels of cyclic AMP and compared it with isoprenaline and salbutamol.

Results In vivo, both drugs caused bronchodilatation with similar potency, but, their effects were short‐lasting. Despite their bronchodilator activity, neither drug improved PC20, when compared with placebo. In vitro, picumeterol was found have intrinsic activity lower than the other β2‐adrenoceptor agonists tested.

Conclusions In the clinical studies, the bronchodilator potencies of picumeterol and GR 63411B were similar. However, both drugs were short‐acting, which is at odds with their activity in vitro. Our data suggest that these compounds display dissociation between bronchodilator activity and protection against MCh‐induced bronchoconstriction. These findings may be explained by low intrinsic activity and need further conformation.
Comparison of nitroprusside and nitroglycerin in inhibition of angiotensin II and other vasoconstrictor‐mediated contraction in human coronary bypass conduits
Authors: Guo‐Wei He  , Yang Cheng‐Qin
Published: October 2003

Aims To compare the effect of nitroprusside (SNP) and nitroglycerin (NTG) on angiotensin II (ANGII), endothelin‐1 (ET‐1), and &agr;1‐adrenoceptor (phenylephrine, PE)‐mediated contraction in internal mammary artery (IMA).

Methods Human IMA segments (n=120) taken from 37 patients were studied. Concentration‐relaxation curves for SNP and NTG were established in IMA precontracted with these vasoconstrictors. Concentration‐contraction curves were also constructed in IMA rings incubated with SNP and NTG (0.1 and 1 &mgr;m ) for 10 min.

Results Both SNP and NTG caused full relaxation with similar EC50 s except NTG was four‐fold more potent than SNP in PE‐induced contraction (−7.92±0.06 vs−7.32±0.2 log m, mean±s.e. mean, P<0.01; 95% confidence interval for the difference of the means: 0.19, 1.01 log m ). Pretreatment with SNP (0.1 and 1 &mgr;m ) significantly depressed the contraction by ANGII from 56.6±7.7% (of 100 mm K+‐contraction) to 18.3±8.6% and 3.9±2.1% (P=0.0001). In four rings treated with SNP, the contraction to ANGII was abolished whereas NTG did not depress ANGII‐mediated contraction. Pretreatment with SNP (1 &mgr;m ), but not NTG, significantly depressed the magnitude of the PE‐induced contraction from 4.7±1.2 to 1.7±0.4 g (P<0.05). Treatment with both SNP and NTG significantly increased the EC50 (−5.09±0.17 log m, P=0.0007 for SNP and −5.40±0.06 log M, P=0.02 for NTG). Pretreatment with SNP did not significantly change either the magnitude or the EC50 of the ET‐1‐induced contraction.

Conclusions SNP may be advantageous compared with NTG in preventing coronary arterial graft contraction. However, once grafts have constricted to ANGII, &agr;1‐adrenoceptor agonists, and ET‐1, NTG may be only marginally advantageous.
Lack of correlation between ABL‐BCR expression and response to interferon‐α in chronic myeloid leukaemia
Authors: Melo Junia V. , Hochhaus Andreas , Yan Xiu‐Hua , Goldman John M.
Published: October 2003

Interferon‐α (IFN‐α) is useful in the treatment of Philadelphia (Ph)‐positive chronic myeloid leukaemia (CML). There is, however, a marked heterogeneity among CML patients in relation to their response to IFN‐α treatment, the reasons for which are unknown. Since the reciprocal ABL‐BCR gene is transcriptionally active in only a proportion of CML patients, it has been suggested that response to IFN‐α may correlate with ABL‐BCR expression. In the present study we have tested 209 Ph‐positive CML patients for expression of ABL‐BCR, BCR‐ABL and the normal BCR and ABL genes by reverse transcriptase/polymerase chain reaction (RT/PCR). Whereas BCR‐ABL, BCR and ABL transcripts were detected in all the patients, ABL‐BCR expression was observed in 59% of the cases. A group of 105 patients within this series was treated with IFN‐α: 33% achieved a complete or major cytogenetic response (<35% Ph‐positive metaphases) and the remaining 67% showed minimal or no response to IFN‐α. The proportions of patients who were ABL‐BCR positive (63%) and ABL‐BCR negative (37%) were the same for good responders and poor responders, suggesting that there is no correlation between ABL‐BCR expression and cytogenetic response to IFN‐α in CML.
Effects of high‐dose granulocyte colony‐stimulating factor on neutrophil functions
Authors: Yasui Kozo , Tsuno Takahisa , Miyabayashi Mari , Yamazaki Munehiro , Komiyama Atsushi
Published: October 2003

We evaluated the effects of high‐dose recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) therapy on N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP)‐induced chemotaxis and superoxide (O −2) production in neutrophils from four patients with aplastic anaemia. The FMLP‐induced chemotaxis and O −2 production in the neutrophils of all four patients were normal before the rhG‐CSF treatment. After the administration of high‐dose rhG‐CSF, chemotaxis in agarose was decreased, adherence and O −2 production were enhanced in all the patients. An excessive increase of neutrophils with augmented adhesiveness and oxygen radical production may be harmful. Care should be taken in regard to neutrophil toxicity when high‐dose G‐CSF is used clinically.
Reverse transcriptase/polymerase chain reaction follow‐up and minimal residual disease detection in t(1;19)‐positive acute lymphoblastic leukaemia
Authors: Privitera Enrica , Rivolta Anna , Ronchetti Domenica , Mosna Giuliana , Giudici Giovanni , Biondi Andrea
Published: October 2003

The t(1;19) is the most frequent recurring chromosomal translocation in childhood acute lymphoblastic leukaemia (ALL). In most cases typical chimaeric E2A‐PBX1 transcripts are expressed as a consequence of this rearrangement, allowing the molecular detection of the t(1;19) at the RNA level. This translocation has been associated with a poor clinical outcome, although intensified chemotherapy has been reported to nullify its adverse prognostic impact. We therefore used reverse transcriptase/polymerase chain reaction (RT‐PCR) to detect residual leukaemic cells at successive times during treatment and to monitor the response to chemotherapy in six t(1;19)‐positive ALL paediatric patients. Five of these patients rapidly achieved molecular remission and no evidence of minimal residual disease (MRD) was found in the remission bone marrows beyond the third month of treatment. One patient still displayed residual leukaemic cells at the end of therapy, although she has been in continuous complete clinical remission (CCR) for 84 months. However, this patient is peculiar in our series in that two different types of chimaeric E2A‐PBX1 transcripts were expressed in her leukaemic cells, only one being detectable in remission.
Autoantibody against a 58 kD molecule in a patient with neutropenia and NK cell deficiency
Authors: Witte T. , Bode F. M. , Hammer M. , Deicher H. , Schmidt R. E.
Published: October 2003

A patient with Evans' syndrome is described who developed intermittently an immunocytopenia consisting of autoimmune neutropenia and natural killer (NK) cell deficiency. During this time an autoantibody binding to a 58 kD antigen expressed on granulocytes, activated NK cells and Epstein‐Barr virus (EBV) transformed B cells was present. Incubation of activated NK cells and NK cell clones with the autoantibody leads to a significant inhibition of NK activity. Therefore the autoantibody may detect a functionally important activation molecule.