bluuebunny/crossref_metadata_2025 huggingface dataset:
Ursodeoxycholic acid and endothelial‐dependent, nitric oxide‐independent vasodilatation of forearm resistance arteries in patients with coronary heart disease
Authors: Sinisalo Juha , Vanhanen Hannu , Pajunen Pia , Vapaatalo Heikki , Nieminen Markku S.
Published: March 2003

Aims Ursodeoxycholic acid (UDCA) has cholesterol lowering and anti‐inflammatory effects and bile acids are reported to exert vasodilator effects; all of these properties might be considered desirable in a drug used in the treatment of patients with coronary heart disease. We investigated a hypothesis that UDCA may dilate arteries and the mechanism of action.

Methods We evaluated effects of a 6‐week treatment with UDCA in 11 coronary heart disease patients on endothelium‐dependent (acetylcholine‐induced) and ‐independent (nitroprusside‐induced) vasodilatations in forearm vasculature by strain‐gauge plethysmography. Healthy individuals (n=14) served as baseline controls.

Results The percentage increase by acetylcholine in the flow of the infused arm relative to the non‐infused arm of coronary heart disease patients during the trial remained unaltered, but vasodilatation to NG‐monomethyl‐l‐arginine+acetylcholine was improved by 161±27% with UDCA vs 83±22% with placebo (mean difference 91% [95% CI 35%, 147%], P=0.016).

Conclusions Six weeks’ UDCA therapy improved endothelium‐dependent nitric oxide‐independent vasodilatation, which might maintain arterial flow in coronary heart disease patients under conditions of impaired nitric oxide production.
Serum concentrations of tramadol enantiomers during patient‐controlled analgesia
Authors: Grond Stefan , Meuser Thomas , Uragg Heinz , Stahlberg Hans J. , Lehmann Klaus A.
Published: March 2003

Aims
 Tramadol, a centrally acting analgesic, is used as a racemate containing 50% of a (+)‐ and 50% of a (−)‐enantiomer. This paper presents the pharmacokinetic results of postoperative patient‐controlled analgesia using (+)‐tramadol, (−)‐tramadol or the racemate.

Methods
 Ninety‐eight patients recovering from major gynaecological surgery were treated in a randomised, double‐blind study with (+)‐tramadol, (−)‐tramadol or the racemate. Following an i.v. bolus up to a maximum of 200 mg, patient‐controlled analgesia with demand doses of 20 mg was made available for 24 h. Prior to each demand, the serum concentrations of the enantiomers of tramadol and its metabolite M1 were measured in 92 patients.

Results
 The mean concentrations of tramadol during the postsurgery phase were 470±323 ng ml−1, 590±410 ng ml−1 and 771±451 ng ml−1 in the (+)‐, racemate‐ and (−)‐group, respectively ((+) vs (−), P<0.05); the mean concentrations of the metabolite M1 were 57±18 ng ml−1, 84±34 ng ml−1 and 96±41 ng ml−1 in the (+)‐, racemate‐ and (−)‐group, respectively ((+) vs (−) and (+) vs racemate, P<0.05). The mean concentrations of (+)‐tramadol and (+)‐M1 were lower in the racemate‐ than in the (+)‐group (P<0.05), those of (−)‐tramadol and (−)‐M1 were lower in the racemate than in the (−)‐group (P<0.05). In the racemate group, the mean serum concentrations of (+)‐tramadol were higher than those of (−)‐tramadol (P<0.05), whereas the mean serum concentrations of (−)‐M1 were higher than those of (+)‐M1 (P<0.05).

Conclusions
 The therapeutic serum concentration of tramadol and M1 showed a great variability. The lowest mean concentrations were measured in the (+)‐group and the highest in (−)‐group. This is in agreement with the clinical finding that (+)‐tramadol is a more potent analgesic than (−)‐tramadol.
A double‐blind, placebo‐controlled investigation of the effects of fexofenadine, loratadine and promethazine on cognitive and psychomotor function
Authors: Hindmarch I. , Shamsi Z. , Stanley N. , Fairweather D. B.
Published: March 2003

Aims
 To assess whether fexofenadine in a range of doses from 80 to 180 mg has any disruptive effects on aspects of psychomotor and cognitive function in comparison with placebo, loratadine and promethazine, an antihistamine known to produce psychomotor and cognitive impairment.

Methods
 Twenty‐four healthy volunteers received fexofenadine 80 mg, 120 mg and 180 mg, loratadine 10 mg, promethazine 30 mg (as a positive internal control) and placebo in a six‐way crossover, double‐blind study. Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1.5, 3, 6, 9, 12 and 24 h post dose. The test battery included critical flicker fusion (CFF), choice reaction time (CRT) and assessment of subjective sedation (LARS). Overall levels of activity were monitored by means of wrist mounted actigraphs throughout each of the 24 h experimental periods.

Results
 Fexofenadine at all doses tested was not statistically different from placebo in any of the tests used and loratadine did not cause any significant impairment of cognitive function. Significant impairments were found following promethazine. Promethazine caused a significant reduction in CFF threshold and this effect was evident up to 12 h post dose (P<0.05). There was a significant increase in recognition reaction time at 3 and 6 h post promethazine administration, and the drug caused a significant (P<0.002) increase in the percentage of ‘sleep‐like’ activity from actigraph records during the daytime.

Conclusions
 Fexofenadine at doses up to 180 mg appears free from disruptive effects on aspects of psychomotor and cognitive function in a study where the psychometric assessments have been shown to be sensitive to impairment, as evidenced by the effects of the verum control promethazine 30 mg.
Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency
Authors: Greenbaum R. , Zucchelli P. , Caspi A. , Nouriel H. , Paz R. , Sclarovsky S. , O'Grady P. , Yee K.‐F. , Liao W.‐C. , Mangold B.
Published: March 2003

Aims To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril.

Methods Patients with congestive heart failure (CHF, NYHA Class II–IV) and chronic renal insufficiency (creatinine clearance ≤30 ml min−1 ) were randomized to receive fosinopril, enalapril or lisinopril in two parallel‐group studies. In the first study 24 patients were treated with 10 mg fosinopril (n=12 patients) or 2.5 mg enalapril (n=12) every morning for 10 consecutive days. In the second study 31 patients were treated with 10 mg fosinopril (n=16 patients) or 5 mg lisinopril (n=15) every morning for 10 consecutive days. Samples of blood were collected for determination of pharmacokinetic parameters. The area under the curve (AUC) between the first and last days of treatment and the accumulation index (AI) were the primary outcome measures.

Results All three angiotensin converting enzyme (ACE) inhibitors exhibited a significant increase in AUC between the first and last days of treatment in both studies. The difference between the AI for fosinoprilat (1.41) and enalaprilat (1.96) was statistically significant (95% CI: 1.05, 1.84). Similarly, the difference between the AI for fosinoprilat (1.21) and lisinopril (2.76) was statistically significant (95% CI: 1.85, 2.69). All three ACE inhibitors completely inhibited serum ACE for 24 h. All treatments were well tolerated.

Conclusions Fosinoprilat exhibits significantly less accumulation than enalaprilat or lisinopril in patients with CHF and renal insufficiency, most probably because fosinoprilat is eliminated by both the kidney and liver, and increased hepatic elimination can compensate for reduced renal clearance in patients with kidney dysfunction.
Can lung deposition data act as a surrogate for the clinical response to inhaled asthma drugs?
Authors: Newman Stephen P.
Published: March 2003

Studies involving the direct measurement of clinical response to inhaled asthma drugs, especially inhaled corticosteroids, may be very difficult to conduct. However, the deposition of drug in the lungs may be considered as a measure of local bioavailability, and may be quantified by radionuclide imaging techniques, or for some drugs by pharmacokinetic methods. This paper reviews evidence for considering lung deposition data as a surrogate for the clinical response to inhaled asthma drugs, based mainly upon a series of case histories. The appropriate use of lung deposition data in regulatory packages, especially to document the equivalence or comparability of two products, offers the possibility of significant time saving in the drug development process, and hence a faster drug development programme for inhaled asthma products.
Effects of sibutramine alone and with alcohol on cognitive function in healthy volunteers
Authors: Wesnes K. A. , Garratt C. , Wickens M. , Gudgeon A. , Oliver S.
Published: March 2003

Aims To investigate the effects of sibutramine in combination with alcohol in a double‐blind, randomised, placebo‐controlled, four‐way crossover study in 20 healthy volunteers.

Methods On each study day each volunteer received either: sibutramine 20 mg+0.5 g kg−1 alcohol; sibutramine 20 mg+placebo alcohol; placebo capsules+0.5 g kg−1 alcohol; or placebo capsules+placebo alcohol. Alcohol was administered 2 h following ingestion of the study capsules. During each study day, assessments of cognitive performance were made prior to dosing, and at 3, 4.5, 6 and 10 h post dosing. Blood alcohol concentration was estimated using a breath alcometer immediately prior to each cognitive performance test session. Each study day was followed by a minimum 7 day washout period.

Results Alcohol was found to produce statistically significant impairments in tests of attention (maximum impairment to speed of digit vigilance=49 ms) and episodic memory (maximum impairment to speed of word recognition=74 ms). Alcohol also increased body sway (maximum increase 17.4 units) and lowered self rated alertness (maximum decrease 13.6 mm). These effects were produced by an inferred blood alcohol level of 53.2 mg dl−1. Sibutramine was not found to potentiate any of the effects of alcohol. There was a small, yet statistically significant, interaction effect observed on the sensitivity index of the picture recognition task. In this test, the combined effects of sibutramine and alcohol were smaller than the impairments produced by alcohol alone. Sibutramine, when dosed alone, was associated with improved performance on several tasks. Sibutramine improved attention (mean speed of digit vigilance improved by 21 ms), picture recognition speed (improvement at 3=81) and motor control (tracking error at 3 h reduced by 1.58 mm). Also sibutramine improved postural stability (reducing body sway at 3 h by 14.2 units). Adverse events reported were unremarkable and consistent with the known pharmacology of sibutramine and alcohol.

Conclusions There was little evidence of a clinically relevant interaction of sibutramine with the impairment of cognitive function produced by alcohol in healthy volunteers. The single statistically significant interaction indicated a reduction, rather than a worsening, of alcohol‐induced impairment when sibutramine is taken concomitantly. Sibutramine when administered alone is associated with improved performance on several tasks.
Epidemiology of drug exposure and adverse drug reactions in two Swiss departments of internal medicine
Authors: Fattinger Karin , Roos Malgorzata , Vergères Patrice , Holenstein Clemens , Kind Brigitt , Masche Urspeter , Stocker David N. , Braunschweig Suzanne , Kullak‐Ublick Gerd A. , Galeazzi Renato L. , Follath Ferenc , Gasser Theo , Meier Peter J.
Published: March 2003

Aims To explore drug exposure, frequency of adverse drug reactions (ADRs), types of ADRs, predisposing risk factors and ADR‐related excess hospital stay in medical inpatients.

Methods Structured data regarding patient characteristics, ‘events’ (symptoms, laboratory results), diagnoses (ICD10) and drug therapy were collected using a computer‐supported data entry system and an interface for data retrieval from electronic patient records. ADR data were collected by ‘event monitoring’ to minimize possible bias by the drug monitor. The causality of each event was assessed in relation to disease(s) and drug therapy.

Results The analysis included 4331 (100%) hospitalizations. The median observation period was 8 days. The median number of different drugs administered per patient and day was 6 and varied between 4 (Q1 ) and 9 (Q3 ) different drugs in 50% of all hospital days. In 41% of all hospitalizations at least one disease‐unrelated event could be possibly attributed to drug therapy. Clinically relevant ADRs occurred in 11% of all hospitalizations. In 3.3% of all hospitalizations ADRs were the cause of hospital admission. The incidence of possibly ADR‐related deaths was 1.4. Factors predisposing for clinically relevant ADRs were female gender and polypharmacy. ADR‐related excess hospital stay accounted for 8.6% of hospital days.

Conclusions These data demonstrate the feasibility of the developed ‘event monitoring’ system for quantitative analysis of ADRs in medical inpatients. With increasing numbers of recorded patients the pharmacoepidemiological database provides a valuable tool to study specific questions regarding drug efficacy and safety in hospitalized patients.
Ziprasidone and the pharmacokinetics of a combined oral contraceptive
Authors: Muirhead G. J. , Harness J. , Holt P. R. , Oliver S. , Anziano R. J.
Published: March 2003

Aims  To determine whether multiple doses of ziprasidone alter the steady‐state pharmacokinetics of the component steroids, ethinyloestradiol and levonorgestrel, of an oral contraceptive; to evaluate the tolerability of a co‐administered combined oral contraceptive and ziprasidone; and to compare plasma concentrations of prolactin in subjects taking a combined oral contraceptive with placebo or ziprasidone.

Methods  Nineteen women taking a combined oral contraceptive (ethinyloestradiol 30 µg day− 1 and levonorgestrel 150 µg day− 1) were enrolled into a double‐blind, placebo‐controlled, two‐way crossover study. They received ziprasidone 40 mg day− 1 in two divided daily doses or placebo for 8 days (days 8–15) in one of two 21 day treatment periods separated by a 7 day washout period. Venous blood samples were collected immediately before and up to 24 h after the morning dose of oral contraceptive and ziprasidone or placebo on day 15 of each 21 day treatment period. These were assayed for ethinyloestradiol and levonorgestrel and the resulting data used to derive pharmacokinetic data for these steroids. Additional samples were collected immediately before and 4 h after the morning dose of oral contraceptive and ziprasidone or placebo on day 15 of each 21 day treatment period for prolactin assay. All observed and volunteered adverse events were recorded throughout the study.

Results  The mean AUC(0,24 h), Cmax and tmax for ethinyloestradiol and the mean AUC(0,24 h) and Cmax for levonorgestrel during ziprasidone co‐administration were not statistically significantly different from corresponding values occurring during placebo co‐administration. The tmax for levonorgestrel was approximately 0.5 h longer. Concomitant therapy with a combined oral contraceptive and ziprasidone did not result in adverse events not previously seen with either preparation alone.

Conclusions  The findings of this study suggest that, based on pharmacokinetic and tolerability data, ziprasidone may be co‐administered with ethinyloestradiol and levonorgestrel without loss of contraceptive efficacy or increased risk of adverse events.
The effects of ketoconazole on ziprasidone pharmacokinetics —a placebo‐controlled crossover study in healthy volunteers
Authors: Miceli J. J. , Smith M. , Robarge L. , Morse T. , Laurent A.
Published: March 2003

Aims  To assess the effects of multiple oral doses of ketoconazole on the single‐dose pharmacokinetics of oral ziprasidone HCl.

Methods  This was a 14‐day, open‐label, randomized, crossover study in 14 healthy subjects aged 18–31 years. Group 1 received oral ketoconazole 400 mg once daily for 6 days, followed by a 2 day wash‐out period and 6 days of placebo administration. Group 2 received placebo followed by ketoconazole. Single oral doses of ziprasidone HCl 40 mg were administered on days 5 and 13 in both groups. Ziprasidone pharmacokinetic parameters were compared between placebo and ketoconazole administration periods.

Results  Co‐administration of ziprasidone with ketoconazole was associated with a modest increase in ziprasidone exposure; mean ziprasidone AUC(0,∞) increased by 33%, from 899 ng ml− 1 h with placebo to 1199 ng ml− 1 h with ketoconazole. Mean Cmax increased by 34%, from 89 ng ml− 1 to 119 ng ml− 1, respectively. The treatment effect on both of these parameters was statistically significant (P< 0.02). Most adverse events were of mild intensity. There were no serious adverse events, laboratory abnormalities, abnormal ECGs, or clinically significant alterations in vital signs throughout the study.

Conclusions  The concurrent administration of ketoconazole and ziprasidone led to modest, statistically significant increases in ziprasidone exposure, although the changes seen were not considered clinically relevant. This suggests that other inhibitors of CYP3A4 are unlikely to significantly affect the pharmacokinetics of ziprasidone.
The effect of carbamazepine on the steady‐state pharmacokinetics of ziprasidone in healthy volunteers
Authors: Miceli J. J. , Anziano R. J. , Robarge L. , Hansen R. A. , Laurent A.
Published: March 2003

Aims  To evaluate the effect of steady‐state carbamazepine administration on the steady‐state pharmacokinetics of ziprasidone in healthy young adults, in an open, randomised, parallel‐group study.

Methods  Twenty‐five subjects were randomized to one of two treatment groups. Group 1 received 20 mg ziprasidone twice daily on days 1 and 2, and a single dose on day 3. A single 100 mg dose of carbamazepine was given once daily on days 5 and 6 and twice daily on days 7 and 8, followed by 200 mg twice daily until day 28 and on the morning only on day 29. Ziprasidone 20 mg was also administered twice daily on days 26 and 27 and in the morning only on day 28. Group 2 received the same treatment regimen with carbamazepine replaced by placebo. Pharmacokinetic data were obtained on days 3 and 28.

Results  Nine subjects in group 1 and 10 in group 2 completed all three treatment periods (ziprasidone, carbamazepine or placebo; and ziprasidone plus carbamazepine or placebo). Carbamazepine administration to group 1 was associated with modest reductions in ziprasidone exposure, with mean decreases in ziprasidone AUC(0,12 h) and Cmax values of 36% and 27%, respectively, on day 28 compared with day 3 (P<0.03). The mean differences between day 28 and day 3 ziprasidone AUC(0,12 h) and Cmax values were also statistically significantly greater in the carbamazepine group than in the placebo group. The mean half‐life of ziprasidone decreased by 1 h from day 3 to day 28 in the subjects receiving carbamazepine, compared with virtually no change in the placebo group. All adverse events were mild or moderate in severity and there were no serious adverse events, or clinically significant changes in ECGs and vital signs throughout the study.

Conclusions  Induction of CYP3A4 with carbamazepine led to a modest reduction (<36%) in steady‐state exposure to ziprasidone that is believed to be clinically insignificant.
Therapeutic drug monitoring of psychotropic medications
Authors: Mitchell Philip B.
Published: March 2003

Therapeutic drug monitoring (TDM) of a number of psychotropic medications has proven to be of value, enabling minimization of the limitations of considerable genetic variability in their metabolism and the high rates of poor compliance with many psychiatric disorders. Therapeutic ranges have been established for lithium, some of the tricyclic antidepressants, and clozapine. TDM has also been shown to be useful in avoiding toxicity (as many psychotropics have narrow therapeutic indices), particularly that due to interactions with other compounds.
A discordance of the cytochrome P450 2C19 genotype and phenotype in patients with advanced cancer
Authors: Williams Marion L. , Bhargava Pankaj , Cherrouk Ilham , Marshall John L. , Flockhart David A. , Wainer Irving W.
Published: March 2003

Aims  To examine the relationship between cytochrome P450 2C19 (CYP2C19) genotype and expressed metabolic activity in 16 patients with advanced metastatic cancer.

Methods  Individual CYP2C19 genotypes were determined by PCR‐based amplification, followed by restriction fragment length analysis, and compared with observed CYP2C19 metabolic activity, as determined using the log hydroxylation index of omeprazole.

Results  All 16 patients had an extensive metabolizer genotype. However, based on the antimode in a distribution of log omeprazole hydroxylation indices from healthy volunteers, four of the patients had a poor metabolizer phenotype and there was a general shift of the remaining 12 patients towards a slower metabolic phenotype. This suggests a reduction in metabolic activity for all patients relative to healthy volunteers. A careful analysis of patient medical records failed to reveal any drug interactions or other source for the observed discordance between genotype and phenotype.

Conclusions  There are no previous reports of a ‘discordance’ between genotype and expressed enzyme activity in cancer patients. Such a decrease in enzyme activity could have an impact on the efficacy and toxicity of chemotherapeutic agents and other drugs, used in standard oncology practice.
CYP2D6 and CYP2C19 genotypes of patients with terodiline cardiotoxicity identified through the yellow card system
Authors: Ford Gary A. , Wood Susan M. , Daly Ann K.
Published: March 2003

Aims
Terodiline has concentration dependent QT prolonging effects and thus the potential for cardiotoxicity. Pharmacogenetic variation in terodiline metabolism could be responsible for cardiotoxicity. We sought to determine whether CYP2D6 (debrisoquine hydroxylase) or CYP2C19 (S‐mephenytoin hydroxylase) status is a risk factor for terodiline cardiotoxicity.

Methods
Using the UK Yellow Card scheme to identify patients, blood samples were obtained from eight patients who survived ventricular tachycardia or torsades de pointes suspected to be due to terodiline, for determination of CYP2D6 and CYP2C19 genotypes. Genotype prevalence was compared with that in published general population groups.

Results
One patient was a CYP2D6 poor metaboliser (CYP2D6*4 homozygous) and a second was heterozygous for CYP2D6*4, a slightly lower frequency for these genotypes compared with the general population (P = 0.31). In the case of CYP2C19, one patient was a poor metaboliser and four were heterozygous for the variant CYP2C19*2 allele, compared with general population frequencies of 2% and 23%, respectively (P = 0.035).

Conclusions
These findings suggest that debrisoquine poor metaboliser status is not primarily responsible for terodiline cardiotoxicity. However, possession of the CYP2C19*2 allele appears to contribute to adverse cardiac reactions to terodiline. The present study demonstrates the feasibility of using spontaneous adverse drug reaction reporting schemes to determine the contribution of genotype for metabolizing enzymes to uncommon adverse drug reactions.
Capillaroscopy and the measurement of capillary pressure
Authors: Shore Angela C.
Published: March 2003

Capillaries play a critical role in cardiovascular function as the point of exchange of nutrients and waste products between the tissues and circulation. Studies of capillary function in man are limited by access to the vascular bed. However, skin capillaries can readily be studied by the technique of capillaroscopy which enables the investigator to assess morphology, density and blood flow velocity. It is also possible to estimate capillary pressure by direct cannulation using glass micropipettes. This review will describe the techniques used to make these assessments and will outline some of the changes that are seen in health and disease.
Kinetics and inhibition of the formation of 6β‐naltrexol from naltrexone in human liver cytosol
Authors: Porter Susan J. , Somogyi Andrew A. , White Jason M.
Published: March 2003

Aims  To determine the kinetics of the formation of 6β‐naltrexol from naltrexone in human liver cytosol, and to investigate the role of potential inhibitors.

Methods  The kinetics of the formation of 6β‐naltrexol from naltrexone were examined in eight human liver cytosol preparations using h.p.l.c. to quantify 6β‐naltrexol and, the extent of inhibition of 6β‐naltrexol formation was determined using chemical inhibitors. The formation of 6β‐naltrexol and the back reaction of 6β‐naltrexol to naltrexone were also examined in a microsomal preparation.

Results  The Vmax, Km and CLint values for the formation of 6β‐naltrexol from naltrexone were in the ranges of 16–45 nmol mg−1 protein h−1, 17–53 µm and 0.3–2.2 ml h−1 mg−1 protein, respectively. The steroid hormones testosterone (Ki = 0.3 ± 0.1 µm) and dihydrotestosterone (Ki = 0.7 ± 0.4 µm) were the most potent competitive inhibitors of 6β‐naltrexol formation, with naloxone, menadione and corticosterone also producing > 50% inhibition at a concentration of 100 µm. The opioid agonists morphine, oxycodone, oxymorphone and hydromorphone, and a range of benzodiazepines showed < 20% inhibition at 100 µm. In the microsomal preparation, there was no formation of naltrexone from 6β‐naltrexol nor any formation of 6β‐naltrexol from naltrexone.

Conclusions  The intersubject variability in the kinetic parameters of 6β‐naltrexol formation could play a role in the efficacy of and patient compliance with naltrexone treatment. This variability could be due in part to a genetic polymorphism of the dihydrodiol dehydrogenase DD4, one of the enzymes reported to be responsible for the formation of 6β‐naltrexol from naltrexone. DD4 also has hydroxysteroid dehydrogenase activity which could account for the potent inhibition by the steroid hormones testosterone and dihydrotestosterone. The clinical significance of the latter finding remains to be established.
Risk factors in the development of adverse reactions to N‐acetylcysteine in patients with paracetamol poisoning
Authors: Schmidt L. E. , Dalhoff K
Published: March 2003

Aims  To identify risk factors in the development of side‐effects to N‐acetylcysteine (NAC) in patients with paracetamol poisoning.

Methods  A retrospective study was carried out based upon the hospital charts of 529 consecutive patients admitted with paracetamol poisoning, all treated with NAC, at the Department of Hepatology, Copenhagen University Hospital (the tertiary care centre of liver disease in Denmark).

Results  Forty‐five patients (8.5%; 95% confidence intervals (CI) 6.4, 11%) developed side‐effects to NAC and 18 patients (3.4%; 95% CI 2.1, 5.4%) developed systemic side‐effects. Asthmatics were 2.9 times (95% CI 2.1, 4.7) more likely to develop side‐effects (Chi‐square: P = 0.004). Side‐effects were of similar severity in asthmatics and nonasthmatics. A history of medical allergy was not a risk factor. Serum paracetamol was lower in patients with side‐effects than in those without (Mann–Whitney: P = 0.00006).

Conclusions  Asthma must be considered a risk factor in the development of side‐effects to NAC. However, the side‐effects are easily managed and there is no reason to withhold NAC from any patient with paracetamol poisoning. Paracetamol itself seems to offer some protection against the development of side‐effects to NAC.
Neuroimaging of histamine H1‐receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second‐generation antihistamine, and (+)‐chlorpheniramine, a classical antihistamine
Authors: Tagawa Masaaki , Kano Michiko , Okamura Nobuyuki , Higuchi Makoto , Matsuda Michiaki , Mizuki Yasuyuki , Arai Hiroyuki , Iwata Ren , Fujii Toshihiko , Komemushi Sadao , Ido Tatsuo , Itoh Masatoshi , Sasaki Hidetada , Watanabe Takehiko , Yanai Kazuhiko
Published: March 2003

Aims  Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood–brain‐barrier and the consequent occupation of brain histamine H1‐receptors. We previously studied the mechanism of sedation caused by antihistamines using positron emission tomography (PET). Recently, we revealed the nonsedative characteristic of ebastine, a second‐generation antihistamine, with cognitive performance tests. In the present study, H1‐receptor occupation by ebastine was examined in the human brain using PET.

Methods  Ebastine 10 mg and (+)‐chlorpheniramine 2 or 6 mg were orally given to healthy male volunteers. PET scans with [11C]‐doxepin, a potent H1‐receptor antagonist, were conducted near tmax of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP=Bmax/Kd) for available brain H1‐receptors was imaged on a voxel‐by‐voxel basis through graphical analysis. By setting regions of interest, the H1‐receptor occupancy of drugs was calculated in several H1‐receptor rich regions.

Results  Brain distribution of radioactivity after ebastine treatment was similar to that without any drugs. However, after the oral administration of 2 mg (+)‐chlorpheniramine, the level was lower than after ebastine and nondrug treatments. Graphical analysis followed by statistical parametric mapping (SPM96) revealed that H1‐receptor rich regions such as cortices, cingulate gyrus and thalamus were regions where the BPs after ebastine were significantly higher than after (+)‐chlorpheniramine (2 mg). H1‐receptor occupancies in cortex were approximately 10% by ebastine and ≥50% by either dose of (+)‐chlorpheniramine (95% confidence interval for difference in the mean receptor occupancies: 27%, 54% for 2 mg and 35%, 62% for 6 mg vs ebastine, respectively). Receptor occupancies increased with increasing plasma concentration of (+)‐chlorpheniramine, but not with concentration of carebastine, an active metabolite of ebastine.

Conclusions  Ebastine (10 mg orally) causes brain histamine H1‐receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)‐chlorpheniramine occupied about 50% of brain H1‐receptors even at a low but sedative dose of 2 mg; occupancy of (+)‐chlorpheniramine was correlated with plasma (+)‐chlorpheniramine concentration.
Development and validation of limited sampling strategies for prediction of the systemic exposure to the novel anticancer agent E7070 (N‐(3‐chloro‐7‐indolyl)‐1,4‐benzenedisulphonamide)
Authors: Van Kesteren Charlotte , Mathôt R. A. A. , Raymond E. , Armand J. P. , Fumoleau P. , Punt C. , Ravic M. , Wanders J. , Beijnen J. H. , Schellens J. H. M.
Published: March 2003

Aims  E7070 is a novel, sulphonamide anticancer agent currently under clinical development for the treatment of solid tumours. The aim of this study was to develop and validate limited sampling strategies for the prediction of E7070 exposure in two different treatment schedules for phase II studies using the Bayesian estimation approach.

Methods  Data from two phase I dose finding studies were used in which E7070 was administered either as a single 1 h infusion or as a daily 1 h infusion for 5 days. Plasma concentration‐time data from 75 patients were randomly divided into an index data set, used for the development of the strategies, and a validation data set. Population pharmacokinetic parameters were derived on the basis of the index data set. The D‐optimality algorithm was used for the selection of optimal time points for both treatment schedules. The developed strategies were compared by assessment of their predictive performance of exposure, expressed as AUC (area under the plasma concentration vs time curve), in the validation data set.

Results  The developed population pharmacokinetic model comprised three compartments, with saturable distribution to one peripheral compartment and both linear and saturable elimination from the central compartment. For the 1 h infusion, a four sample strategy was selected which resulted in unbiased and accurate predictions of AUC (bias 0.74%, precision 13%). A five sample strategy was generated for the daily times five schedule yielding unbiased (bias 3.2%) and precise (12% precision) predictions of AUC.

Conclusions  Optimal sampling strategies were developed and validated for estimation of E7070 exposure in two different treatment schedules. Both schedules enabled accurate and unbiased predictions of AUC.
Is quinine a suitable probe to assess the hepatic drug‐metabolizing enzyme CYP3A4?
Authors: Wanwimolruk Sompon , Paine Mary F. , Pusek Susan N. , Watkins Paul B.
Published: March 2003

Aims To evaluate the antimalarial agent quinine as a potential in vivo probe for hepatic cytochrome P450 (CYP) 3A4 activity.

Methods Ten healthy adult volunteers received, by randomized crossover design, either a single oral dose of quinine sulphate (600 mg) alone, or quinine sulphate (600 mg) plus the CYP3A4 inhibitor troleandomycin (TAO; 500 mg every 8 h). Plasma and urine samples were collected before quinine administration, and up to 48 h thereafter, then analysed by h.p.l.c. for both quinine and its CYP3A4‐generated metabolite, 3‐hydroxyquinine. During both phases, the erythromycin breath test (ERMBT) was administered at specific times to assess hepatic CYP3A4 activity.

Results Compared with control, TAO treatment significantly decreased the mean time‐averaged ERMBT result by 77% (95% CI, 68, 85%), the mean apparent oral clearance of quinine (CL/F ) by 45% (95% CI, 39, 52%), and the mean apparent formation clearance of 3‐hydroxyquinine (CL3‐OH) by 81% (95% CI, 76, 87%). There was no correlation between the TAO‐mediated percent decrease in the time‐averaged ERMBT result and the percent decrease in CL/F or in CL3‐OH. When TAO and control treatments were analysed separately, there were no significant correlations between the time‐averaged ERMBT result and CL/F, CL3‐OH, or single plasma quinine concentration at 12, 24, and 48 h.

Conclusions Quinine may be a useful probe to detect inhibition of liver CYP3A4 activity within an individual. Further studies are needed to determine whether it can provide a quantitative measure of CYP3A4 activity suitable for intersubject comparison.
Population pharmacokinetics of intranasally administered low dose melatonin
Authors: Helfrich E. , Neef C. , Merkus F. W. H. M.
Published: March 2003

Melatonin is an endogenous hormone secreted by the pineal gland and plays a role in the regulation of the circadian rhythms, sleep and mood. Several studies evaluated the use of oral melatonin in sleep disorders, jet lag and shift work. No side‐effects have been reported in these trials [1]. However, it is known that oral melatonin shows poor bioavailability, either due to poor absorption, large first‐pass metabolism or both [2]. Other routes of administration, in particular nasal, have been described [3].

Eight healthy male volunteers (mean age 25 years) received, in an open randomized cross‐over fashion, placebo and intranasal melatonin 200 and 400 µg. Blood was sampled 15 times during 8 h. The study was approved by the Ethics Committee. Melatonin was determined by r.i.a. Plasma melatonin concentrations were adjusted for the mean endogenous concentration after placebo. We calculated the pharmacokinetic parameters of intranasal melatonin by using the MW\Pharm programme [4] according to the ITSB method. The AUC(0, 8 h) was obtained by the trapezoidal rule. The model was validated by Monte Carlo simulation.

Melatonin intranasal kinetics could best be described by a 2‐compartment model (Table 1). Melatonin 200 and 400 µg provided high blood plasma concentrations after fast absorption. The elimination half‐life of melatonin was 44±7 min and 60±20 min after dosing respectively 200 and 400 µg (P>0.05). Absorption was too rapid to be fitted. Monte Carlo analysis showed that data differed significantly (P<0.05) from the fitted population parameters.

Pharmacokinetic parameters after intranasal administration of 200 and 400 µg melatonin.

Parameters
200 µg (n=7)
95% CI

Median±d.f.
Median±s.d.

AUC(0, 8 h)&!emsp;(µg l−1 h)

2.99±1.16
2.06, 3.92

V
d/F(l kg−1 LBMc)
1.41±0.28

1.11, 1.67

k
el (h−1)
1.04±0.14

0.91, 1.16

k
12 (h−1)
0.10±0.12

−0.01, 0.22

k
21 (h−1)
0.05±0.04

0.01, 0.09

400 µg (n=8)

Parameters
Median±d.f.
Median±s.d.
95% CI

AUC(0, 8 h)(µg l−1 h)

5.98±2.23
4.12, 7.84

V
d/F (l kg−1 LBMc)
1.61±0.69

1.04, 2.18

k
el (h−1)
0.75±0.22

0.57, 0.93

k
12 (h−1)
0.19±0.08

0.13, 0.25

k
21 (h−1)
0.02±0.01

0.01, 0.03

AUC: area under the curve, F: absolute bioavailability, Vd/F: volume of distribution, kel: elimination rate constant, k12, k21: rate constants between compartments.

The pharmacokinetic parameters could not be validated by a Monte Carlo simulation probably due to large interindividual variability. Because the dose adjusted AUC(0, 8 h) for the 400 µg nasal dose was equal to the AUC(0, 8 h) for the 200 µg nasal dose (P<0.05), there appears to be linear absorption in the 200 to 400 µg dose range.
Lichen sclerosus premenarche: autoimmunity and immunogenetics
Authors: Powell J. , Wojnarowska F. , Winsey S. , Marren P. , Welsh K.
Published: March 2003

Lichen sclerosus is among the most frequently seen paediatric vulval disorders. In adults a strong association between lichen sclerosus and autoimmune diseases, and also with HLA class II locus DQ7, has been well demonstrated in women and a weaker association in men. These associations have not previously been studied in children, although in other autoimmune diseases, the HLA associations have been strongest in children. We performed HLA tissue typing and looked for autoimmune associations in a group of 30 children with vulval lichen sclerosus. HLA DQ7 was present in 66% of female children with lichen sclerosus compared with 31% in controls. Previous studies reported DQ7 in 51% of adult female patients and 45% of male patients. Sixteen per cent of the children were homozygous for DQ7 as opposed to 5% of controls. In the childhood group, only 4% had another autoimmune disease, but 56% of their parents or grandparents did. Age differences make comparison difficult, but the family history of autoimmunity appears to be strong in the early-onset group, in addition to the stronger association with DQ7.
Surveillance of occupational skin disease: EPIDERM and OPRA
Authors: Cherry N. , Meyer J.D. , Adisesh A. , Brooke R. , Owen-Smith V. , Swales C. , Beck M.H.
Published: March 2003

Consultant dermatologists in the U.K. have been reporting to EPIDERM, a voluntary surveillance scheme for occupational skin disease, since February 1993; reporting by occupational physicians to the scheme began in May 1994 and was superseded in January 1996 by OPRA (Occupational Physicians Reporting Activity). Currently 244 dermatologists and 790 occupational physicians report incident cases to these schemes. During the 6 years to January 1999 a total of 12,574 new cases of occupational skin disease was estimated from reports by consultant dermatologists and 10,136 cases estimated from occupational physicians (since May 1994). The annual incidence of occupational contact dermatitis using data from both schemes was 12·9 per 100,000 workers. The incidence of contact dermatitis per 100,000 workers increased with age in men from 4·9 (age 16–29 years) to 6·6 (age 45–60 years); in women a higher rate (9·5) was apparent in the younger age group, with lower rates in older female workers. High rates in young workers were associated with wet work and in older workers with exposure to oils. For men, high rates of contact dermatitis were seen in reports from both schemes for chemical operatives, machine tool setters and operatives, coach and spray painters and metal workers. For women, high rates were found for hairdressers, biological scientists and laboratory workers, nurses and those working in catering. The most frequent agents for contact dermatitis were rubber chemicals and materials (14·1% of cases reported by dermatologists), soaps and cleaners (12·7%), nickel (11·9%), wet work (11·1%), personal protective equipment (6·2%), petroleum products (6·3%), cutting oils and coolants (5·6%), and epoxy and other resins (6·1%). In the 1608 estimated cases of skin cancer all but 4% were attributed to ultraviolet radiation. Cases of contact urticaria attributed to latex peaked in 1996, with a decline in cases since that time.
Prevalence of solar damage and actinic keratosis in a Merseyside population
Authors: Memon A.A. , Tomenson J.A. , Bothwell J. , Friedmann P.S.
Published: March 2003

This study examines the prevalence of sun-related damage to the skin in a caucasian population in north-west England. The importance of constitutional factors (complexion, skin type and age) as well as environmental and occupational exposures for the development of actinic keratosis (AK) and skin cancers was assessed in people over 40 years of age attending outpatient clinics (non-dermatology) at four centres in north-west England (Mersey region). Nine hundred and sixty-eight volunteers (531 men and 437 women) were recruited. The overall prevalence of AK was 15·4% in men and 5·9% in women. The prevalence was strongly related to age in both sexes, being 34·1% and 18·2%, respectively, in men and women aged 70 years and above, and was most strongly related to two objective signs of sun exposure, namely degree of solar elastosis and presence of solar lentigines. The prevalence of AK was higher in subjects with red hair and freckles, particularly women. There was no evidence of an increased prevalence of AK in relation to any occupation. There was a high prevalence of seborrhoeic keratosis and viral warts in both sexes, which was age-related in the case of seborrhoeic keratosis. Ten cases of basal cell carcinoma, eight cases of Bowen’s disease and one case of malignant melanoma were identified. This study shows that the sun exposure received in ‘normal’ life in England is sufficient to cause potentially malignant skin damage in a significant proportion of the population.
Nailfold video capillaroscopy in psoriasis
Authors: Bhushan M. , Moore T. , Herrick A.L. , Griffiths C.E.M.
Published: March 2003

Changes in the microvasculature are considered to play an important part in the pathogenesis of psoriasis and its associated arthritis. The novel method of nailfold video capillaroscopy is an extension of the technique of widefield nailfold microscopy which has been of diagnostic and predictive use in the in vivo study of the microcirculation in systemic sclerosis and other connective tissue disorders. However, similar studies in patients with psoriasis and psoriatic arthritis and/or nail changes have produced conflicting results. We tested the hypothesis that any abnormalities in nailfold capillaries of either a quantitative or qualitative nature might be observed more readily in subjects with pathology adjacent to the nailfold, i.e. distal interphalangeal (DIP) joint changes and/or nail dystrophy, when using this technique. Forty-four patients with psoriasis were recruited (21 males, 23 females). Twelve patients had psoriasis alone, 13 had psoriasis and nail changes, six had DIP joint involvement with changes of psoriasis elsewhere, and 13 had psoriasis, DIP arthritis and nail changes. Capillary density and standard capillary dimensions were studied and compared with those of 44 age- and sex-matched control subjects. There was a significant (P < 0·05) decrease in capillary loop density in patients with either psoriasis plus nail disease (14·5 ± 5·7 capillaries per 3 mm field) or psoriasis plus nail and DIP joint disease (14·3 ± 5·0) when compared with controls (19·2 ± 3·8). In patients with psoriatic arthritis affecting the DIP joints, there was a statistically significant (P < 0·05) decrease in arterial and venous capillary limb diameters, and this was also seen in those with arthritis associated with nail changes. However, there was no difference in capillary dimensions between patients with psoriasis and/or nail changes when compared with normal controls. Morphological abnormalities previously described in the literature were not noted in any of our four patient groups. Our findings of diminution in both nailfold capillary bed density and dimensions of the arterial and venous capillary limbs suggest that vascular injury, previously noted in ultrastructural studies, may play a part in the pathogenesis of psoriatic arthritis. However, in contrast to previous studies, we found no specific pattern of a morphological nature of nailfold capillaries in patients with psoriasis with or without nail changes, when compared with normal controls.
Depigmented hypertrichosis following Blaschko’s lines associated with cerebral and ocular malformations: a new neurocutaneous, autosomal lethal gene syndrome from the group of epidermal naevus syndromes?
Authors: Schauder S. , Hanefeld F. , Noske U.M. , Zoll B.
Published: March 2003

The lines of Blaschko represent one of the cutaneous patterns of mosaicism followed by various skin disorders. Developmental abnormalities affecting other tissues derived from the embryonic ectoderm and mesoderm are occasionally associated. We describe a 30-year-old man with depigmented, bilateral hypertrichosis and dilated follicular orifices following Blaschko’s lines associated with cerebral and ocular malformations. The findings suggest a previously unreported neurocutaneous, autosomal lethal gene syndrome from the group of epidermal naevus syndromes.
Red facial pseudochromhidrosis
Authors: Thami G.P. , Kanwar A.J. ,   MAMTA
Published: March 2003

We describe a 9-year-old girl with pseudochromhidrosis simulating apocrine chromhidrosis. Treatment with topical and systemic erythromycin resulted in complete clearance of the reddish discoloration of the face. No relapse or recurrence was observed over a 3-month period.
Photosensitive mycosis fungoides or actinic reticuloid?
Authors: De Silva B.D. , Mclaren K. , Kavanagh G.M.
Published: March 2003

We report two patients who satisfied the diagnostic criteria for actinic reticuloid (AR) on initial presentation, in whom genotypic analysis of early skin biopsies failed to show T-cell gene receptor rearrangements. Both patients progressed to widespread skin involvement associated with histopathological and genotypic features of mycosis fungoides (MF). Arguably, these patients may have had photosensitive MF from the outset, but their clinical features, phototesting, and subsequent demonstration of a T-cell gene receptor rearrangement in the skin could also suggest progression of AR to MF.
Longitudinal study on activated factors XII and VII levels during normal pregnancy
Authors: De Moerloose  , Amiral  , Vissac  , Reber
Published: March 2003

Levels of activated factor XII (FXIIa) and VII (FVIIa) were determined in 100 women with uneventful pregnancies. Samples were divided into five study intervals: three during pregnancy, one at delivery and one 3 d postpartum.

The median (range) for FXIIa levels were 3.4 ng/ml (1.2–9.1) from 11 to 20 weeks, 4.6 ng/ml (1.4–15.2) from 21 to 30 weeks, 5.4 ng/ml (1.9–14.3) from 31st week to delivery, 5.2 (1.3–11.4) at delivery and 4.3 (1.8–8.5) ng/ml in the postpartum sample. For FVIIa the median and range levels for the five periods were 4.9 (1.7–77.3), 7.2 (2.5–80.4), 11.1 (2.9–90.6), 12.0 (3.1–64.1) and 8.2 (4.0–23.5) ng/ml. Although the increase of FVIIa was higher than that of FXIIa during pregnancy, the overall changes of FXIIa and FVIIa were highly correlated (P < 0.0001). At each time period the changes of FVIIa correlated with FVII:C which was not the case with FVII:Ag. These data indicate that during pregnancy both the contact phase and extrinsic pathway are activated.