bluuebunny/crossref_metadata_2025_split huggingface dataset:
Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double‐blind, placebo‐controlled study
Authors: McCleane Gary 
Published: March 2003

Aims
To assess the analgesic efficacy of topical administration of 3.3% doxepin hydrochloride, 0.025% capsaicin and a combination of 3.3% doxepin and 0.025% capsaicin in human chronic neuropathic pain.
Methods
A randomized, double‐blind, placebo‐controlled study of 200 consenting adult patients. Patients applied placebo, doxepin, capsaicin or doxepin/capsaicin cream daily for 4 weeks. Patients recorded on a daily basis overall pain, shooting, burning, paraesthesia and numbness using a 0–10 visual analogue scale during the week prior to cream application (baseline levels) and for the 4 week study period. Side‐effects and desire to continue treatment were also recorded.
Results
Overall pain was significantly reduced by doxepin, capsaicin and doxepin/capsaicin to a similar extent. The analgesia with doxepin/capsaicin was of more rapid onset. Capsaicin significantly reduced sensitivity and shooting pain. Burning pain was increased by doxepin and by capsaicin and to a lesser extent by doxepin/capsaicin. Side‐effects were minor. One patient requested to continue placebo cream, 17 doxepin cream, 13 capsaicin and 9 the combination of doxepin and capsaicin.
Conclusions
Topical application of 3.3% doxepin, 0.025% capsaicin and 3.3% doxepin/0.025% capsaicin produces analgesia of similar magnitude. The combination produces more rapid analgesia.
Ovarian hormones in man: their effects on resting vascular tone, angiotensin converting enzyme activity and angiotensin II‐induced vasoconstriction
Authors: Lee Alison F. C. , McFarlane Lesley C. , Struthers Allan D. 
Published: March 2003

Aims
Oestrogens in women have been shown to cause vasodilation which may reflect alterations in the activity of vascular angiotensin converting enzyme (ACE) and/or sensitivity to angiotensin II. The aim of this study was to assess the effect of ovarian hormones on vascular tone, vascular ACE activity and vasoconstriction to angiotensin II in males.
Methods
Eight volunteers were randomised in a crossover design to oestradiol, medroxy‐progesterone, and placebo. Vasoconstriction to angiotensin I and angiotensin II was assessed by forearm plethysmography.
Results
Although baseline forearm flow was increased with oestradiol, suggesting generalized vasodilation, there were no changes in the vasoconstrictor responses to angiotensin I or angiotensin II. Medroxy‐progesterone affected neither baseline flow nor vasoconstrictor responses. The results expressed as percentage reduction in flow (mean ± s.d.) were: angiotensin I 48 pmol ml−1: placebo −48 ± 14%; oestradiol −42 ± 16%; medroxyprogesterone −43 ± 8% and for angiotensin II 16 pmol ml−1: placebo −42 ± 10%; oestradiol −39 ± 11%; medroxyprogesterone −46 ± 13%.
Conclusions
Acute administration of oestradiol caused vasodilation in males, the effect was not due to alterations in vascular ACE activity or to altered sensitivity to angiotensin II.
Parkinson's disease and CYP1A2 activity
Authors: Forsyth, J. T. , Grünewald, R. A. , Rostami‐Hodjegan, A. , Lennard, M. S. , Sagar H. J. , Tucker G. T. 
Published: March 2003

Aims
MPTP, a neurotoxin which induces parkinsonism is partially metabolized by the enzyme CYP1A2. Smoking appears to protect against Parkinson's disease (PD) and cigarette smoke induces CYP1A2 activity. Thus, we investigated the hypothesis that idiopathic PD is associated with lower CYP1A2 activity using caffeine as a probe compound.
Methods
CYP1A2 activity was assessed using saliva paraxanthine (PX) to caffeine (CA) ratios. Caffeine half‐life was also estimated from salivary concentrations of caffeine at 2 and 5 h post dose. 117 treated and 40 untreated patients with PD and 105 healthy control subjects were studied.
Results
PX/CA ratios were 0.57, 0.93 and 0.77 in treated patients, untreated patients and healthy control subjects, respectively, with no significant differences between study groups (95% CI: treated patients vs controls −0.24, 0.57; untreated patients vs controls −0.75, 0.35). However, patients with PD (treated or untreated) had caffeine half‐lives shorter than that in controls (treated patients: 262 min, untreated patients: 244 min, controls: 345 min; 95% CI: controls vs treated patients 23, 143 (P = 0.003); controls vs untreated patients 19, 184 (P = 0.011)). Amongst the patients with PD, caffeine half‐life was also inversely related to the age of onset of disease (P = 0.012); gender and concomitant drugs did not influence this significantly.
Conclusions
Based on PX/CA ratio, there was no evidence of decreased CYP1A2 activity in patients compared with control subjects. The observed decrease in the elimination half‐life of caffeine in PD may be caused by increased CYP2E1 activity, an enzyme that also contributes to the metabolism of caffeine. The latter warrants further investigation.
Drug use of children in the community assessed through pharmacy dispensing data
Authors: Schirm Eric , Van Den Berg Paul , Gebben Henkjan , Sauer Pieter , De Jong‐van den Berg Lolkje 
Published: March 2003

Aims
To determine the extent of drug use in children and the types of drugs that children use.
Methods
Cross‐sectional study and cohort study, using computerized pharmacy dispensing records for all children aged 0–16 years in the northern part of The Netherlands in 1998. The main outcome measures were proportion of children that used drugs (per sex and age group), mean number of drugs per child, 10 most widely used drug groups and cumulative proportions of drugs users (per drug group) during the first 2 years of life.
Results
Drug use was the highest among infants, decreased till adolescence and increased from there. Overall, approximately 60% of all children used at least one drug in 1998. At younger ages, boys used more drugs than girls and at older ages girls used more drugs than boys. Systemic antibiotics were used by 21% of the children and were by far the most widely used drugs. Other frequently used drugs were analgesics (10%), corticosteroids for dermatologic use (9%), anthistamines (8%) and antiasthmatics (7%). Approximately 10% of the children had used at least one drug at the age of 1 month and at the age of 2 years this proportion was 81%.
Conclusions
The majority of children was exposed to one or more drugs and this exposure started at very young age. This shows the importance of good guidelines for drug use in children and emphasizes the necessity of research of pharmacokinetic and pharmacodynamic properties in children to obtain safety, efficacy and quality evidence of these drugs.
Stereoselective halofantrine disposition and effect:concentration‐related QTc prolongation
Authors: Abernethy Darrell R. , Wesche David L. , Barbey Jean T. , Ohrt Colin , Mohanty Sarina , Pezzullo John C. , Schuster Brian G. 
Published: March 2003

Aims  1) To characterize the variability of multiple‐dose halofantrine pharmacokinetics over time in healthy adults, 2) to correlate the pharmacodynamic measure electrocardiographic (ECG) QT interval with (+)‐ and (−)‐halofantrine plasma concentration and 3) to evaluate the safety and tolerance of halofantrine hydrochloride given over time to healthy adults.Methods  Twenty‐one healthy subjects were enrolled and 13 completed the study (180 days). Subjects received either 500 mg of racemic halofantrine once daily in the fasted state for 42 days, or placebo, and then halofantrine washout was documented for the following 138 days. Pharmacokinetic and pharmacodynamic (ECG QTc) measurements were obtained.Results  Mean accumulation half‐times (days) for halofantrine were: 7.0 ± 4.8 [(+)‐halofantrine] and 7.3 ± 4.8 [(−)‐halofantrine]. Mean steady‐state concentrations were: 97.6 ± 52.0 ng ml−1[(+)‐halofantrine] and 48.5 ± 20.8 [(−)‐halofantrine]. Steady‐state oral clearance was: 139 ± 73 l h−1[(+)‐halofantrine] and 265 ± 135 l h−1[(−)‐halofantrine]. Peak plasma concentrations of both (+)‐ and (−)‐halofantrine were attained at 6 h and maximal ECG QTc prolongation was at 4–8 h following drug administration. Fourteen of 16 subjects who received active drug had ECG QTc prolongation that was positively correlated with both (+)‐ and (−)‐halofantrine concentration. The five subjects who received placebo had no demonstrable change in ECG QTc throughout the study.
Conclusions
Halofantrine accumulates extensively and shows high intersubject pharmacokinetic variability, is associated with concentration‐related ECG QTc prolongation in healthy subjects, and is clinically well tolerated in this subject group.
Non‐sedating antihistamine drugs and cardiac arrhythmias – biased risk estimates from spontaneous reporting systems?
Authors: De Bruin M. L. , Van Puijenbroek E. P. , Egberts A. C. G. , Hoes A. W. , Leufkens H. G. M. 
Published: March 2003

Aims  This study used spontaneous reports of adverse events to estimate the risk for developing cardiac arrhythmias due to the systemic use of nonsedating antihistamine drugs and compared the risk estimate before and after the regulatory action to recall the over‐the‐counter status of some of these drugs.Methods  All suspected adverse drug reactions (ADRs) reported until July 1999 to the Netherlands Pharmacovigilance Foundation Lareb were used to calculate the ADR reporting odds ratio, defined as the ratio of exposure odds among reported arrhythmia cases, to the exposure odds of other ADRs (noncases), adjusted for gender, age, reporter, year of reporting and comedication, stratified for the periods before and after the governmental decision in the Netherlands.Results  Seven‐hundred and thirty‐seven cases of arrhythmia were reported, out of which there were 43 instances where the patients were using nonsedating antihistamines. In general nonsedating antihistamines are associated with cardiac arrhythmia to a higher extent in comparison with other drugs (ADR reporting odds ratio 2.05 [95% CI: 1.45, 2.89]). The association between arrhythmias and nonsedating antihistamine drugs calculated before 1998 was not significantly higher than 1 (OR 1.37 [95% CI: 0.85, 2.23]), whereas the risk estimate calculated after the governmental decision did significantly differ from 1 (OR 4.19 [95% CI: 2.49, 7.05]).Conclusions  Our data suggest that nonsedating antihistamines might have an increased risk for inducing arrhythmias. Our findings, however, strongly suggest that the increased risk identified can at least partly be explained by reporting bias as a result of publications about and mass media attention for antihistamine induced arrhythmias.
Pharmacokinetics and pharmacodynamics of combination chemotherapy with paclitaxel and epirubicin in breast cancer patients
Authors: Danesi Romano , Innocenti Federico , Fogli Stefano , Gennari Alessandra , Baldini Editta , Di Paolo Antonello , Salvadori Barbara , Bocci Guido , Conte Pier Franco , Del Tacca Mario 
Published: March 2003

Aims  To investigate the pharmacokinetics and pharmacodynamics of epirubicin and paclitaxel in combination, as well as the effects of paclitaxel and its vehicle Cremophor EL on epirubicin metabolism.Methods  Twenty‐seven female patients with metastatic breast cancer received epirubicin 90 mg m−2 i.v. followed 15 min or 30 h later by a 3 h i.v. infusion of paclitaxel 175, 200 and 225 mg m−2. Plasma concentrations of paclitaxel, epirubicin and epirubicinol were measured and the relationship between neutropenia and drug pharmacokinetics was evaluated using a sigmoid maximum effect (Emax) model. Finally, the influence of paclitaxel and Cremophor EL on epirubicin metabolism by whole blood was examined.Results  An increase in epirubicinol plasma concentrations occurred after the start of the paclitaxel infusion, resulting in a significant increase in the area under the plasma concentration‐time curve (AUC) of epirubicinol (+0.5 µmol l−1 h [95% CI for the difference: 0.29, 0.71],+0.66 µmol l−1 h [95% CI for the difference: 0.47, 0.85] and +0.82 µmol l−1 h [95% CI for the difference: 0.53, 1.11] at paclitaxel doses of 175, 200 and 225 mg m−2, respectively), compared with epirubicin followed by paclitaxel 30 h later (0.61±0.1 µmol l−1 h). A significant increase in epirubicin AUC (+0.74 µmol l−1 h [95% CI for the difference: 0.14, 1.34] and +1.09 µmol l−1 h [95% CI for the difference: 0.44, 1.74]) and decrease in drug clearance (CLTB) (−25.35 l h−1 m−2[95% CI for the difference: −50.18, −0.52] and −35.9 l h−1 m−2[95% CI for the difference −63,4,−8,36]) occurred in combination with paclitaxel 200 and 225 mg m−2 with respect to the AUC (3.16±0.6 µmol l−1 h) and CLTB (74.4±28.4 l h−1 m−2) of epirubicin followed by paclitaxel 30 h later. An Emax relationship was observed between neutropaenia and the time over which paclitaxel plasma concentrations were equal to or greater than 0.1 µmol l−1 (tC0.1). The tC0.1 value predicted to yield a 50% decrease in neutrophil count was 7.7 h. Finally, Cremophor EL markedly inhibited the metabolism of epirubicin to epirubicinol in whole blood.Conclusions  Paclitaxel/Cremophor EL affects the disposition of epirubicinol and epirubicin. Furthermore, the slope factor of the Emax relationship between neutropenia and tC0.1 of paclitaxel suggests that the drugs might also interact at the pharmacodynamic level.
Caffeine in apnoeic Asian neonates: a sparse data analysis
Authors: Lee How Sung , Khoo Yok Moi , Chirino‐Barcelo Yazmin , Tan Kim Leong , Ong Dorothy 
Published: March 2003

Aims  To monitor plasma caffeine concentrations and adverse effects and to study the pharmacokinetics of caffeine in neonatal apnoea in the local Asian population after intravenous administration of caffeine.Methods  Eighteen neonates with apnoea were treated with caffeine citrate at a loading dose of 10 mg caffeine base kg−1 and a maintenance dose of 2.5 mg kg−1 day−1. Blood samples, three after loading and two after the maintenance dose on day 2, 3, 7, 14 and 21 were taken and analysed for caffeine and its main metabolites using solid phase extraction and h.p.l.c. Adverse effects were monitored. Sparse data pharmacokinetic analysis was performed using P‐Pharm.Results  Mean caffeine concentrations varied from 10 to 20 mg l−1 throughout treatment (range 3.6–28.4 mg l−1). These concentrations were efficacious; less so in those with lower concentrations. Adverse effects included gastrointestinal disturbances, diuresis and hyperglycaemia. Pharmacokinetic parameter estimates [mean (coefficient of variation%)] were CL=0.00628 (17.5%) l h−1 and V=0.961 (20.3%) l. CL (l h−1)=0.004248 * wt(kg)+0.00154; r=0.8, P<0.01, explained 64% of the variation. V (l)=0.6299 * wt(kg)+0.259; r=0.67, P<0.01, explained 45% of variation. Model‐predicted compared with observed plasma concentrations in a separate group of 10 neonates were unbiased and of good precision.Conclusions  The dosing regimen studied was suitable for our local Asian neonates as it resulted in therapeutic caffeine concentrations for adequate treatment of apnoea. Adverse effects were tolerable. Therefore, to avoid a higher incidence of adverse effects, this regimen should be retained and not increased as proposed by other workers. CL and V were within values of those reported for neonatal apnoea. Sparse data analysis showed that weight alone was adequate as the influential variable for the accurate prediction of individual pharmacokinetic parameters, plasma concentrations and for dosage adjustment if required.
Involvement of CYP2C9 and UGT2B7 in the metabolism of zaltoprofen, a nonsteroidal anti‐inflammatory drug, and its lack of clinically significant CYP inhibition potential
Authors: Furuta Shigeru , Akagawa Nobuyoshi , Kamada Emiko , Hiyama Akio , Kawabata Yoshihiro , Kowata Nobuhiko , Inaba Atsuhiro , Matthews Anne , Hall Michael , Kurimoto Tadashi 
Published: March 2003

Aims
To identify the cytochrome P450 (CYP) and UDP‐glucuronosyltransferase (UGT) isoforms responsible for the formation of the primary metabolite(s) of zaltoprofen, and to predict possible drug interactions by investigating the inhibition of CYP isoforms in vitro.
Methods
The metabolism of zaltoprofen was studied in vitro using recombinant CYP and UGT isoform cDNA‐expression systems. The effects of selective isoform inhibitors on zaltoprofen metabolism were studied using human liver microsomes. The inhibitory effects of zaltoprofen on the metabolism of selective probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 were also determined in human liver microsomes.
Results
Zaltoprofen was extensively metabolized by CYP2C9 and UGT2B7. CYP2C9 catalysed sulphoxidation but not hydroxylation of zaltoprofen. In the human liver microsomal metabolism study, zaltoprofen metabolism was markedly inhibited by sulphaphenazole, a selective inhibitor of CYP2C9. In the drug interaction study, negligible inhibition (< 15%) of the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 was apparent at 5 µg ml−1, the maximum plasma concentration   observed   in   humans   after   oral   administration   of   an   80 mg   zaltoprofen  tablet. However, zaltoprofen inhibited CYP2C9 by 26% at 5 µg ml−1. At higher concentrations, zaltoprofen produced some inhibition of CYP2C9 (IC50 = 19.2 µg ml−1; 64.4 µm) and CYP3A4 (IC50 = 53.9 µg ml−1; 181 µm). The free drug concentrations in plasma (0.02 µg ml−1, 67.0 nm) at the Cmax of the clinically effective doses are much lower than the IC50 values corrected for the nonspecific binding ratio of zaltoprofen to microsomal protein (15.5 µg ml−1 for CYP3A4, 49.5 µg ml−1 for CYP3A4). Furthermore, the maximum free drug concentrations in the hepatic intracellular was calculated to be 0.068 µg ml−1 and the increase in the AUC in the presence of zaltoprofen was estimated to be only 0.4% for CYP2C9 substrates and 0.1% for CYP3A4 substrates, respectively.
Conclusions
Zaltoprofen is predominantly metabolized by CYP2C9 and UGT2B7, and is considered unlikely to cause significant drug interactions in vivo when coadministered with CYP substrates at clinically effective doses.
Central and peripheral effects of sustained caffeine use: tolerance is incomplete
Authors: Watson Joanne , Deary Ian , Kerr David 
Published: March 2003

Aims
It is widely held that tolerance develops to the effects of sustained caffeine consumption. This study was designed to investigate the effects of chronic, staggered caffeine ingestion on the responses of an acute caffeine challenge, during ­euglycaemia.
Methods
Twelve healthy volunteers were randomized using a double‐blind, cross‐over design to take either 200 mg caffeine (C‐replete) or placebo (C‐naïve) twice daily for 1 week. Following baseline measurements being made, the responses to 200 mg caffeine (blood‐pressure, middle cerebral artery velocity, mood and cognitive performance) were examined over the subsequent 120 min. Blood glucose was not allowed to fall below 4.0 mmol l−1.
Results
After the caffeine challenge, middle cerebral artery blood velocity decreased in both conditions but was greater in the C‐naïve condition (−8.0 [‐10.0, −6.1] cm s−1vs−4.9 [‐6.8, −2.9] cm s−1 C‐replete, P < 0.02). Systolic blood pressure rise was not significantly different in C‐naïve, although this rise was more sustained over time (P < 0.04). Mood was adversely affected by regular caffeine consumption with tense aspect of mood significantly higher at baseline in C‐replete 11.6 ± 0.6 C‐naïve vs 16.3 ± 1.6 C‐replete, P < 0.01). Cognitive performance was not affected by previous caffeine exposure.
Conclusions
Overall these results suggest that tolerance is incomplete with respect to both peripheral or central effects of caffeine.
Preliminary evidence of an association of tumour necrosis factor microsatellites with increased risk of multiple basal cell carcinomas
Authors: Hajeer A.H. , Lear J.T. , Ollier W.E.R. , Naves M. , Worthington J. , Bell D.A. , Smith A.G. , Bowers W.P. , Jones P.W. , Strange R.C. , Fryer A.A. 
Published: March 2003

Abstract
Tumour necrosis factor alpha (TNF-α) appears important in ultraviolet-induced immunosuppression, suggesting that it is a susceptibility candidate for cutaneous basal cell carcinoma (BCC). We now describe data on the association between TNF microsatellite polymorphisms, first on susceptibility in 202 controls and 133 cases each having two to 30 BCCs, and secondly, within the cases, on BCC numbers. The data show that the proportions of individuals with TNF a1- and a7-containing genotypes were significantly different (P = 0·0271, P = 0·0393, respectively) between cases and controls. Secondly, within the cases, TNF alleles d4 (P = 0·023) and d6 (P = 0·006) alone, and the TNF a2–b4–d5 haplotype (P = 0·007), were significantly associated with the number of BCC lesions. These preliminary data provide the first evidence that TNF microsatellite polymorphism may influence the pathogenesis of multiple BCC.
Angiomatoid (malignant) fibrous histiocytoma as a second tumour in a child with neuroblastoma
Authors: Gambini C. , Haupt R. , Rongioletti F. 
Published: March 2003

Abstract
Neuroblastoma occurring as a disseminated disease in children has a poor prognosis. Haematogenous metastases usually involve the marrow, bone, liver and skin. A second neoplasm may also develop. We describe a child with retroperitoneal neuroblastoma (stage 3) who developed a nodular mass in the inguinal area which was suspected to be a metastasis. Histopathology disclosed an angiomatoid (malignant) fibrous histiocytoma, and excision was curative. The occurrence of angiomatoid (malignant) fibrous histiocytoma as a second tumour in a patient with neuroblastoma has not previously been reported.
c-Myc expression in human anagen hair follicles
Authors: Rumio C. , Donetti E. , Imberti A. , Barajon I. , Prosperi E. , Brivio M.F. , Boselli A. , Lavezzari E. , Veraldi S. , Bignotto M. , Castano P. 
Published: March 2003

Abstract
The hair follicle represents a very attractive organ system for studying the precise balance between cell proliferation, growth, differentiation, and death of cells, because it periodically and regularly regenerates, retaining its morphogenetic signals throughout its life. One of the most intriguing oncogenes which is able to induce both cell growth and apoptosis, depending upon the environmental conditions, is c-myc. The aim of the present study was to investigate its presence and localization in human hair follicles by immunohistochemistry and immunofluorescence. Our observations demonstrated the consistent presence of two clusters of c-Myc-expressing cells in anagen follicles, located in two annular regions of the inner root sheath, at the border between cells characterized by putative trichohyalin granules and cells which are keratinized. The lower group belongs to Henle’s layer, while the upper group belongs to Huxley’s layer. c-Myc oncoprotein seems to favour apoptosis/differentiation and may be a marker for terminal differentiation of trichocytes, at least in the inner root sheath. Our findings agree with the interpretation that the complex morphology of the hair follicle reflects its complex function; the extrusion of a highly organized multicellular structure, the hair shaft, driven by another highly organized multicellular structure, the inner root sheath.