bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concentration‐effect relationships of two infusion rates of the imidazoline antihypertensive agent rilmenidine for blood pressure and development of side‐effects in healthy subjects
Authors: De Visser S. J. , Van Gerven J. M. A. , Schoemaker R. C. , Cohen A. F. 
Published: March 2003

Aims  The aim of this study was to compare the effect profiles of i.v. administered rilmenidine aimed at the same target plasma concentration, but attained with different rates.Methods  The study was placebo‐controlled, randomized, double‐blind, double‐dummy, three‐way, cross‐over in nine healthy volunteers. All subjects randomly received either a fast infusion, a slow infusion or a placebo infusion. The target concentration was set at 8 ng ml−1 with a fivefold difference in the time to reach the maximum concentration. Saccadic eye movements, electroencephalography (EEG), blood pressure and heart rate were measured every half hour. Drug plasma concentrations, adverse events, salivary flow and visual analogue scales were obtained every hour.Results  Changes in systolic/diastolic blood pressure at the end of the infusion were (mean ± s.d.) 13.3 ± 16.4/7.9 ± 7.5 mmHg with the fast infusion and 16.3 ± 12.7/10.2 ± 7.9 mmHg during the slow infusion, compared with 0.0 ± 13.2/1.3 ± 8.3 mmHg for the placebo occasion. Decrease of saccadic peak velocity (SPV) at the end of the infusion was 18.0 ± 5.2% during the fast infusion, 23.0 ± 7.0% with the slow infusion, and 6.1 ± 5.2% with placebo. PK/PD analysis showed similar concentration‐dependent linear reduction in SPV and blood pressure up to the maximum observed rilmenidine plasma level for both the fast and the slow infusion.Conclusions  The rate of infusion of rilmenidine in healthy volunteers does not influence the PK/PD relationship of saccadic eye movements and blood pressure up to the maximum observed rilmenidine plasma concentrations. Rilmenidine causes clear concentration‐dependent blood pressure reductions in healthy volunteers.
Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice
Authors: Sturrock N. D. C. , Lannon B. , Fay T. N. 
Published: March 2003

Aims To determine whether metformin pretreatment has beneficial effects in clomiphene resistant infertile women with polycystic ovary syndrome (PCOS) in an infertility clinic.Methods This was a randomized placebo controlled double‐blind crossover study of 3 months metformin (1500 mg day−1)/placebo, followed by 3 months metformin/placebo together with clomiphene (50–100 mg for 5 days) for three cycles in clomiphene resistant women with PCOS. The primary outcomes were restoration of spontaneous menses, ovulation induction (spontaneous or clomiphene induced) and pregnancy. Secondary endpoints were changes in biochemical parameters related to androgens and insulin.Results Twelve women completed the metformin arm and 14 the placebo arm. Spontaneous menstruation resumed in five metformin treated patients and in six placebo treated women, P=0.63. No women given metformin spontaneously ovulated, although one patient given placebo did, P=0.30. There was no difference in the efficacy of clomiphene between the two groups with ovulation being induced in five (out of 12) metformin treated women and four (out of 14) placebo treated women, P=0.63. Pregnancy occurred in three (out of 12) women given metformin and two (out of 14) women given placebo, P=0.59.Conclusions Metformin is not always beneficial when given to clomiphene resistant infertile women with PCOS in clinical practice.
Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin
Authors: Kosoglou Teddy , Meyer Ingo , Veltri Enrico P. , Statkevich Paul , Yang Bo , Zhu Yali , Mellars Lillian , Maxwell Stephen E. , Patrick James E. , Cutler David L. , Batra Vijay K. , Affrime Melton B. 
Published: March 2003

Aims  The primary aims of these two single‐centre, randomized, evaluator‐blind, placebo/positive‐controlled, parallel‐group studies were to evaluate the potential for pharmacodynamic and pharmacokinetic interaction between ezetimibe 0.25, 1, or 10 mg and simvastatin 10 mg (Study 1), and a pharmacodynamic interaction between ezetimibe 10 mg and simvastatin 20 mg (Study 2). Evaluation of the tolerance of the coadministration of ezetimibe and simvastatin was a secondary objective.Methods  Eighty‐two healthy men with low‐density lipoprotein cholesterol (LDL‐C) ≥130 mg dl−1 received study drug once daily in the morning for 14 days. In Study 1 (n=58), five groups of 11–12 subjects received simvastatin 10 mg alone, or with ezetimibe 0.25, 1, or 10 mg or placebo. In Study 2 (n=24), three groups of eight subjects received simvastatin 20 mg alone, ezetimibe 10 mg alone, or the combination. Blood samples were collected to measure serum lipids in both studies. Steady‐state pharmacokinetics of simvastatin and its β‐hydroxy metabolite were evaluated in Study 1 only.Results  In both studies, reported side‐effects were generally mild, nonspecific, and similar among treatment groups. In Study 1, there were no indications of pharmacokinetic interactions between simvastatin and ezetimibe. All active treatments caused statistically significant (P<0.01) decreases in LDL‐C concentration vs placebo from baseline to day 14. The coadministration of ezetimibe and simvastatin caused a dose‐dependent reduction in LDL‐C and total cholesterol, with no apparent effect on high‐density lipoprotein cholesterol (HDL‐C) or triglycerides. The coadministration of ezetimibe 10 mg and simvastatin 10 mg or 20 mg caused a statistically (P<0.01) greater percentage reduction (mean −17%, 95% CI −27.7, −6.2, and −18%, −28.4, −7.4, respectively) in LDL‐C than simvastatin alone.Conclusions  The coadministration of ezetimibe at doses up to 10 mg with simvastatin 10 or 20 mg daily was well tolerated and caused a significant additive reduction in LDL‐C compared with simvastatin alone. Additional clinical studies to assess the efficacy and safety of coadministration of ezetimibe and simvastatin are warranted.
Population pharmacokinetics of nevirapine in an unselected cohort of HIV‐1‐infected individuals
Authors: De Maat Monique M. R. , Huitema Alwin D. R. , Mulder Jan W. , Meenhorst Pieter L. , Van Gorp Eric C. M. , Beijnen Jos H. 
Published: March 2003

Aims
To study the population pharmacokinetics of nevirapine and to identify relationships between patient characteristics and pharmacokinetics in an unselected population of patients attending our outpatient clinic.
Methods
Ambulatory HIV‐1‐infected patients from the outpatient clinic of the Slotervaart Hospital who were being treated with a nevirapine‐containing regimen were included. During each visit, blood samples were collected for the determination of nevirapine plasma concentrations and clinical chemistry parameters. Variables that were collected at baseline were serology for hepatitis B (HBV) and C (HCV) viruses, liver enzymes, and total bilirubin (TBR). In addition, information about concomitant use of St John's wort and patient demographics were included. The pharmacokinetics of nevirapine were described by first‐order absorption and elimination using nonlinear mixed effect modelling (NONMEM V1.1). Population pharmacokinetic parameters (apparent clearance (CL/F), volume of distribution (V/F), absorption rate constant (ka)) were estimated, as were interindividual, interoccasion, and residual variability in the pharmacokinetics. The influence of patient characteristics on the pharmacokinetics of nevirapine was determined.
Results
From 173 outpatients a total number of 757 nevirapine plasma concentrations at a single random time point and full pharmacokinetic curves for 13 patients were available resulting in a database of 1329 nevirapine plasma concentrations. Mean CL/F, V/F, and ka were 3.27 l h−1, 106 l, and 01.66 h−1, respectively. CL/F of nevirapine was correlated with weight, chronic HCV infection, and baseline aspartate aminotransferase (ASAT). Chronic HCV and baseline ASAT> 1.5 × upper limit of normal (ULN) decreased CL/F by 27.4% and 13.2%, respectively, whereas an increase in body weight of 10 kg increased CL/F by 0.14 l h−1. A trend towards a lower CL/F in patients of the Negroid race was observed. No significant covariates were found for V/F.
Conclusions
The pharmacokinetics of nevirapine were adequately described by our population pharmacokinetic model. Weight, chronic HCV infection, and baseline ASAT were found to be significant covariates for CL/F of nevirapine. The model incorporating these significant covariates may be an important aid in further optimizing nevirapine‐containing therapy.
The unbound percentage of saquinavir and indinavir remains constant throughout the dosing interval in HIV positive subjects
Authors: Boffito Marta , Hoggard Patrick G. , Reynolds Helen E. , Bonora Stefano , Meaden E Rhiannon , Sinicco Alessandro , Di Perri Giovanni , Back David J. 
Published: March 2003

Aims
To measure the unbound plasma concentrations of saquinavir (SQV) and indinavir (IDV) and to relate them to the total plasma concentrations in order to establish the unbound percentage of protease inhibitors in vivo during a full dosage interval profile.
Methods
HIV‐infected   subjects   (n = 35;   median   CD4   cell   count = 340 × 106 cells l−1, range: 120–825; viral load < 50 copies ml−1 in 22/35) treated with SQV or IDV containing regimens were studied. Plasma drug samples were collected at 0, 2, 4, 8 and 12 h postdose for the twice daily regimens and 0, 1, 2, 4 and 8 h for the three times daily regimens. Ultra‐filtration was used to separate unbound IDV and SQV in plasma and their respective concentrations were measured by a fully validated method using high performance liquid chromatography‐mass spectometry (h.p.l.c.‐MS/MS).
Results
Based on the ratio AUCunbound/AUCtotal, the median unbound percentage (95% CI for differences) of SQV and IDV from all the samples studied was 1.19% (0.99, 1.58%) and 36.3% (35.1, 44.2%), respectively. No significant difference was seen in the percentage binding of SQV between patients receiving SQV alone (median = 1.49%) or with ritonavir (median = 1.09%; P = 0.141; 95% CI for difference between medians = −0.145, 0.937) over the pharmacokinetic profile. Similarly, no significant difference was seen in the percentage binding of IDV in patients receiving IDV alone (median 35.2%) or with ritonavir (median = 41.3%; P = 0.069; 95% CI for difference between medians = −0.09, 15.4). The unbound concentrations of SQV (P < 0.0001; 95% CI for r  2 = 0.634, 0.815) and IDV (P < 0.0001; 95% CI for r  2 = 0.830, 0.925) remained constant as a proportion of total concentration over the full dosing profile.
Conclusions
These in vivo data confirm previously published in vitro measurements of SQV and IDV protein binding. The unbound percentage of both protease inhibitors remained constant over the dosing interval.
Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers
Authors: Gale Donna Donigi , Landells Linda J. , Spina Domenico , Miller Alan J. , Smith Kate , Nichols Terry , Rotshteyn Yakov , Tonelli Alfred , Lacouture Peter , Burch Ronald M. , Page Clive P. , O'Connor Brian J. 
Published: March 2003

Aims  To assess the pharmacokinetic and pharmacodynamic profile of the novel PDE4 inhibitor V11294A (3‐(3‐cyclopentyloxy‐4‐methoxybenzyl)‐6‐ethylamino‐8‐isopropyl‐3H purine hydrochloride) in healthy male volunteers.Methods  This was a double‐blind, single dose, randomized crossover study in eight healthy volunteers who received a single oral, fasting dose of V11294A (300 mg) or placebo. Blood samples were taken before and 0.5, 1, 2, 2.5, 3, 4, 6, 9, 12, 18 and 24 h after oral dosing for determination of plasma concentrations of V11294A. Blood samples were also taken before and 3 and 24 h after dosing for the assessment of the effect of V11294A on mononuclear cell proliferation and tumour necrosis factor (TNF) release in whole blood.Results  Following a single oral dose of 300 mg V11294A, plasma concentrations of V11294A and its active metabolite V10332 reached Cmax (ng ml−1; mean ± s.d.; 1398 ± 298, 1000 ± 400, respectively) after 2.63 ± 0.79 and 5.9 ± 2.3 h, respectively. For V11294A and V10332, t1/2 were 9.7 ± 3.9 and 9.5 ± 1.7 h, and AUC(0,∞) were 18100 ± 6100 and 18600 ± 8500 ng ml−1 h, respectively. At 3 h dosing, plasma concentrations of V11294A and V10332 (3‐(3‐cyclopentyloxy‐4‐methoxy‐benzyl)‐8‐isopropyl‐3H‐purin‐6‐ylamine) were 1300 ± 330 and 860 ± 300 ng ml−1, 7 and 3 times their in vitro IC50s for inhibition of TNF release and proliferation, respectively. Treatment with V11294A resulted in a significant reduction of lipopolysaccharide (LPS)‐induced TNF release at 3 h (P < 0.001) and at 24 h (P < 0.05) post ingestion. The amount of TNF released (pmol ml−1) in response to a submaximal concentration of LPS (4 ng ml−1) was not significantly altered following placebo treatment (before 681 ± 68 vs 3 h postdose 773 ± 109, P = 0.27). In contrast, there was a significant reduction in the amount of TNF released following treatment with V11294A (before 778 ± 87 vs 3 h postdose 566 ± 72, P = 0.02). Phytohaemagluttinin (PHA) stimulated the incorporation of [3H]‐thymidine in whole blood prior to drug administration. V11294A inhibited the PHA‐induced proliferation at 3 h (P < 0.05). No adverse reactions were noted following single oral administration of V11294A.Conclusions  A single oral 300 mg dose of V11294A administered to healthy volunteers results in plasma concentrations adequate to inhibit activation of inflammatory cells ex vivo, which persists for at least 24 h without any adverse reactions.
Bisphosphonate (olpadronate) retention and its determinants in Paget's disease of bone
Authors: Cremers S. , Eekhoff E. , Dam S. v. , Den Hartigh J. , Hamdy H. , Vermeij P. , Papapoulos S. 
Published: March 2003

Bisphosphonates (BPs) are the treatment of choice for Paget's disease of bone. They concentrate selectively in the skeleton at active sites and suppress osteoclastic bone resorption. Understanding the pharmacokinetics and pharmacodynamics can lead to improvements in the management of patients. Because of the specific pharmacology of BPs, the amount of BP delivered to the skeleton is likely to determine its effect. This amount can be estimated by measuring the whole body retention (WBR) of the BP [1].In the present study BP WBR was investigated in 75 patients with active Paget's disease of bone, and PK/PD relationships were explored.The BP WBR (WBR=dose BP−amount excreted in urine) was investigated during 5 days of intravenous treatment with olpadronate 8 mg day−1. Relationships between WBR, body weight, renal function and pretreatment disease activity (serum alkaline phosphatase (sAP), urinary hydroxyproline and urinary cross‐linked N‐telopeptides of type 1 collagen, both corrected for renal function (uOHP/Cr, uNTx/Cr)) were investigated. The relationships between change in biochemical parameters of bone metabolism (to day 5 of treatment and to nadir) and pretreatment disease activity and WBR corrected for body weight (WBR/BW) were investigated (Pearson correlation test). Statistical significance was regarded as P<0.05.The mean WBR during the 5 day treatment period was 47 ± 14% of the dose administered (range 13% to 91%). The WBR and WBR/BW were significantly related to renal function (r=−0.43 and −0.56, respectively). Correlation with the activity of the disease was examined after logarithmic transformation of the bone turnover data. All pretreatment biochemical parameters of bone turnover measured were significantly correlated with WBR and WBR/BW of olpadronate (r=0.50, 0.61 and 0.57, respectively for WBR/BW), even after adjustment for renal function.The decreases in biochemical parameters of bone turnover were significantly related to the pretreatment values of these parameters (e.g. r=0.96 for the change of sAP from pretreatment to nadir and 0.99 for uNTx/Cr). They were also significantly related to olpadronate WBR/BW (e.g. r=0.57 (uOHP/Cr), r=0.50 (uNTx/Cr) and r=0.35 (uSAP) for the change to nadir).The decrease in bone turnover by intravenous olpadronate in patients with Paget's disease of bone strongly depends on the pretreatment rate of bone turnover. This may be explained, at least partially, by the amount of BP delivered to the skeleton, which is related to renal function and rate of bone turnover.This is the first clinical study on PK/PD relationships of a BP, where the specific pharmacology of BPs is taken into account. Future studies and more longitudinally obtained data can help in better understanding the PK/PD properties of BPs in patients with Paget's disease of bone.
Hand dermatosis in upper secondary school pupils: 2-year comparison and follow-up
Authors: Yngveson M. , Svensson Å. , Johannisson A. , Isacsson Å. 
Published: March 2003

AbstractThe purpose of this comparative study was to record the prevalence and to estimate the incidence of self-reported hand dermatosis in a cohort of upper secondary school pupils on two different occasions, in 1995 and 1997. A previously validated questionnaire was used. Of the 1273 pupils invited to participate, 1136 (89·2%) responded to the questionnaire. The 1-year prevalence increased, although not significantly, from 9·6% in 1995 to 10·5% in 1997. For girls, the 1-year prevalence increased significantly, from 12·4% to 15·7%, while for boys the 1-year prevalence decreased, but not significantly, from 6·7% to 5·1%. The cumulative incidence was significantly higher (P &lt; 0·001) among the girls (10·5%) than among the boys (2·8%). Multiple logistic regressions showed that the highest risk factors for 1-year prevalence in 1995 were having self-reported childhood eczema, and a family history of atopic eczema or asthma. In 1997, the highest risk factors were self-reported childhood eczema, female gender and a family history of atopic eczema. This study has identified the point at which the genders diverge with regard to hand dermatosis, with boys tending to recover, while girls show a steady or even increasing prevalence.
Use of mycophenolate mofetil in the treatment of paraneoplastic pemphigus
Authors: Williams J.V. , Marks JR. J.G. , Billingsley E.M. 
Published: March 2003

Abstract
Paraneoplastic pemphigus (PNP) is a rare autoimmune blistering disease with circulating antibodies that bind the cell surface of the epidermis and other non-stratifying epithelia, and immunoprecipitate a complex of four or five proteins (250 kDa, 230 kDa, 210 kDa, 190 kDa and occasionally 170 kDa). 1, 2 Combinations of immunosuppressive agents are usually required to obtain even partial control of the skin lesions. 3 Mucous membrane lesions are refractory to treatment. We describe a patient with PNP whose skin and oral lesions are quiescent following treatment with oral mycophenolate mofetil.
Two cases of Merkel cell tumour arising in patients with chronic lymphocytic leukaemia
Authors: Ziprin P. , Smith S. , Salerno G. , Rosin R.D. 
Published: March 2003

Abstract
Chronic lymphocytic leukaemia (CLL) has been associated with an increased incidence of second neoplasms, especially skin cancers such as basal and squamous cell carcinomas. No association with the rarer skin cancer, the Merkel cell tumour (MCT), has previously been reported. Two patients with MCT had a previous diagnosis of CLL. MCT is an aggressive skin cancer, as up to 45% of patients have lymph node involvement at presentation and 5-year disease-free survival is as low as 30%. It is most commonly found on sun-exposed areas of the body, and ultraviolet radiation together with drug-induced or CLL-induced immunosuppression may be the underlying mechanism in the observed relationship between CLL and other skin cancers.
Viral folliculitis on the face
Authors: Jang K-A. , Kim S-H. , Choi J-H. , Sung K-J. , Moon K-C. , Koh J-K. 
Published: March 2003

Abstract
The common clinical presentations of herpes simplex virus (HSV) and molluscum contagiosum (MC) are well known to dermatologists. However, folliculitis due to these viruses is an infrequently reported entity and might be considered a sign of immunosuppression [such as infection with human immunodeficiency virus, (HIV)], especially in cases of folliculitis due to MC. The purpose of this study was to describe the clinical and histopathological characteristics of viral folliculitis due to HSV and MC. We retrospectively collected all our cases with histologically proven folliculitis due to HSV and MC between 1994 and 1999. A total of seven patients aged 7–54 years was identified. Prior to establishment of the diagnosis of folliculitis due to HSV and MC, they were treated with topical antibiotics or topical steroids, without improvement. Tentative diagnoses were bacterial folliculitis, syringoma, perifollicular fibrosis, contact dermatitis or pseudolymphoma. Biopsy of the lesions revealed multiple molluscum bodies in the follicular epithelium with sparing of the epidermis in four patients, and ballooning degeneration and intranuclear viral inclusions in the follicular epithelium in the other three. Three patients had evidence of underlying immune suppression, such as pregnancy, chronic viral hepatitis B and nasopharyngeal carcinoma. One patient had suffered from epilepsy for 4 years. Testing for HIV by enzyme-linked immunosorbent assay was negative in the four patients in whom this was performed, and T-cell subsets were normal in the three patients in whom these were quantified. In cases of molluscum folliculitis treated with simple curettage, the lesions cleared without scarring or recurrence. In cases of herpetic folliculitis, the lesions improved with antihistamines or aciclovir. MC or HSV should be considered in cases that present with folliculitis-like dermatoses but which are refractory to anti-infective and anti-inflammatory treatment.
Expression of Fc receptors for IgG during acute and chronic cutaneous inflammation in atopic dermatitis
Authors: Kiekens R.C.M. , Thepen T. , Bihari I.C. , Knol E.F. , Van De Winkel J.G.J. , Bruijnzeel-Koomen C.A.F.M. 
Published: March 2003

AbstractAtopic dermatitis is an allergic skin disease characterized by elevated total and antigen-specific serum IgE and IgG4 levels. In acute and chronic cutaneous inflammation, large cellular infiltrates including T cells, dendritic cells and macrophages are found, especially in the dermis. These cells play an important part in the regulation of local inflammatory reactions. Receptors binding IgG (FcγR) are involved in dendritic cell and macrophage function. In this study, we examined the in vivo distribution and cellular expression of the three classes of leucocyte FcγR in human skin during acute and chronic cutaneous inflammation in atopic dermatitis. Atopy patch test skin was used as a model for acute inflammation in atopic dermatitis, while chronic lesional skin was used to investigate FcγR expression in chronically inflamed skin. In atopy patch test sites no increase in the number of CD1a+ dendritic cells and a slight increase in macrophages compared with non-lesional skin was observed. Our results showed increased expression of FcγRI (CD64) and FcγRIII (CD16) in acutely inflamed skin as well as in chronically inflamed lesional skin, compared with healthy and non-lesional atopic dermatitis skin. FcγRI was expressed by RFD1+, RFD7+ and CD68+, but not by CD1a+ dermal dendritic cells. RFD1+ dendritic cells and CD68+ macrophages were the main FcγRIII-expressing cells during the acute inflammatory reaction. The significant increase in expression of FcγRIII (CD16) and FcγRI (CD64) probably results from upregulation of the receptors on resident cells. Insight into the presence of FcγR+ cells in human skin during inflammation is important both for our understanding of skin immune reactions and the development of new therapeutic concepts.