bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic drug monitoring of lopinavir/ritonavir given alone or with a non‐nucleoside reverse transcriptase inhibitor
Authors: Solas Caroline , Poizot‐Martin Isabelle , Drogoul Marie‐Pierre , Ravaux Isabelle , Dhiver Catherine , Lafeuillade Alain , Allegre Thierry , Mokhtari Malika , Moreau Jacques , Lepeu Gérard , Petit Nathalie , Durand Alain , Lacarelle Bruno 
Published: December 2004

AimsTo evaluate the interindividual variability in the plasma concentrations of lopinavir in the context of routine monitoring with or without treatment with a non‐nucleoside reverse transcriptase inhibitor and to assess the interaction between the coformulation of lopinavir/ritonavir and efavirenz or nevirapine.MethodsPlasma trough and peak concentrations (Ctrough, Cmax) of lopinavir from 182 HIV‐1‐infected patients were analysed by high‐performace liquid chromatography. Three lopinavir/ritonavir regimens were assessed, namely (A) 400 mg lopinavir/100 mg ritonavir twice daily given alone (n = 125), (B) 400/100 mg twice daily together with a non‐nucleoside reverse transcriptase inhibitor (n = 25), and (C) 533/133 mg twice daily together with a non‐nucleoside reverse transcriptase inhibitor (n = 32).ResultsMedian (ng ml−1) Ctrough and Cmax lopinavir (interquartile range, CV) were: (A) 4852 (3198–6891, 56%) and 8501 (6333–11 584, 41%), (B) 2979 (1704–5186, 74%) and 5612 (3362–11 704, 76%) and (C) 5082 (2696–7226, 74%) and 9757 (4883–12 963, 60%). Median Ctrough of lopinavir was lower in patients taking both efavirenz [P = 0.01, 95% confidence interval (CI) for difference between medians 343, 2713] and nevirapine (P = 0.019, 95% CI for difference between medians 354, 3681) compared with those taking lopinavir/ritonavir alone. A higher interindividual variability was observed when lopinavir/ritonavir was given with a non‐nucleoside reverse transcriptase inhibitor. The risk of achieving a ‘suboptimal’Ctrough of lopinavir (below a threshold of 3000 ng ml−1) was statistically higher in patients treated with a non‐nucleoside reverse transcriptase inhibitor (P < 0.001, 95% CI for difference between percentages 8.8, 43.1%) compared with those receiving lopinavir/ritonavir alone.ConclusionsOur results confirmed the interaction between lopinavir and efavirenz, and also demonstrated a significant interaction between the former drug and nevirapine, resulting in lower Ctrough of lopinavir. The wide interpatient variability in this interaction suggests that therapeutic drug monitoring may be useful in optimizing the dose of lopinavir.
Blood–brain barrier transport of morphine in patients with severe brain trauma
Authors: Ederoth Per , Tunblad Karin , Bouw René , Lundberg C. Johan F. , Ungerstedt Urban , Nordström Carl‐Henrik , Hammarlund‐Udenaes Margareta 
Published: December 2004

AimsIn experimental studies, morphine pharmacokinetics is different in the brain compared with other tissues due to the properties of the blood–brain barrier, including action of efflux pumps. It was hypothesized in this clinical study that active efflux of morphine occurs also in human brain, and that brain injury would alter cerebral morphine pharmacokinetics.MethodsPatients with traumatic brain injury, equipped with one to three microdialysis catheters in the brain and one in abdominal subcutaneous fat for metabolic monitoring, were studied. The cerebral catheter locations were classified as ‘better’ and ‘worse’ brain tissue, referring to the degree of injury. Morphine (10 mg) was infused intravenously over a 10‐min period in seven patients in the intensive care setting. Tissue and plasma morphine concentrations were obtained during the subsequent 3‐h period with microdialysis and regular blood sampling.ResultsThe area under the concentration–time curve (AUC) ratio of unbound morphine in brain tissue to plasma was 0.64 (95% confidence interval 0.40, 0.87) in ‘better’ brain tissue (P < 0.05 vs. the subcutaneous fat/plasma ratio), 0.78 (0.49, 1.07) in ‘worse’ brain tissue and 1.00 (0.86, 1.13) in subcutaneous fat. The terminal half‐life and Tmax were longer in the brain vs. plasma and fat, respectively. The relative recovery for morphine was higher in ‘better’ than in ‘worse’ brain tissue. The Tmax value tended to be shorter in ‘worse’ brain tissue.ConclusionsThe unbound AUC ratio below unity in the ‘better’ human brain tissue demonstrates an active efflux of morphine across the blood–brain barrier. The ‘worse’ brain tissue shows a decrease in relative recovery for morphine and in some cases also an increase in permeability for morphine over the blood–brain barrier.
Clinical inhibition of CYP2D6‐catalysed metabolism by the antianginal agent perhexiline
Authors: Davies Benjamin J. L. , Coller Janet K. , James Heather M. , Gillis David , Somogyi Andrew A. , Horowitz John D. , Morris Raymond G. , Sallustio Benedetta C. 
Published: December 2004

AimsPerhexiline is an antianginal agent that displays both saturable and polymorphic metabolism via CYP2D6. The aim of this study was to determine whether perhexiline produces clinically significant inhibition of CYP2D6‐catalysed metabolism in angina patients.MethodsThe effects of perhexiline on CYP2D6‐catalysed metabolism were investigated by comparing urinary total dextrorphan/dextromethorphan metabolic ratios following a single dose of dextromethorphan (16.4 mg) in eight matched control patients not taking perhexiline and 24 patients taking perhexiline. All of the patients taking perhexiline had blood drawn for CYP2D6 genotyping as well as to measure plasma perhexiline and cis‐OH‐perhexiline concentrations.ResultsMedian (range) dextrorphan/dextromethorphan metabolic ratios were significantly higher (P < 0.0001) in control patients, 271.1 (40.3–686.1), compared with perhexiline‐treated patients, 5.0 (0.3–107.9). In the perhexiline‐treated group 10/24 patients had metabolic ratios consistent with poor metabolizer phenotypes; however, none was a genotypic poor metabolizer. Interestingly, 89% of patients who had phenocopied to poor metabolizers had only one functional CYP2D6 gene. There was a significant negative linear correlation between the log of the dextrorphan/dextromethorphan metabolic ratio and plasma perhexiline concentrations (r2 = 0.69, P < 0.0001). Compared with patients with at least two functional CYP2D6 genes, those with one functional gene were on similar perhexiline dosage regimens but had significantly higher plasma perhexiline concentrations, 0.73 (0.21–1.00) vs. 0.36 (0.04–0.69) mg l−1 (P = 0.04), lower cis‐OH‐perhexiline/perhexiline ratios, 2.85 (0.35–6.10) vs. 6.51 (1.84–11.67) (P = 0.03), and lower dextrorphan/dextromethorphan metabolic ratios, 2.51 (0.33–39.56) vs. 11.80 (2.90–36.93) (P = 0.005).ConclusionsPerhexiline significantly inhibits CYP2D6‐catalysed metabolism in angina patients. The plasma cis‐OH‐perhexiline/perhexiline ratio may help to both phenotype patients and predict those in whom perhexiline may be most likely to cause clinically significant metabolic inhibition.
Kinetics of myeloid and lymphocyte recovery and infectious complications after unrelated umbilical cord blood versus HLA‐matched unrelated donor allogeneic transplantation in adults
Authors: Hamza Nashaat S. , Lisgaris Michelle , Yadavalli Gopala , Nadeau Laura , Fox Robert , Fu Pingfu , Lazarus Hillard M. , Koc Omer N. , Salata Robert A. , Laughlin Mary J. 
Published: December 2004

SummarySources for allogeneic stem cells for patients with haematological disorders lacking a histocompatible sibling donor include matched unrelated donor (MUD) and umbilical cord blood (UCB). A total of 51 patients with haematological disorders, treated with myeloablation and transplantation with either unrelated human leucocyte antigen (HLA) partially matched UCB (28 patients) or HLA‐matched MUD grafts (23 patients) during 1997–2003, were evaluated for life‐threatening infections, haematological reconstitution, graft versus host disease, relapse and event‐free survival (EFS). The median duration of neutropenia after transplantation was longer (29 d vs. 14 d) in the UCB group. The probability of donor‐derived neutrophil engraftment by day 42 was 0·86 [95% confidence interval (CI) 0·71–1·0] in UCB recipients versus 0·96 (95% CI 0·87–1·0) in MUD recipients surviving >28 d. Overall infection rates were higher in UCB recipients, particularly at the early time points (before day +50) after transplantation. Graft failure occurred in five UCB recipients and two MUD recipients and was associated with the occurrence of bacteraemia during neutropenia. The EFS at 3‐year follow‐up was 0·25 in UCB and 0·35 in MUD recipients. UCB transplantation in adults is associated with delayed neutrophil and lymphocyte recovery compared with MUD grafting, and higher rates of bacteraemia at early time points after transplantation.
Increased sensitivity to IL‐4 in cystic fibrosis patients with allergic bronchopulmonary aspergillosis
Authors: Knutsen A. P. , Hutchinson P. S. , Albers G. M. , Consolino J. , Smick J. , Kurup V. P. 
Published: December 2004

Background:  Allergic bronchopulmonary aspergillosis (ABPA) is characterized by a heightened Th2 CD4+ T‐cell response to Aspergillus fumigatus allergens and a hyper‐immunoglobulin (Ig)E state compared with cystic fibrosis patients without ABPA. We hypothesize that one reason for this response is increased sensitivity to interleukin (IL)‐4 in ABPA resulting in increased expression of CD23 and CD86 and leading to a positive amplification mechanism that increases Th2 CD4+ T cell responses.Methods:  Peripheral blood mononuclear cells (PBMC) were isolated from seven ABPA CF and 19 non‐ABPA CF patients and 16 nonatopic controls and stimulated with rIL‐4 (range 0.1–10 ng/ml) and rIL‐13 (range 1–10 ng/ml) for 48 h. The number of CD23 molecules and percentages of CD23+ B cells were quantified by flow cytometry. Both phorbol 12‐myristate 13‐acetate (PMA)/ionomycin (IO) and antigen stimulated, toxoid and Asp f2/f3/f4, PBMC were examined for cytoplasmic cytokine synthesis enumerated by cytokine staining using flow cytometry to measure Th2 and Th1 CD3+ T cells.Results:  The numbers of CD23 molecules on B‐cells were significantly elevated at time 0 in ABPA CF patients compared with both non‐ABPA CF patients and nonatopic controls. Following IL‐4 stimulation in vitro, the numbers and percentages of CD23 expression on B cells were significantly up‐regulated in ABPA CF patients compared with non‐ABPA CF patients and controls. The IL‐13 stimulation up‐regulated CD23 expression; however, there was no significant difference in ABPA CF patients compared with non‐ABPA CF patients and controls. The percentages of interferon (IFN)‐γ+ CD3+T cells following PMA/IO stimulation were significantly decreased in both ABPA and non‐ABPA CF patients compared with controls. There were no significant differences of IL‐4+ and IL‐13+ CD3+ T cells between ABPA and non‐ABPA CF patients. When tetanus toxoid stimulated T cells were examined, both ABPA and non‐ABPA CF patients had significantly decreased IFN‐γ+ CD3+ T cells compared with controls. In Asp f2/f3/f4 stimulated T cells, ABPA CF patients had significantly increased IL‐4+ CD3+ T cells compared with non‐ABPA CF patients and controls.Conclusions:  ABPA CF patients have increased sensitivity to IL‐4 but not to IL‐13 up‐regulation of CD23 molecules compared with non‐ABPA CF patients. There were decreased percentages of IFN‐γ+ and IL‐2+ Th1 T cells in CF patients compared with nonatopic controls but similar percentages of IL‐4+ Th2 T cells in all three groups. However, ABPA CF patients had increased frequency of Aspergillus‐stimulated Th2 T cells. This indicated that there is skewing of Th2 T cells in ABPA CF patients. Thus, in CF ABPA patients there is increased Th2 T cells and increased sensitivity to IL‐4.
Frequency of allergic rhinitis to laboratory animals in university employees as confirmed by chamber challenges
Authors: Ruoppi P. , Koistinen T. , Susitaival P. , Honkanen J. , Soininen H. 
Published: December 2004

Background:  Occupational risk for laboratory animal allergy (LAA) is well known, but prevention is often insufficient and new cases keep appearing.Methods:  A questionnaire on work‐related symptoms was sent to all laboratory animal workers in Kuopio University. Subjects with rhinitis were invited to an examination for LAA, which consisted of an otorhinolaryngological examination and skin prick testing (SPT) with 16 common environmental allergens and two to five relevant laboratory animals. In cases of occupational sensitization, a challenge test was performed.Results:  The questionnaire was completed by 156 of 245 (64%) subjects. Rhinitis was reported by 65 of the respondents (42%) of whom 47 were examined for LAA. The duration of exposure before the onset of rhinitis varied from 1 month to 18 years. Twenty‐seven persons (57%) had a history of some previous atopic symptoms. Forty subjects (85%) showed positive reactions in SPT, 24 (51%) for laboratory animals. Fifteen of the 26 animal challenge tests performed were positive, confirming the diagnosis of occupational allergic rhinitis in three subjects, occupational dermatitis in five and both diseases in seven subjects. The frequency of occupational allergic rhinitis among all participants was 10 of 156 (6%).Conclusions:  Atopic constitution and work‐related sensitization were common in rhinitic laboratory animal workers. Occupational allergic disease was diagnosed in nearly every third case.
Corticosteroid allergy in asthma
Authors: Kilpiö K. , Hannuksela M. 
Published: December 2004

Background: Glucocorticosteroids form the basis of therapy for asthma and other allergic diseases. However, they frequently cause delayed contact allergy and occasionally immediate allergy. The purpose of this study was to investigate the occurrence of corticosteroid allergy among patients with asthma and with some complaints caused by inhaled corticosteroids.Methods: Patch tests with corticosteroids were performed in 51 asthma patients with side‐effects from inhalant corticosteroids and in 50 symptom‐free asthma patients using the Finn Chamber® system. The corticosteroids and their vehicles were: betamethasone‐17‐valerate 1% in petrolatum, hydrocortisone‐17‐butyrate (Hc‐17‐B) 1% in ethanol, tixocortol‐21‐pivalate 1% in petrolatum, budesonide 0.1% in petrolatum, beclomethasone dipropionate 0.1 and 0.5% in petrolatum and as inhalant powder 200 μg, and fluticasone propionate 0.1 and 0.5% in petrolatum and as inhalant powder 250 μg. The results were read twice, on D4–5 and again on D10.Results: Two patients in the symptomatic group reacted to corticosteroids in patch tests, one to betamethasone‐17‐valerate, Hc‐17‐B and budesonide, and the other to budesonide and Hc‐17‐B. The first patient suffered from widespread eczematous dermatitis when using beclomethasone. Fluticasone caused oropharyngeal irritation, hoarseness and shortness of breath. The second patient experienced a severe rash after the fourth budesonide inhalation. She had used various topical corticosteroids for her atopic dermatitis without any side‐effects. None of the symptom‐free patients showed positive results.Conclusions: Delayed allergy to corticosteroids occurs occasionally in asthma, perhaps in the same frequency as in dermatitis. A positive patch test reaction usually means clinical allergy, i.e. the patient cannot use that particular steroid. Cross allergy between corticosteroids is common. However, such patients usually tolerate some other common corticosteroids.
Skin test evaluation in nonimmediate allergic reactions to penicillins
Authors: Torres M.‐J. , Sánchez‐Sabaté E. , Álvarez J. , Mayorga C. , Fernández J. , Padial A. , Cornejo‐García J.‐A. , Bellón T. , Blanca M. 
Published: December 2004

Background:  Nonimmediate reactions (NIR) to aminopenicillins (AP) are frequent. Although patch testing (PT) and intradermal testing (IT) are used for diagnosis, comparative results have never been adequately performed. We compared PT and IT in subjects with NIR to AP.Methods:  Twenty‐one subjects with NIR to AP and positive IT were re‐evaluated. Skin tests were performed with amoxicillin (AX) and ampicillin (AM) at different concentrations in petrolatum, 50, 25, and 5% w/w, for PT and in saline, 20, 2, and 0.2 mg/ml for both PT and IT. Skin biopsies from the site of the positive response were studied with haematoxylin–eosin and immunohistochemistry.Results:  In the re‐evaluation, one case was IT and PT negative and was excluded; 20 were IT positive and 18 PT positive for both AX and AM. Decreasing concentrations of AP induced a reduction in positivity in both methods when diluted in saline, but not when mixed in petrolatum (PT only). With both PT and IT, immunohistochemical studies showed a perivascular mononuclear infiltrate with CD4 and CD8 memory cells expressing perforin and granzyme B.Conclusions:  Both tests appear valuable for the diagnosis of NIR to AP. However, IT diagnosed more patients than PT. The vehicle (saline or petrolatum) had no influence on the response, although in the former the concentration was critical. The immunohistochemical analysis showed skin infiltrates compatible with a T‐cell drug reaction.
Allergenic pollen records (15 years) and sensitization in patients with respiratory allergy in Thessaloniki, Greece
Authors: Gioulekas D. , Papakosta D. , Damialis A. , Spieksma F. , Giouleka P. , Patakas D. 
Published: December 2004

Background:  Very limited allergenic pollen records exist in Greece so far; moreover, there is a lack of investigation on patient sensitization. The above data are necessary for respiratory allergy diagnosis and treatment worldwide.Methodology:  Daily records and identification of 16 airborne pollen species were made using a Burkard trap (1987–2001). Skin sensitivity to 13 most common pollen extracts was investigated, in a sample of 1311 asthmatics with atopy, admitted to the Out‐Patient Clinic for Asthma (1990–2001). Skin sensitivity to 55 allergens, including 13 pollen extracts, was detected by skin prick test.Results:  The following pollen concentrations were recorded: cypress (24.9% of the total), oak (20.8%), wall pellitory (13.6%), olive (9.1%), pine (8.9%), grasses (6.3%), plane (5.4%), hazel (3%), goosefoot (2.5%) and poplar (1.4%). The respective percentages of birch, ragweed, mugwort, willow, alder and elm were lower than 1%. The highest counts of airborne pollen grains were detected from March to June. Regarding patient sensitization, sensitivity was detected to: grasses in 530 patients (40.4%), olive 417 (31.8%), goosefoot 240 (18.3%), wall pellitory 201 (15.3%), mugwort 198 (15.1%), plantain 194 (14.6%), cypress 166 (12.7%), hazel 126 (9.6%), pine 122 (9.3%), poplar 111 (8.4%), plane 107 (8,2%), oak 99 (7.6%) and to birch 89 patients (6.8%). The sensitivity to pollen grains displays preponderance (57.9%) to males.Conclusions:  For the first time in Thessaloniki, Greece, 15‐year allergenic pollen records were conducted. Clinical observations confirm that the pollen mainly implicated in respiratory allergy symptoms are grasses, olive and wall pellitory.
Allergy markers in adults in relation to the timing of pet exposure: the EGEA* study
Authors: Oryszczyn M.‐P. , Annesi‐Maesano I. , Charpin D. , Kauffmann F. 
Published: December 2004

Background: Studies suggest that early childhood exposure to pets may protect from the development of atopy, but limited information is available on adults. The association of allergy markers in adulthood with current and childhood exposure to pets was studied considering retrospectively the window of exposure.Methods: Immunoglobulin E (IgE), skin prick tests (SPT), eosinophils were related to exposure to pets in 187 adult asthmatic cases and 243 controls from the Epidemiological Study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA) study. Analyses were redone after exclusion of subjects who removed pets or experienced symptoms to animals to take into account selection in that retrospective study.Results: In asthmatic cases, current exposure to pets was unrelated to SPT positivity (+), whereas childhood exposure was significantly related to less SPT+ to any allergen, and to cat in particular, with an association restricted to those exposed before 2 years of age [OR = 0.30 (CI 0.12–0.76)]. Considering the relative timing of exposure in relation to asthma onset showed that the protective effect of exposure to pets occurs for pet exposure starting before asthma onset [OR for SPT+ = 0.19 (CI 0.08–0.48)].Conclusion: Results support the hypothesis that exposure to pets in early life, and in particular before asthma onset, may protect against allergen sensitization in adulthood.
Mucosal T‐cell phenotypes in persistent atopic and nonatopic rhinitis show an association with mast cells
Authors: Powe D. G. , Huskisson R. S. , Carney A. S. , Jenkins D. , McEuen A. R. , Walls A. F. , Jones N. S. 
Published: December 2004

Background:  Allergic rhinitis is characterized by selective expansion of T cell subsets with a CD4+ phenotype. Recently, we identified a subpopulation of nonallergic rhinitis subjects with increased epithelial mast cell and eosinophil populations, suggestive of local mucosal allergy. Previously, T cell subsets have not been characterized in this subselection of nonallergic subjects and furthermore, their relationship to mast cell and basophil effector cells remain unidentified.Objective:  To determine if a subpopulation of nonallergic subjects with idiopathic rhinitis (IR) have localized allergy confined to their nasal mucosa by comparing the T cell subsets and major histocompatibility complex (MHC) II expressing cells to persistent allergic rhinitis (PAR). Furthermore, the relationship between T cell subsets and mast cells/basophils was investigated.Methods:  None of the symptomatic patients in this study were clinically allergen‐challenged. Nasal turbinate mucosa was removed from patients with PAR, IR and normal controls. Morphometry was performed on immunostained sections for T cell subset populations including CD3+, CD4+, CD8+, CD25+, CD45RA+, CD45RO+, human leucocyte antigen (HLA)‐DRα (MHC class II), mast cell tryptase and for basophils.Results:  Subjects with persistent allergic rhinitis differed to normal controls in showing significantly increased numbers of total (CD3+), activated (CD25+) and allergen‐naïve (CD45RA+) T lymphocytes in their nasal mucosa (P < 0.025). The naïve CD45RA+ memory T cells correlated to mucosal mast cells in PAR (P = 0.03). IR patients differ to allergic subjects in showing significantly reduced numbers of epithelial HLA‐DRα+ cells (P = 0.007), but increased numbers of CD8+ lymphocytes (P = 0.02). The CD8+ T cells correlated with mucosal mast cell numbers (P = 0.02). In both rhinitis groups, basophils were present in very low numbers obviating the need for statistical analysis.Conclusion:  PAR is characterized by increased numbers of CD3+, CD25+ and CD45RA+ T lymphocytes compared with normal mucosa. Allergic and nonallergic rhinitis groups can be separated by significant differences in the number of epithelial antigen presenting cells (APCs) (HLA‐DRα+) and sub‐epithelial activated (CD25+) T cells. Moreover, IR patients do not significantly differ to their allergic counterparts with respect to total (CD3+) and naïve (CD45RA+) T cell numbers, or numbers of epithelial activated (CD25+) lymphocytes. IR subjects show significantly increased numbers of CD8+ lymphocytes compared with control mucosa and although our findings suggest that the initiating inflammatory events may differ, both rhinitis groups show a similarity in pathology involving mucosal mast cells with an association to infiltrating T cells.