bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of genetic variants on pain and analgesia
Authors: Stamer Ulrike M. , Zhang Lan , Stüber Frank 
Published: October 2008

Genomic variations' influence on basal pain sensitivity, the likelihood of significant pain and development of chronic pain diseases is the target of current investigations. Catechol‐O‐methyltransferase (COMT) and the μ‐opioid receptor (OPRM1) genes are frequently studied “candidate genes”. This article reviews recent studies of human genetics of pain which implicate polymorphisms in these candidate genes.Associations of COMT and OPRM1 genetic variants were reported with sensitivity to pain, analgesic requirements as well as side effects of pharmacotherapy in either experimental pain settings or in patients suffering from acute or chronic pain. However, attempts to directly link genotypes to pain states remain largely unsuccessful up to date. Studies associating pain or analgesic demands to single nucleotide polymorphisms or haplotypes showed inconsistent results in the majority. There is a need for sufficiently powered studies to adequately address this topic. Innovative techniques and accelerating methodologic advances in the field of genetic analysis will help to reveal associations between genetic variants and pain in the near future.
Modern Burma Studies: A Survey of the Field
Authors: SELTH ANDREW 
Published: October 2008

AbstractBurma has never been a popular subject for academic research but, since a massive pro-democracy uprising drew worldwide attention to the country in 1988, the number of scholars and students engaged in the field has grown considerably. However, they still face a number of major challenges. Along with other kinds of area studies, Burma studies have been accused by academics from the more ‘scientific’ disciplines of being too narrowly focused and lacking theoretical rigour. Also, it has been difficult to conduct research in Burma's closed society. While the latest military government has relaxed some controls, field work is still constrained and reliable sources are hard to find. Often, the knowledge gap has been filled by myths and misconceptions. Adding to these problems, since 1988 the Burma studies community has become highly polarised, with political and moral factors often featuring more prominently in the public debate than considered arguments based on objective analysis. All these factors have adversely affected modern Burma studies and restricted understanding of this deeply troubled country by both scholars and the wider community.
GENERALIZED MIXED QUASI-COMPLEMENTARITY PROBLEMS IN TOPOLOGICAL VECTOR SPACES
Authors: FRAJZADEH ALI P. , NOOR MUHAMMAD ASLAM 
Published: October 2008

AbstractIn this paper, we introduce and consider a new class of complementarity problems, which are called the generalized mixed quasi-complementarity problems in a topological vector space. We show that the generalized mixed quasi-complementarity problems are equivalent to the generalized mixed quasi variational inequalities. Using a new type of KKM mapping theorem, we study the existence of a solution of the generalized mixed quasi-variational inequalities and generalized mixed quasi-complementarity problems. Several special cases are also discussed. The results obtained in this paper can be viewed as extension and generalization of the previously known results.
COMPUTABLE STRONGLY ERGODIC RATES OF CONVERGENCE FOR CONTINUOUS-TIME MARKOV CHAINS
Authors: LIU YUANYUAN , ZHANG HANJUN , ZHAO YIQIANG 
Published: October 2008

AbstractIn this paper, we investigate computable lower bounds for the best strongly ergodic rate of convergence of the transient probability distribution to the stationary distribution for stochastically monotone continuous-time Markov chains and reversible continuous-time Markov chains, using a drift function and the expectation of the first hitting time on some state. We apply these results to birth–death processes, branching processes and population processes.
A NOTE ON THE HU–HWANG–WANG CONJECTURE FOR GROUP TESTING
Authors: LEU MING-GUANG 
Published: October 2008

AbstractHu et al. [“A boundary problem for group testing”, SIAM J. Algebraic Discrete Meth.2 (1981), 81–87] conjectured that the minimax test number to find d defectives in 3d items is 3d−1, a surprisingly difficult combinatorial problem about which very little is known. In this article we state three more conjectures and prove that they are all equivalent to the conjecture of Hu et al. Notably, as a byproduct, we also obtain an interesting upper bound for M(d,n).
MISSILE CONTROL DESIGN BASED ON THE LINEAR MULTIPLE SLIDING MODE RECURSIVE METHOD
Authors: SHI Y. J. , MA G. F. 
Published: October 2008

AbstractTo ensure that the elevator of a cruise missile is operating within the design specification in high-attitude flight, we present a design method for the construction of a sliding mode recursive variable structure controller. In this design method, a target sliding mode surface is first designed without considering the engineering specification of the elevator. Secondly, by using this specification, the critical state is solved. Then, the transitional sliding mode surfaces are designed recursively by using the critical state of the previous sliding mode surface so that the state will move smoothly from one transitional sliding mode surface to the next until the target sliding mode surface. This design method is based on linear sliding mode variable structure theory. Thus, the controller obtained is simple in structure and practical. Furthermore, the elevator will operate within the engineering specification. The simulation results show the effectiveness of the proposed method.
Human papillomavirus in the placenta and umbilical cord blood
Authors: SARKOLA MARJA E. , GRÉNMAN SEIJA E. , RINTALA MARJUT A.M. , SYRJÄNEN KARI J. , SYRJÄNEN STINA M. 
Published: October 2008

AbstractObjective. To analyze human papillomavirus (HPV) DNA in umbilical cord blood and in placenta, including its cellular localization. Design. Longitudinal prospective study. Setting. Maternity Unit of Turku University Hospital, and MediCity, University of Turku. Samples. Placental and cord blood samples obtained at delivery from 315 mothers and 311 neonates included in the Finnish HPV Family Study. Methods. HPV testing by nested PCR and sequencing. Tyramide amplified in situ hybridization (ISH) for viral DNA localization in placenta. Correlation to mother's and neonate's oral and genital HPV status and maternal demographic data. Main outcome measures. Detection and cellular localization of HPV DNA. Results. HPV DNA was detected in 4.2 and 3.5% of placenta and cord blood samples, respectively, including HPV types 16, 6, 83 and 39. In placenta, HPV6 and 16 DNA was localized in syncytiotrophoblasts. Abnormal cytology increased the risk of HPV+ placenta and cord blood. History of genital warts was the only independent predictor of cord blood HPV in multivariate analysis (adjusted OR=4.0, 95% CI: 1.09–14.54, p = 0.036). HPV DNA in cord blood increased the risk of genital (OR=4.0, 95% CI: 1.08–14.83, p = 0.048) and oral (OR=4.4, 95% CI: 1.17–16.14, p = 0.039) HPV DNA carriage of the neonate. HPV+ placenta increased the risk of oral HPV of the neonate (OR=8.6, 95% CI: 2.73–27.13, p = 0.0001). Delivery mode did not predict HPV status of the neonate. Conclusions. HPV DNA is detected in placental trophoblasts and umbilical cord blood. The presence of HPV DNA at these sites increases the risk of a neonate testing HPV‐positive at birth.
The effects of repeated dermal application of capsaicin to the human skin on pain and vasodilatation induced by intradermal injection of acid and hypertonic solutions
Authors: DEL BIANCO ELENA , GEPPETTI PIERANGELO , ZIPPI PAOLA , ISOLANI DUNIA , MAGINI BEATRICE , CAPPUGI PIETRO 
Published: October 2008

The effect of repeated capsaicin application on the skin of the volar surface of the forearm on the pain sensation and on the increase in blood flow induced by intradermal injection of low pH media or hypertonic solutions was investigated in 13 healthy volunteers.Low pH media (4, and 2.5) were obtained by adding HCl to 0.9% saline. Hypertonic solutions (300 and 600 mM) were obtained by adding NaC1 to pH 7.4, 0.9% saline. Capsaicin (1% in 50% ethanol) was painted on the volar skin of one forearm, chosen at random, for 7 days. The contralateral forearm was treated with the capsaicin vehicle. Pain was assessed by a visual analogue scale and skin blood flow by a laser doppler flowmeter.Pain sensation and increase in blood flow (both peak and area under the curve) induced by low pH media were markedly reduced in the capsaicin pretreated side. Capsaicin pretreatment also reduced the increase in blood flow, but did not affect the pain response induced by hypertonic saline solutions.Repeated application of capsaicin to the human skin inhibits both the sensory (pain) and ‘efferent’ (vasodilatation) responses induced by low pH media, whereas it reduces the vasodilatation, but not the pain caused by hypertonic media.Repeated application of capsaicin to the human skin, a therapy used in various diseases, discriminates between sensory, but not ‘efferent’ responses induced by different stimuli.
Dose dependent time course of the analgesic effect of a sustained‐release preparation of tramadol on experimental phasic and tonic pain
Authors: THÜRAUF N. , FLEISCHER W. K. , LIEFHOLD J. , SCHMID O. , KOBAL G. 
Published: October 2008

The aim of this study was to investigate the analgesic effect and its duration of a new sustained‐release preparation of tramadol in an experimental pain model based on pain‐related chemosomatosensory evoked potentials (CSSEPs) and subjective intensity estimates of painful phasic and tonic stimuli.Twenty volunteers participated in a randomised, double‐blind, three‐fold crossover study. Measurements were obtained before and 0.5, 1, 4, 6, and 12 h after administration of the drug (100 mg, 200 mg and placebo orally). CSSEPs were recorded after stimulation of one nostril with phasic, painful CO2pulses. The other nostril was stimulated with a constant stream of dry air, which produced a tonic painful sensation. Subjects rated the perceived intensity of phasic and tonic stimuli via visual analogue scales. In order to test for nonspecific effects, acoustic evoked potentials (AEPs) were recorded, the spontaneous EEG was analysed in the frequency domain, the subject's vigilance was assessed in a tracking task, and the side effects of the drug were monitored.The sustained‐release preparation of tramadol produced a significant dose‐related decrease in CSSEP amplitudes when compared with placebo. The reduction in amplitudes outlasted the observation period of 12 h, demonstrating the prolonged duration of the analgesic effect.A dose‐related significant decrease could be observed for the estimates of tonic pain. Similar to the decrease of amplitudes of the CSSEP, the reduction of the ratings of tonic pain outlasted the observation period of 12 h. The observed slight decrease in the estimates of phasic pain under medication did not reach a statistically significant level when compared with placebo. No significant effect could be demonstrated for the perception of the phasic and the tonic pain as determined by the McGill‐Questionnaire.A significant dose‐related increase in the estimates of the side effects ‘drowsiness’, ‘vertigo’ and ‘sickness’ but not for ‘tiredness’ could be demonstrated.
Pharmacokinetics and tolerability of meloxicam after i.m. administration
Authors: NARJES H. , TÜRCK D. , BUSCH U. , HEINZEL G. , NEHMIZ G. 
Published: October 2008

1 The pharmacokinetics and tolerability of a new nonsteroidal anti‐inflammatory drug (NSAID), meloxicam, administered i.m., were investigated in two studies conducted in healthy male volunteers. Study 1 was an open, placebo‐controlled design in which 32 volunteers were randomized to a single ascending i.m. dose of meloxicam (5, 10, 20, and 30 mg) or placebo. Study 2 had an open, randomized two way crossover design in which 12 volunteers received single i.m. and i.v. doses of meloxicam (15 mg).2 Meloxicam showed an excellent tolerability in both studies. No effect was seen on serum creatinphosphokinase (CK, the isoenzyme of the skeletal muscle enzyme, CK‐MM, was determined).3 Following i.m. administration meloxicam was rapidly and completely absorbed (mean absolute bioavailability 102%). Dose‐proportionality was demonstrated with respect to Cmax (maximum plasma concentration) and AUC (extrapolated area under the plasma concentration‐time curve from zero time to infinity) over a range of 5–30 mg.4 Intravenous administration of meloxicam (15 mg) resulted in higher initial plasma concentrations (C3min, i.e. concentration in plasma 3 min after start of injection = 2.99 ± 0.75 μg·ml‐1) than after i.m. injection (Cmax: 1.62 ± 0.20 mg ml‐1). All other pharmacokinetic parameters were similar for both routes of administration (apparent elimination half‐life = 15–22 h; plasma clearance = 7–9 ml min‐1).5 In conclusion, the excellent tolerability of i.m. meloxicam together with its rapid and complete absorption may provide an alternative to oral administration of this drug.
Venlafaxine oxidationin vitrois catalysed by CYP2D6
Authors: OTTON S. V. , BALL S. E. , CHEUNG S. W. , INABA T. , RUDOLPH R. L. , SELLERS E. M. 
Published: October 2008

1 Several selective 5‐HT reuptake inhibitors (SSRIs) are inhibitors of the genetically polymorphic drug metabolizing enzyme, CYP2D6. We studied the interaction of venlafaxine, a new SSRI, with CYP2D6 in human liver microsomes.2 Venlafaxine was a less potent inhibitor of this enzyme activityin vitrothan other SSRIs tested. The average apparentKivalues determined using CYP2D6‐dependent dextromethorphanO‐demethylation were: 33, 52 and 22 μM for rac‐venlafaxine, R(+)‐venlafaxine and S(‐)‐venlafaxine, respectively,vs0.065 to 1.8 μM for paroxetine, fluoxetine, norfluoxetine, fluvoxamine and sertraline.3 Microsomes from human livers (n= 3) and from yeast transformed with an expression plasmid containing human CYP2D6 cDNA catalyzed theO‐demethylation of venlafaxine, which is the major metabolic pathwayin vivo.Intrinsic metabolic clearance values (Vmax/Km) indicated that S(‐)‐venlafaxine was cleared preferentiallyviathis pathway.4 In microsomes from CYP2D6‐deficient livers (n= 2),Vmax/KmaxofO‐demethylation of venlafaxine was one to two orders of magnitude lower and was similar to the rate ofN‐demethylation.5 Studies with chemical probes which preferentially inhibit P450 isoforms suggested that CYP3A3/4 is involved in venlafaxineN‐demethylation.6 Thesein vitrofindings predict phenotypic differences in the kinetics of venlafaxinein vivo, although the clinical importance of this is unclear asO‐demethylvenlafaxine is pharmacologically similar to the parent drug. The findings also predict relatively limited pharmacokinetic interaction between venlafaxine and other CYP2D6 substrates.
Pharmacokinetic evaluation of proguanil: a probe phenotyping drug for the mephenytoin hydroxylase polymorphism
Authors: SOMOGYI ANDREW A. , REINHARD HELEN A. , BOCHNER FELIX 
Published: October 2008

1 Proguanil (PG) oxidative metabolism to cycloguanil (CG) has been linked to the CYP2C19–mediated genetic polymorphism in S‐mephenytoin oxidative metabolism. In many countries, rac‐mephenytoin can no longer be administered to humans and hence proguanil may be a more suitable probe for phenotyping purposes.2 There are limited data on the pharmacokinetics of PG and CG and in particular, whether there is a relationship between the urinary metabolic ratio of PG and its partial intrinsic clearance to CG.3 The disposition of a 100 mg oral dose of PG was investigated in 10 subjects with widely varying metabolic ratios (pre‐study urinary metabolic ratio CG to PG = 0.068 to 1.11). Blood samples and all urine were collected for 96 h and assayed for PG and CG by h.p.l.c.4 The urinary recovery of PG ranged from 30 to 69% of the dose and for CG from 2.8 to 32% of the dose. The overall urinary recovery of PG plus CG ranged from 54 to 77% of the dose. The AUC for PG ranged from 3.2 to 9.5 mg 1‐1 h whereas for CG it was from 0.02 to 0.71 mg 1‐1 h. The partial intrinsic clearance to CG ranged 25–fold from 0.41 to 10.11 h‐15 There was a highly significant (r2= 0.96, P < 0.001) relationship between the urinary metabolic ratio for PG (as CG/PG) and its partial intrinsic clearance to CG.6 These data have provided evidence for the justification of the use of the urinary metabolic ratio of proguanil for population phenotyping purposes, provided systematic variation in renal drug clearance between populations is considered.
In vitrointeraction of the antipsychotic agent olanzapine with human cytochromes P450 CYP2C9, CYP2C19, CYP2D6 and CYP3A
Authors: RING BARBARA J. , BINKLEY SHELLY N. , VANDENBRANDEN MARK , WRIGHTON STEVEN A. 
Published: October 2008

1 The ability of olanzapine to inhibit the metabolism of marker catalytic activities for the cytochromes P450 CYP3A, CYP2D6, CYP2C9, and CYP2C19 was examined. This inhibitory capability was compared with that obtained with clozapine and known inhibitory compounds for the same cytochromes P450.2 Olanzapine, clozapine, and ketoconazole were all found to non‐competitively inhibit 1′‐hydroxy midazolam formation, form selective for CYP3A, yieldingKi, values of 491, 99 and 0.11 μM, respectively. The 1′‐hydroxylation of bufuralol, form selective for CYP2D6, was competitively inhibited by olanzapine (Ki= 89μM), clozapine (Ki= 19 μM), and quinidine (Ki= 0.03 μM). Tolbutamide metabolism to 4–hydroxy tolbutamide, form selective for CYP2C9, was competitively inhibited by clozapine and phenytoin (Kiof 31 μM and 17 μM, respectively). Olanzapine non‐competitively inhibited tolbutamide metabolism with aKiof 715 μM. The marker catalytic activity for CYP2C19 mediated metabolism, 4′‐hydroxy S‐mephenytoin formation, was competitively inhibited by clozapine (Ki= 69 μM) and omeprazole (Ki= 4.1 μM). Non‐competitive inhibition of CYP2C19 mediated metabolism was seen with olanzapine with aKiof 920 μM.3 The calculated percent inhibition by olanzapine of substrates metabolized by CYP3A, CYP2D6, CYP2C9, and CYP2C19 was modeled assuming a total plasma concentration in the therapeutic range (0.2 μM). Total olanzapinevsunbound olanzapine was used to model the worst case (most conservative) situation. In all cases, the calculated percent inhibition of these cytochromes P450 by olanzapine was <0.3%, suggesting that there would be littlein vivoinhibition of the metabolism of substrates of these enzymes when co‐administered with olanzapine.
Identification of drugs inhibiting thein vitrometabolism of tacrolimus by human liver microsomes
Authors: CHRISTIANS UWE , SCHMIDT GUDRUN , BADER AUGUSTINUS , LAMPEN ALFONS , SCHOTTMANN RENATE , LINCK ANNETTE , SEWING KARL‐FRIEDRICH 
Published: October 2008

1 Tacrolimus, an immunosuppressive macrolide, is metabolized by enzymes of the cytochrome P450 3A subfamily. In this study, 34 drugs were tested for their interactions with tacrolimus metabolism by human liver microsomes.2 Fifteen drugs which inhibit thein vitrometabolism of tacrolimus were identified: bromocriptine, corticosterone, dexamethasone, ergotamine, erythromycin, ethinyloestradiol, josamycin, ketoconazole, miconazole, midazolam, nifedipine, omeprazole, tamoxifen, troleandomycin and verapamil.
A pharmacokinetic interaction study of didanosine coadministered with trimethoprim and/or sulphamethoxazole in HIV seropositive asymptomatic male patients
Authors: SRINIVAS N. R. , KNUPP C. A. , BATTEIGER B. , SMITH R. A. , BARBHAIYA R. H. 
Published: October 2008

R. A. SMITH31 The pharmacokinetics of didanosine, trimethoprim, and sulphamethoxazole were evaluated in ten HIV seropositive asymptomatic patients as single agents and upon coadministration of single doses.2 Using a randomized, balanced incomplete block crossover study with at least a 1–week washout period between successive treatments, each patient under fasting conditions received four of the following five treatments: 200 mg didanosine as a single agent; 200 mg trimethoprim +1000 mg sulphamethoxazole; 200 mg trimethoprim + 200 mg didanosine; 1000 mg sulphamethoxazole + 200 mg of didanosine and; 200 mg trimethoprim +1000 mg sulphamethoxazole + 200 mg didanosine.3 Serial blood and urine samples were collected following the administration of each treatment. Plasma and urine samples were analyzed using high‐pressure liquid chromatography (h.p.l.c.)/ultraviolet assays specific for unchanged didanosine, trimethoprim and/or sulphamethoxazole.4 Percent urinary recovery (%UR) and renal clearance (CLR) emerged as consistently affected parameters, being decreased in the case of didanosine (35%,P= 0.016) and trimethoprim (32%,P= 0.019) and increased in the case of sulphamethoxazole (39%,P= 0.079), when all three agents were coadministered. The magnitude of the changes in didanosine CLRand %UR values was no greater when both trimethoprim and sulphamethoxazole were coadministeredvswhen each single agent was given with didanosine, suggesting that any effect was not additive.5 Other key parameters such as CmaxAUC, andt1/2for didanosine (1309.9 ng ml‐1, 1796.9 ng ml‐1h, and 1.61 h, respectively), trimethoprim (1.96 pg ml‐1, 22.86 μg ml‐1h, and 9.03 h, respectively) or sulphamethoxazole (58.62 μg ml‐1, 799.7 μg ml‐1h and 9.84 h, respectively) were not affected when didanosine was coadministered with either trimethoprim (didanosine: 1751.9 ng ml‐1, 2158.0 ng ml‐1h, and 1.28 h; trimethoprim: 1.81 μg ml‐1, 28.89 μg ml‐1h, and 11.4 h), sulphamethoxazole (didanosine: 1279.3 ng ml‐1, 1793.2 ng ml‐1h, and 1.61 h; sulphamethoxazole: 53.57 μg ml‐1, 732.1 μg ml‐1h, and 8.95 h), or the combination of trimethoprim and sulphamethoxazole (didanosine: 1283.7 μg ml‐1, 1941.8 ng ml‐1h, and 1.38 h; trimethoprim: 1.59 μg ml‐1, 26.68 μg ml‐1h, and 11.3 h; sulphamethoxazole: 59.48 μg ml‐1, 760.9 μg ml‐1h, and 9.47 h).6 Because the observed differences in CLRand %UR are small and not considered to be clinically relevant, it is not necessary to alter the dosing regimens of didanosine, trimethoprim or sulphamethoxazole when administered in combination to HIV seropositive patients.
Lack of interaction between flucloxacillin and methotrexate in pa tien t s with rheumatoid arthritis
Authors: HERRICK ARIANE L. , GRENNAN DAVID M. , GRIFFEN KERRY , AARONS LEON , GIFFORD LARRY A. 
Published: October 2008

1 The aim of the study was to examine the potential pharmacokinetic interaction between methotrexate and flucloxacillin.2 Ten rheumatoid arthritis patients participated in the interaction study. Subjects were allocated to either methotrexate alone (5–15 mg per week) or methotrexate plus flucloxacillin (500 mg four times a day 48 h prior to sampling) in a random order.3 There was a statistically, but not clinically, significant decrease in methotrexate AUC (1307 ± 389vs1212 ± 394 μg 1‐‐1h) in the presence of flucloxacillin. Cmaxand tmaxparameters for methotrexate were not significantly altered in the presence of flucloxacillin.4 Data from an additional 10 rheumatoid arthritis patients, starting on methotrexate, were added to the data from the placebo arm of the interaction study and a model dependent pharmacokinetic analysis was performed. The plasma concentration profiles were best described by a two‐compartment model with a mean clearance of 11.9 (± 1.7) 1 h‐1and an initial volume of distribution of 31.2 (± 2.6) 1. The pronounced intersubject variability in the pharmacokinetic parameters was not related to any of the available covariate information.5 Our findings suggest that no important clinical interaction occurs between flucloxacillin and methotrexate in patients with rheumatoid arthritis.