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Biomedical subjects

J M White

Publications and source records attributed to J M White.

At least 73 records · Page 4Linked to original sources
PubMed2000

Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients.

AIMS: To investigate the steady-state pharmacokinetics of (R)- and (S)-methadone in a methadone maintenance population. METHODS: Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma alpha1-acid glycoprotein concentrations were quantified by radial immunoassay. RESULTS: (R)-methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)-methadone, while AUCtau_¿u¿ss (167%) was significantly (P < 0. 001) greater. There were no significant (P > 0.2) differences between the methadone enantiomers for AUCtauss, steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%. CONCLUSIONS: Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic-pharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.

Adult↗
PubMed2000

Kinetics and inhibition of the formation of 6beta-naltrexol from naltrexone in human liver cytosol.

AIMS: To determine the kinetics of the formation of 6beta-naltrexol from naltrexone in human liver cytosol, and to investigate the role of potential inhibitors. METHODS: The kinetics of the formation of 6 beta-naltrexol from naltrexone were examined in eight human liver cytosol preparations using h.p.l.c. to quantify 6 beta-naltrexol and, the extent of inhibition of 6 beta-naltrexol formation was determined using chemical inhibitors. The formation of 6 beta-naltrexol and the back reaction of 6 beta-naltrexol to naltrexone were also examined in a microsomal preparation. RESULTS: The Vmax, Km and CLint values for the formation of 6 beta-naltrexol from naltrexone were in the ranges of 16-45 nmol mg-1 protein h-1, 17-53 microM and 0.3-2.2 ml h-1 mg-1 protein, respectively. The steroid hormones testosterone (Ki = 0.3 +/- 0.1 microM) and dihydrotestosterone (Ki = 0.7 +/- 0.4 microM) were the most potent competitive inhibitors of 6 beta-naltrexol formation, with naloxone, menadione and corticosterone also producing > 50% inhibition at a concentration of 100 microM. The opioid agonists morphine, oxycodone, oxymorphone and hydromorphone, and a range of benzodiazepines showed < 20% inhibition at 100 microM. In the microsomal preparation, there was no formation of naltrexone from 6beta-naltrexol nor any formation of 6beta-naltrexol from naltrexone. CONCLUSIONS: The intersubject variability in the kinetic parameters of 6beta-naltrexol formation could play a role in the efficacy of and patient compliance with naltrexone treatment. This variability could be due in part to a genetic polymorphism of the dihydrodiol dehydrogenase DD4, one of the enzymes reported to be responsible for the formation of 6beta-naltrexol from naltrexone. DD4 also has hydroxysteroid dehydrogenase activity which could account for the potent inhibition by the steroid hormones testosterone and dihydrotestosterone. The clinical significance of the latter finding remains to be established.

Adult↗
PubMed2000

Changes in alcohol history taking and management of alcohol dependence by interns at The Royal Adelaide Hospital.

OBJECTIVE: The objective of this study is to determine whether the presence of a drug and alcohol unit and comprehensive medical education have made a difference to the detection and management of alcohol-related problems in a general teaching hospital. METHODS: Data were obtained from hospital case notes before and after the introduction of the drug and alcohol unit and medical education. Samples of general admissions and admissions with an alcohol diagnosis were obtained. The outcome measures included alcohol history taking, quantification of alcohol consumption and management of alcohol dependence. RESULTS: It was found that for the general admission sample, interns were more likely to take an alcohol history, both in the accident and emergency (A&E) department and on the ward, in 1994 compared to 1988. The difference in the A&E department was statistically significant (P = 0.009). In the A&E department in 1994 there was a greater prevalence of alcohol history taking for male patients (odds ratio (OR) 10.09, 95% confidence interval (CI) 1.89 to 53.70, P = 0.007) compared with female patients (OR = 1.81, 95% CI 0.38 to 8.57, P = 0.045). There were no differences in alcohol history taking by interns in the samples of alcohol-related admissions. There were no statistically significant differences in the prevalence of documenting alcohol histories quantitatively in either sample. The use of alcohol withdrawal charts, ordering diazepam for alcohol withdrawal and ordering drugs which conformed to the hospital formulary all increased significantly by 1994. The prevalence of ordering thiamine and consulting the drug and alcohol unit both decreased slightly by 1994, but not significantly. CONCLUSION: Improvements have been found in the detection and management of alcohol use since the introduction of the Drug and Alcohol Unit and medical education, but there is still room for further improvement and particular areas where greater attention is needed are identified.

Alcohol Drinking↗
PubMed2000

Comparison of methods for teaching clinical skills in assessing and managing drug-seeking patients.

AIMS: New medical graduates lack clinical skills in assessing and managing patients seeking drugs of dependence. This study compares the effectiveness of three different clinical skills training methods, with similar content, which were developed to teach these skills to senior medical students. METHODS: A preliminary survey indicated that common problems seen by primary care practitioners included both new and previously known patients seeking either benzodiazepines or opiates. The common content of the teaching was determined from this survey. A didactic small group tutorial (DT), a video-based tutorial (VBT) using professional actors, and a computer-aided instruction package using digitized video (CAI) were developed with this common content, and trialled with undergraduate medical students over 2 years in a parallel-group design. Outcome was assessed by student feedback, performance on a case-based written examination and by a structured evaluation of interviews with simulated patients requesting drugs. Comparison was also made between methods on the basis of knowledge tests. RESULTS: No difference was seen in written examination and simulated patient outcomes between the three groups. However, the VBT was thought by the students to be preferable to other methods. The estimated development costs of CAI were higher, but total costs over a 6-year period were lower than for the DT and VBT. The results suggest that clinical skills can be taught equally effectively through several different methods. Collaboration between institutions in the development of widely applicable CAI tools should be an efficient and economical mode of teaching with a wide range of applications.

Clinical Competence↗
PubMed2000

Pulpal responses to cooling tooth temperatures.

This investigation measured pulpal blood flow and sensitivity to electrical stimulation as tooth temperatures were lowered. Dark rubber dams were placed on test teeth before placement of the cooling device in an attempt to shield gingival microcirculation. Laser Doppler flowmetry was used to measure pulp blood flow, whereas sensory thresholds were recorded simultaneously using an electric pulp tester. As tooth temperatures were lowered, the teeth became less responsive. Pulp blood flow also slowed, but did not completely stop. Results indicated that sensory thresholds were altered, and in some subjects, abolished, without total cessation of pulpal blood flow.

Adult↗
PubMed2000

Systematic review processes and the management of opioid withdrawal.

OBJECTIVE: To assess the diversity of research on the management of opioid withdrawal, identify sources of heterogeneity and provide a context for subsequent systematic reviews to establish evidence-based best practice. METHODS: References were identified through searches of multiple electronic databases and handsearching the reference lists of retrieved articles. The principal criterion for inclusion in the literature mapping process was that it be a study of an intervention intended to manage the process of opioid withdrawal. RESULTS: Of 218 references assessed, all participants were dependent on heroin in 41% and on methadone or l-alpha acetyl methadol (LAAM) in 24%. More than 17 different types of treatment approach were identified. Only 42% of references used a rating instrument to assess withdrawal severity and reported sufficient results to indicate the timing and magnitude of the peak and/or duration of withdrawal. The type of rating instrument used and the way in which results were reported varied enormously. A clear parameter for completion of detoxification was used for 37% of references. CONCLUSIONS: The capacity for rigorous systematic reviews of the management of opioid withdrawal is currently limited. There are multiple sources of heterogeneity that will need to be taken into account. IMPLICATIONS: The use of narrative reviews and observational studies are important complements to formal systematic reviews in the establishment of evidence-based practice in any area that combines aspects of psychology, behaviour, social context and medical treatment.

Humans↗
PubMed2000

Critical role for the cysteines flanking the internal fusion peptide of avian sarcoma/leukosis virus envelope glycoprotein.

The transmembrane subunit (TM) of the envelope glycoprotein (Env) of the oncovirus avian sarcoma/leukosis virus (ASLV) contains an internal fusion peptide flanked by two cysteines (C9 and C45). These cysteines, as well as an analogous pair in the Ebola virus GP glycoprotein, are predicted to be joined by a disulfide bond. To examine the importance of these cysteines, we mutated C9 and C45 in the ASLV subtype A Env (EnvA), individually and together, to serine. All of the mutant EnvAs formed trimers that were composed of the proteolytically processed surface (SU) and TM subunits. All mutant EnvAs were incorporated into murine leukemia virus pseudotyped virions and bound receptor with wild-type affinity. Nonetheless, all mutant EnvAs were significantly impaired ( approximately 1,000-fold) in their ability to support infectivity. They were also significantly impaired in their ability to mediate cell-cell fusion. Our data are consistent with a model in which the internal fusion peptide of ASLV-A EnvA exists as a loop that is stabilized by a disulfide bond at its base and in which this stabilized loop serves an important function during virus-cell fusion. The fusion peptide of the Ebola virus GP glycoprotein may conform to a similar structure.

Alpharetrovirus↗
PubMed2000

The central proline of an internal viral fusion peptide serves two important roles.

The fusion peptide of the avian sarcoma/leukosis virus (ASLV) envelope protein (Env) is internal, near the N terminus of its transmembrane (TM) subunit. As for most internal viral fusion peptides, there is a proline near the center of this sequence. Robson-Garnier structure predictions of the ASLV fusion peptide and immediate surrounding sequences indicate a region of order (beta-sheet), a tight reverse turn containing the proline, and a second region of order (alpha-helix). Similar motifs (order, turn or loop, order) are predicted for other internal fusion peptides. In this study, we made and analyzed 12 Env proteins with substitutions for the central proline of the fusion peptide. Env proteins were expressed in 293T cells and in murine leukemia virus pseudotyped virions. We found the following. (i) All mutant Envs form trimers, but when the bulky hydrophobic residues phenylalanine or leucine are substituted for proline, trimerization is weakened. (ii) Surprisingly, the proline is required for maximal processing of the Env precursor into its surface and TM subunits; the amount of processing correlates linearly with the propensity of the substituted residue to be found in a reverse turn. (iii) Nonetheless, proteolytically processed forms of all Envs are preferentially incorporated into pseudotyped virions. (iv) All Envs bind receptor with affinity greater than or equal to wild-type affinity. (v) Residues that support high infectivity cluster with proline at intermediate hydrophobicity. Infectivity is not supported by mutant Envs in which charged residues are substituted for proline, nor is it supported by the trimerization-defective phenylalanine and leucine mutants. Our findings suggest that the central proline in the ASLV fusion peptide is important for the formation of the native (metastable) Env structure as well as for membrane interactions that lead to fusion.

Alpharetrovirus↗
PubMed2000

Rationale and treatment approach in minimally invasive dentistry.

BACKGROUND: Current methods of detecting caries, especially fissure caries, are inaccurate, causing some caries to go undetected until it has reached more advanced stages. Minimally invasive dentistry is a philosophy in which the goal of intervention to conserve healthy tooth structure. The authors review the rationale and role of air abrasion in successful practice in the 21st century that includes the philosophy of minimal intervention. CLINICAL IMPLICATIONS: This objective encompasses a range of clinical procedures that includes assessment of caries risk to reinforce patient self-help, early detection of the disease before lesion cavitation to fortify the oral environment, restoration of fissure caries with maximum retention of sound tooth structure and sealant placement in unaffected areas. This conservative approach minimizes the restoration/re-restoration cycle, thus benefiting the patient over a lifetime.

Dental Caries↗
PubMed2000

The use of polymer-bound triphenylphosphine in the stereochemical inversion of secondary alcohols.

Polymer-bound triphenylphosphine can replace triphenylphosphine in the Mitsunobu reaction to generate stereochemically inverted secondary alcohols. This method is comparable with the standard Mitsunobu reaction in terms of inversion of stereochemistry, yield, and reaction time, even for sterically very hindered secondary alcohols. The special merit of this reaction is that the excess polymer-bound triphenylphosphine and its by-products are easily removed by filtration from the reaction products.

Alcohols↗
PubMed2000

State of the science of music interventions. Critical care and perioperative practice.

Music therapy is an easy to administer, relatively inexpensive, noninvasive intervention that can reduce anxiety and pain in critical care and perioperative patients. Libraries of relaxing music selections need to be compiled, reflecting diverse musical tastes. Providing patients with the opportunity to partake in music therapy sessions, selecting their own music, and providing them with quiet, uninterrupted time to listen to the music provides patients with a sense of control and separation from the multiple environmental stressors they are experiencing. Although there is now an extensive empirical base for the therapeutic usefulness of music therapy, particularly with the myocardial infarction population, few hospitals have adopted music therapy programs. Patient satisfaction and outcomes clearly have improved after music therapy sessions have been implemented. Further study with more diverse samples with a wider variety of medical conditions is indicated. Most of these studies used only one or two music sessions. It is not known whether effectiveness of music therapy sessions improves with repeated exposures. Further, there are little data with respect to optimal time for implementation of music therapy, length of music therapy sessions, or types of music to use. The effects of cultural diversity have not been addressed. Music therapy can improve the quality of care that critical care and perioperative nurses deliver to their patients.

Critical Care↗
PubMed1999

Role of the integrin-associated protein CD9 in binding between sperm ADAM 2 and the egg integrin alpha6beta1: implications for murine fertilization.

CD9 is a tetraspan protein that associates with several beta1 integrins, including alpha6beta1. Because alpha6beta1 is present on murine eggs and interacts with the sperm-surface glycoprotein ADAM 2 (fertilin beta), we first asked whether CD9 is present on murine eggs and whether it functions in sperm-egg binding and fusion. CD9 is present on the plasma membrane of oocytes in the ovary as well as on eggs isolated from the oviduct. The anti-CD9 mAb, JF9, potently inhibits sperm-egg binding and fusion in vitro in a dose-dependent manner. JF9 also disrupts binding of fluorescent beads coated with native fertilin or a recombinant fertilin beta disintegrin domain. (Both ligands bind to the egg via alpha6beta1.) Immunohistochemistry showed that CD9 is undetectable in the uterine epithelium, appears basolaterally and as prominent apical patches on the epithelium in the region between the uterus and the oviduct, and then persists apically in the oviduct. The integrin alpha6A subunit is found in similar apical patches in the region between the uterus and oviduct, but is confined to the basal aspect of the epithelium in the uterus and oviduct. Hence, alpha6A and CD9 both are expressed on the apical epithelial surface at the uterine-oviduct junction. These findings correlate with the observation that fertilin beta "knockout" sperm traverse the uterus but do not progress into the oviduct, contributing to the infertility of fertilin beta(-/-) male mice. Our results suggest that high-avidity binding between fertilin beta (ADAM 2) and alpha6beta1 requires cooperation between alpha6beta1 and CD9. Such cooperation may assist sperm passage into the oviduct as well as sperm-egg interactions.

ADAM Proteins↗
PubMed1999

Cutting edge: the tyrosine phosphatase SHP-1 regulates thymocyte positive selection.

The binding kinetics of the TCR for its interacting ligand and the nature of the resulting signal transduction event determine the fate of a developing thymocyte. The intracellular tyrosine phosphatase SHP-1 is a potential regulator of the TCR signal transduction cascade and may affect thymocyte development. To assess the role of SHP-1 in thymocyte development, we generated T cell-transgenic mice that express a putative dominant negative form of SHP-1, in which a critical cysteine is mutated to serine (SHP-1 C453S). SHP-1 C453S mice that express the 3.L2 TCR transgene are increased in CD4 single positive cells in the thymus and are increased in cells that express the clonotypic TCR. These data suggest that the expression of SHP-1 C453S results in increased positive selection in 3.L2 TCR-transgenic mice and support a role for SHP-1 thymocyte development.

Animals↗
PubMed1999

Treatment of mouse oocytes with PI-PLC releases 70-kDa (pI 5) and 35- to 45-kDa (pI 5.5) protein clusters from the egg surface and inhibits sperm-oolemma binding and fusion.

The effect of phosphatidyinositol-specific phospholipase C (PI-PLC) on mouse sperm-egg interaction was investigated in this study to determine if glycosyl-phosphatidylinositol (GPI)-anchored proteins are involved in mammalian fertilization. When both sperm and zona-intact oocytes were pretreated with a highly purified preparation of PI-PLC and coincubated, there was no significant effect on sperm-zona pellucida binding; however, fertilization was reduced from 59.6% (control group) to 2.8% (treatment group). A similar reduction in fertilization rates was found when zona-intact oocytes were treated with PI-PLC and washed prior to incubation with untreated sperm. The effect of PI-PLC on sperm binding and fusion with zona-free oocytes was then investigated. Treatment of sperm with PI-PLC had no significant effect on sperm-egg binding or fusion. However, treatment of eggs with PI-PLC significantly reduced sperm-egg binding and fusion from 6.2 bound and 2.1 fused sperm per egg in the control group to 2.1 bound and 0.02 fused sperm per egg in the treatment group. This decrease in sperm-egg binding and fusion depended on the dose of PI-PLC employed, with a maximal inhibitory effect on binding and fusion at 5 and 1 U/ml, respectively. PI-PLC-treated oocytes could be artificially activated by calcium ionophore, demonstrating that the oocytes were functionally viable following treatment. Furthermore, treatment of oocytes with PI-PLC did not reduce the immunoreactivity of the non-GPI-anchored egg surface integrin, alpha6beta1. Taken together, these observations support the hypothesis that PI-PLC affects fertilization by specifically releasing GPI-anchored proteins from the oolemma. In order to identify the oolemmal GPI-anchored proteins involved in fertilization, egg surface proteins were labeled with sulfo-NHS biotin, treated with PI-PLC, and analyzed by two-dimensional gel electrophoresis followed by avidin blotting. A prominent high-molecular-weight protein cluster (approximately 70 kDa, pI 5) and a lower molecular weight (approximately 35-45 kDa, pI 5.5) protein cluster were released from the oolemmal surface as a result of PI-PLC treatment. It is likely that these GPI-anchored egg surface proteins are required for sperm-egg binding and fusion.

Animals↗
PubMed1999

Evidence that distinct states of the integrin alpha6beta1 interact with laminin and an ADAM.

Integrins can exist in different functional states with low or high binding capacity for particular ligands. We previously provided evidence that the integrin alpha6beta1, on mouse eggs and on alpha6-transfected cells, interacted with the disintegrin domain of the sperm surface protein ADAM 2 (fertilin beta). In the present study we tested the hypothesis that different states of alpha6beta1 interact with fertilin and laminin, an extracellular matrix ligand for alpha6beta1. Using alpha6-transfected cells we found that treatments (e.g., with phorbol myristate acetate or MnCl2) that increased adhesion to laminin inhibited sperm binding. Conversely, treatments that inhibited laminin adhesion increased sperm binding. Next, we compared the ability of fluorescent beads coated with either fertilin beta or with the laminin E8 fragment to bind to eggs. In Ca2+-containing media, fertilin beta beads bound to eggs via an interaction mediated by the disintegrin loop of fertilin beta and by the alpha6 integrin subunit. In Ca2+-containing media, laminin E8 beads did not bind to eggs. Treatment of eggs with phorbol myristate acetate or with the actin disrupting agent, latrunculin A, inhibited fertilin bead binding, but did not induce laminin E8 bead binding. Treatment of eggs with Mn2+ dramatically increased laminin E8 bead binding, and inhibited fertilin bead binding. Our results provide the first evidence that different states of an integrin (alpha6beta1) can interact with an extracellular matrix ligand (laminin) or a membrane-anchored cell surface ligand (ADAM 2).

ADAM Proteins↗
PubMed1999

Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: comparison of those who do and do not experience withdrawal and concentration-effect relationships.

OBJECTIVE: To determine plasma racemic methadone concentration-effect relationships for subjective and objective responses and whether pharmacokinetic and/or pharmacodynamic factors influence withdrawal severity. METHODS: Eighteen patients enrolled in a public methadone maintenance program, nine of whom experienced significant withdrawal, received constant doses of methadone once daily for at least 2 months. During an interdosing interval, 13 blood samples were collected to measure plasma racemic methadone concentrations (patients); subjective (withdrawal severity, direct opioid effects, and pain threshold) and objective (pupil diameter and respiratory rate) opioid effects were quantified on 11 occasions (all participants). The sigmoid Emax model was used to relate plasma concentrations and effects and to calculate the slope factor (N). The rate of decline in plasma concentration during each hour from the peak to the trough concentration was calculated. RESULTS: There was an inverse relationship between plasma concentrations and withdrawal severity and pupil diameter, as well as a direct relationship with subjective opioid effects and pain threshold. The mean N values were 5.4+/-0.9 for withdrawal severity, 5.1+/-1.1 for subjective opioid effects, 1.2+/-0.1 for pupil diameter, and 2.8+/-0.7 for pain threshold. Withdrawal severity correlated with the maximum rate of decrease in plasma concentration (P < .01). There were no differences between those who reported significant withdrawal and those who did not with respect to mean area under the plasma concentration versus time curve and predose plasma concentration, but maximal rate of decline was greater in the former group (74.5 versus 42.1 ng/mL/h). CONCLUSIONS: In this group of long-term methadone-maintained recipients, opioid responses were strongly correlated with changes in plasma racemic methadone concentrations. For the subjective responses, notably withdrawal, small changes in plasma concentrations translate into relatively large changes in effect; therefore, clinically important withdrawal is a consequence of more rapid decline in methadone concentration.

Adult↗
PubMed1999

Acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA) in Sprague-Dawley and Dark Agouti rats.

Ingestion of MDMA ("ecstasy") by humans can cause acute toxicity manifested by hyperthermia and death. Demethylenation of MDMA is catalyzed by cytochrome P-450 2D6 (CYP2D6) and cytochrome P-450 2D1 (CYP2D1) in humans and rats, respectively, and is polymorphically expressed. It has been proposed that CYP2D6 deficiency may account for the unexplained toxicity of MDMA. The female Dark Agouti rat is deficient in CYP2D1, and serves as a model for the human poor metabolizer. We investigated thermogenic and locomotor actions of MDMA in adult female Sprague-Dawley (CYP2D1 replete) and Dark Agouti rats. MDMA (2, 5, and 10 mg/kg) and saline were injected subcutaneously at ambient temperatures of 22 and 31 degrees C. There was no difference in core temperature responses between the two rat strains. Hypothermia occurred in the first 30 min and temperature elevation thereafter. MDMA increased locomotor activity in Sprague-Dawley but not in Dark Agouti rats. However, MDMA had pronounced lethal effects at 31 degrees C ambient in the Dark Agouti rats only. We conclude that the poor metaboliser phenotype may predispose to lethality, but the mechanism is as yet unknown.

Alcohol Oxidoreductases↗