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Biomedical subjects

P Wilcox

Publications and source records attributed to P Wilcox.

At least 19 recordsLinked to original sources
PubMed2006

Predictors of pulmonary exacerbations in patients with cystic fibrosis infected with multi-resistant bacteria.

BACKGROUND: This study examined characteristics of adult and adolescent patients with cystic fibrosis (CF) to determine factors associated with an increased risk of pulmonary exacerbations. METHODS: 249 patients with CF infected with multidrug resistant bacteria were recruited and prospectively followed for up to 4.5 years until they experienced a pulmonary exacerbation severe enough to require intravenous antibiotics. Multivariable regression analyses were used to compare the characteristics of patients who experienced an exacerbation with those who did not. RESULTS: 124 of the 249 patients (50%) developed a pulmonary exacerbation during the first year and 154 (62%) experienced an exacerbation during the 4.5 year study period. Factors predictive of exacerbations in a multivariable survival model were younger age (OR 0.98, 95% CI 0.96 to 0.99), female sex (OR 1.45, 95% CI 1.07 to 1.95), lower forced expiratory volume in 1 second (FEV(1)) (OR 0.98, 95% CI 0.97 to 0.99), and a previous history of multiple pulmonary exacerbations (OR 3.16, 95% CI 1.93 to 5.17). Chronic use of inhaled corticosteroids was associated with an increased risk of exacerbation (OR 1.92, 95% CI 1.00 to 3.71) during the first study year. CONCLUSIONS: Patients who experience pulmonary exacerbations are more likely to be younger, female, using inhaled steroids, have a lower FEV(1), and a history of multiple previous exacerbations. It is hoped that knowledge of these risk factors will allow better identification and closer monitoring of patients who are at high risk of exacerbations.

Adolescent↗
PubMed2004

Adoptive immunotherapy with donor lymphocyte infusions and interleukin-2 after high-dose therapy and autologous stem cell rescue for multiple myeloma.

In an attempt to induce a graft-versus-myeloma effect, we administered donor lymphocyte infusions (DLI) after high-dose therapy with autologous stem cell transplant rescue to seven patients with refractory or relapsed multiple myeloma. High-dose therapy consisted of melphalan, idarubicin and etoposide (days -9 to -6) followed by autologous stem cell infusion on day 0. DLI (five of seven donors with two or three HLA antigens mismatched) were administered on days +1, +5 and +10 along with IL-2 (from day +1 through +12). Six of the seven patients developed acute graft-versus-host disease (GVHD), which resolved spontaneously, coincidentally with autologous hematopoietic reconstitution. One patient failed to engraft and received a second autologous graft. One patient died from complications of a pulmonary hemorrhage after experiencing GVHD. With a minimum follow-up of 38 months, five patients remain without disease progression in complete remission or with minimal residual disease. In this setting, DLI/IL-2 is biologically active resulting in GVHD. A graft-versus-myeloma effect is suggested by the improved outcome of our small cohort of high-risk patients. The use of partially mismatched related donors makes this approach potentially available to nearly all patients.

Adoptive Transfer↗
PubMed2003

Early microdose drug studies in human volunteers can minimise animal testing: Proceedings of a workshop organised by Volunteers in Research and Testing.

Testing the safety and efficacy of a successful human medicine involves many laboratory animals, which can sometimes be subjected to considerable suffering and distress. Also, it is necessary to extrapolate from the test species to humans. UK and European legislation requires that Replacement, Reduction and Refinement of animal procedures (the Three Rs) are implemented wherever possible. Over the last decade, there has been substantial progress with applying in vitro and in silico methods to both drug efficacy and safety testing. This paper is a report of the discussions and recommendations arising from a workshop on the role that might be played by human volunteer studies in the very early stages of drug development. The workshop was organised in November, 2001 by Volunteers in Research and Testing, a group of individuals in the UK which launched an initiative in 1994 to identify where and how human volunteers can participate safely in biomedical studies to replace laboratory animals. It was considered that conducting pre-Phase I very low dose human studies (sub-toxic and below the dose threshold for measurable pharmacological or clinical activity) could enable drug candidates to be assessed earlier for in vivo human pharmacokinetics and metabolism. Moreover, accelerator mass spectrometry (AMS), nuclear magnetic resonance (NMR) spectroscopy and positron emission tomography (PET) are potentially useful spectrometric and imaging methods that can be used in conjunction with such human studies. Some, limited animal tests would still be required before pre-Phase I microdose studies, to take account of the potential risk posed by completely novel chemicals. The workshop recommended that very early volunteer studies using microdoses should be introduced into the drug development process in a way that does not compromise volunteer safety or the scientific quality of the resulting safety data. This should improve the selection of drug candidates and also reduce the likelihood of later candidate failure, by providing in vivo human ADME data, especially for pharmacokinetics and metabolism, at an earlier stage in drug development than is currently the case.

Animal Testing Alternatives↗
PubMed1998

Decision-making about breast cancer susceptibility testing: how similar are the attitudes of physicians, nurse practitioners, and at-risk women?

PURPOSE: To determine what consumers and providers would want to discuss about breast cancer susceptibility testing (BCST) and their preferred role in testing decisions. METHODS: We surveyed 426 at-risk women, 143 nurse practitioners, and 296 physicians in five specialties in Maryland. RESULTS: All groups believe it is important to discuss how the chance of breast cancer can be reduced and what the chances are of getting breast cancer if the test is positive. Both provider groups attributed more importance than consumers to discussing whether cancer can occur if the test is negative. Discussing the risk of depression and anxiety was more important to providers than consumers. Eighty-two percent of women would want their providers to make a recommendation about testing, but only 43% of nurse practitioners and 68% of physicians would do so. Eighteen percent of physicians underestimated the importance of informed consent for testing and 34% of discussing the risk of insurance discrimination. Fewer than 6% of women, if found to have a mutation, would be likely to undergo prophylactic mastectomy, whereas 12% of nurse practitioners and 34% of physicians would be likely to recommend such surgery. One third of respondents in all three groups supported testing a 13-year old daughter of a mutation-carrier. CONCLUSION: Physicians should place greater value on informed consent and discussing practical aspects of testing, and physicians and nurse practitioners should pay more attention to the limitations of testing children, insurance discrimination, and consumers' desire for provider recommendations. In light of the limited discordance between nurse practitioners and consumers, nurse practitioners can play an increasing role in education and counseling about BCST.

Adult↗
PubMed1996

Extended harvest times are not necessary for the detection of in vitro clastogens in regulatory cytogenetics studies.

The choice of harvest time in in vitro cytogenetics assays is a critical factor in determining the sensitivity of the assay for detecting clastogenic potential. As yet there is no harmonization of regulatory requirements in this aspect. It has been suggested that the use of extended harvest times can improve the sensitivity of detecting some chemicals which either induce cell cycle delay or produce lesions which induce chromosome aberrations at divisions subsequent to the first post-treatment mitosis. The incidence of such chemicals encountered in the routine testing of chemicals for regulatory submissions is not known. Therefore a large database of 550 chemicals tested in nine laboratories using standard regulatory protocols, including a late harvest time, was assessed for the incidence of chemicals uniquely positive only at a delayed harvest time. The number of such chemicals was very low ( < 0.2%) and the chromosome damage induced by these chemicals may not result from direct genotoxic mechanisms. Based on these data it is recommended that there is no need to include an extended harvest time in in vitro cytogenetics assays except where it might help to resolve an equivocal result.

Animals↗
PubMed1996

A comparison of conventional metaphase analysis of Giemsa-stained chromosomes with multi-colour fluorescence in situ hybridization analysis to detect chromosome aberrations induced by daunomycin.

Chromosome aberrations induced by daunomycin, a widely used positive control compound for in vitro cytogenetics assays, were identified by multi-colour fluorescence in situ hybridization with probes for chromosomes 1, 2 and 3. The frequency and distribution of aberration types were compared to conventional metaphase analysis of Giemsastained chromosomes from parallel human lymphocyte cultures. Multi-colour chromosome painting was a more sensitive method for detecting daunomycin-induced chromosome aberrations compared with conventional metaphase analysis because: (i) a higher level of statistical significance was achieved at low doses; and (ii) the increases in aberration frequencies compared with controls were greater. The majority of exchanges identified by Giemsastaining were unstable and were likely to lead to cell death. In contrast, those detected by FISH were mostly stable exchanges which may be transmitted to cell progeny. Multicolour FISH using whole chromosome probes may provide an elegant solution to the problem of identifying non-lethal, heritable exchange events. The benefit of this technique is the quantification of a cytogenetic endpoint directly associated with carcinogenesis.

Adult↗
PubMed1996

High-dose tumor necrosis factor alpha produces an impairment of hamster diaphragm contractility. Attenuation with a prostaglandin inhibitor.

We have investigated the influence of the cytokine tumor necrosis factor alpha (TNF alpha), an important mediator of sepsis, on in vitro hamster diaphragm contractility. Costal diaphragm strips were excised and mounted on an experimental apparatus consisting of a force transducer and servomotor. Preparations were randomized to incubation in one of the following solutions: (1) indomethacin 10(-6) M (n = 5); (2) TNF alpha (0.1 ng/ml) (n = 5); (3) TNF alpha (500 ng/ml) (n = 5); and (4) TNF alpha (500 ng/ml) plus indomethacin (10(-6)) (n = 5). Baseline contractile parameters measured at optimal length included twitch and tetanic tension, half relaxation time, time to peak tension, force frequency response (10-80 Hz), and fatigability to response to repetitive stimulation. After 90-min incubation in one of the solutions, an identical stimulation protocol was repeated. Initial twitch and tetanus parameters were similar between groups. Maximal twitch tension and tetanic tension decreased significantly, as did tetanic stimulations at 10-80 Hz in the TNF group (500 ng/ml) (p < 0.05). Coincubation with indomethacin decreased but did not completely abolish changes in diaphragm function caused by the higher dose of TNF. There were no significant changes in twitch or tetanus parameters, or in response to repetitive stimulation after incubation in the lower dose TNF group (0.1 ng/ml). We conclude that TNF causes impairment of in vitro diaphragm contractility at high incubation concentrations of TNF and that this effect can be partially blocked by prostaglandin synthetase inhibition. No significant deleterious effect on in vitro contractility was detected at concentrations of TNF similar to serum levels in human sepsis.

Animals↗
PubMed1995

The effect of PHA stimulation on lymphocyte sub-populations in whole-blood cultures.

Although lymphocytes in phytohaemagglutinin (PHA)-stimulated whole blood cultures are routinely used to assess genotoxin-induced chromosome damage, very little information is available on the effect of PHA on the various cell populations present, and there appear to be no data for the protocols used in routine genotoxicity assays. In this study, we used flow cytometric analysis to examine the size/complexity of the white blood cell (WBC) population and the expression of key antigenic markers by the lymphocytes over a 96-h period following PHA stimulation. The changes in the WBC population are complex, and would seem to represent different populations dying out, remaining static or starting to divide. The initial decrease seen in overall cell numbers probably reflects death of the neutrophil and monocyte populations. The subsequent increase in cell numbers appears to be due to division of the lymphocytes and, by 96 h post-stimulation, they comprise about half the total cell number and, as expected, > 90% are activated T-cells; it seems reasonable to assume that these represent the target cells in genotoxicity assays. Although we do not suggest that these findings should alter the routine conduct of clastogenicity assays using PHA-stimulated whole-blood cultures, they indicate that such tests are empirical and that closer investigation will only confirm their relatively imprecise nature.

Cell Division↗
PubMed1994

Evaluation of pyrazole and ethanol induced S9 fraction in bacterial mutagenicity testing.

A major constitutive enzyme in the liver of the uninduced rat is cytochrome P450-2E1. This isozyme has been shown to metabolize a number of carcinogens, including low molecular weight nitrosamines and a number of compounds normally regarded as non-mutagenic in the Ames test, e.g. aniline, urethane and benzene. Using the standard induction procedures [Aroclor 1254 or a combination of phenobarbitone (PB) and beta-naphthoflavone (beta-NF)] the level of CYP2E1 in rat liver is actually suppressed and it has been suggested that this may account for the negative findings with these compounds in the Ames test. S9 fractions were prepared from rats pre-treated with pyrazole or ethanol (inducers of CYP2E1) and then used in the Ames test (or pre-incubation modification) with urethane, acetaminophen, aniline, benzene, procarbazine and N-nitrosopyrrolidine. Both pyrazole and ethanol induced S9 were superior to PB/beta-NF-S9 and uninduced-S9 for the activation of N-nitrosopyrrolidine, a known CYP2E1 substrate. However, there was no evidence of mutagenic activity with urethane, aniline, benzene, procarbazine or acetaminophen. As these compounds have demonstrated genotoxicity in vivo, additional important metabolic pathways must be required which are not present in rat liver S9 fraction.

Animals↗
PubMed1994

Spontaneous pulmonary hemorrhage after thrombolytic therapy for acute myocardial infarction.

We report a case of 63-year-old man who developed massive pulmonary hemorrhage following intravenous streptokinase for acute myocardial infarction. Pulmonary hemorrhage was diagnosed by the triad of hemoptysis, a drop in hematocrit, and a new unilateral infiltrate on chest radiograph. This diagnosis was confirmed by autopsy findings. Pulmonary hemorrhage has rarely been reported following thrombolytic therapy. We believe that pulmonary hemorrhage is a rare but a potentially life-threatening complication of thrombolytic therapy and should be considered in the differential diagnosis of pulmonary infiltrates or falling hemoglobin after thrombolytic therapy for acute myocardial infarction with no obvious site of bleeding.

Drug Therapy, Combination↗
PubMed1993

Report of the Association of British Pharmaceutical Industries Collaborative Study Group. Collaborative study to evaluate the inter/intra laboratory reproducibility and phenotypic stability of Salmonella typhimurium TA97a and TA102.

A collaborative trial was carried out to determine the intra/interlaboratory variability of Salmonella typhimurium strains TA102 and TA97a with regard to spontaneous revertant frequency and in response to four model mutagens (cumene hydroperoxide and bleomycin for strain TA102, and 4-nitrophenylenediamine and 4-aminoantipyrine for strain TA97a). A secondary objective of the trial was to monitor the stability of the strains after storage for up to 8 months and identify any technical problems associated with their use. Thirteen different laboratories participated in the trial, all receiving identical stock cultures of the bacterial strains and samples from the same batch of mutagenic compound. A standard protocol was followed and two independent experiments were carried out within 1 month of receipt of the strains/compounds (phase I), and again after a period of 6-8 months (phase II). Comparative studies with the standard strain TA100 after treatment with 4-nitrophenylenediamine were carried out as part of phase II. Overall, both strains gave acceptably consistent results in different laboratories and are considered useful for screening purposes when used under standardized conditions. One major source of interlaboratory variability identified for TA102 appears to be the sensitivity of different types of automatic colony counter for detecting the micro-colony revertants that this strain produces.

Ampyrone↗
PubMed1992

Sensitivity of Salmonella typhimurium TA97a to the type of agar used for preparation of Vogel-Bonner plates.

Recent problems with the supply of Difco bacto agar have forced some laboratories to evaluate alternative agars for use in the Salmonella/microsome assay. This led to the independent observation in two laboratories (Boots and Glaxo) that Salmonella typhimurium TA97a is sensitive to certain types of agar that may be used to prepare Vogel-Bonner minimal medium plates. A programme of work was, therefore, undertaken to investigate this phenomenon; 9-aminoacridine hydrochloride (at Boots) and 4-nitro-o-phenylenediamine (at Glaxo) were tested against TA1537 and TA97a using Vogel-Bonner plates prepared with a number of different agars. Three agars (Lab M, Difco Bi-tek and Beckton Dickinson granulated) were identified which, although supporting normal growth of TA1537 revertant colonies, gave much reduced control counts and responses to the mutagens with TA97a. One agar, Becton Dickinson grade A, gave poor responses with TA1537 but produced satisfactory results with TA97a. In contrast to the Vogel-Bonner plates, varying the type of agar used in the top agar overlays had little effect on the responses obtained. On the basis of these comparisons, Becton Dickinson purified agar was selected as a suitable alternative to Difco bacto and it was concluded that laboratories using agars other than these, or purchasing pre-poured plates without specifying the type of agar, should be made aware of potential problems with TA97a.

Agar↗
PubMed1992

Monocyte inflammatory mediators impair in vitro hamster diaphragm contractility.

Sepsis has been shown to impair ventilatory muscle function. To determine whether this can be attributed to direct effects of inflammatory mediators on muscle fibers, we carried out in vitro studies on hamster costal diaphragm. Baseline measurements included supramaximal peak twitch (Pt) and tetanic tension (Po), twitch half relaxation time (1/2RT) and time-to-peak tension (TTP), and force frequency response (15 to 80 Hz). Fatigability was evaluated using 60-Hz stimulations at a duty cycle of 0.4 until tension fell to 50% of baseline. Preparations were then incubated in one of the following for 60 min: (1) Krebs solution (n = 5), (2) nonstimulated monocyte supernatant (n = 5), or (3) lipopolysaccharide-stimulated monocyte supernatant (n = 5). Baseline Pt, Po, 1/2RT, TTP, force frequency response, and fatigue profile were similar between groups. After incubation there was a significant fall in Pt (mean +/- SD, 538 +/- 65 to 288 +/- 13 g/cm2, p < 0.05) and Po (1,268 +/- 132 to 921 +/- 64 g/cm2, p < 0.05) in the LPS group, with no change in the other groups. There was no change in TTP; however, 1/2RT was lower in the LPS-stimulated group after incubation (p < 0.05). There was a rightward shift in the force frequency response for the LPS-stimulated group (p < 0.05). When normalizing for initial Po, there was no significant change in the time to fatigue for any of the three groups. This study demonstrated that monocyte secretory products impair diaphragmatic contractility in vitro by a direct effect on muscle fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Investigations into the induction of aneuploidy and polyploidy in mammalian cells by the anti-tussive agent noscapine hydrochloride.

Noscapine, a non-narcotic, centrally-acting anti-tussive drug induces polyploidy in Chinese hamster CHL cells; further studies were carried out to investigate whether similar effects could be induced in other rodent cells (Chinese hamster V79) and in human lymphocytes. In both cases, large increases in the frequency of polyploid cells were induced at test concentrations ranging from 15 to 120 micrograms/ml after 24 and 48 h continuous treatment in the absence of S9 mix. In addition, spindle damage was observed in V79 cells and human skin fibroblasts after 24 h treatment with test concentrations of 30 and 60 micrograms/ml. Furthermore, after treatment of human skin fibroblasts there was a marked increase in the proportion of cells containing chromosomes which had become dislocated from the spindle. Treatment of the mouse/human hybrid cell line R3-5 induced a significant increase in the number of 6-thioguanine resistant colonies and it was confirmed cytogenetically that these colonies had arisen due to loss of human chromosome 2. From these experiments it can be concluded that noscapine induces polyploidy in both rodent and human somatic cells, and that this could arise through a direct effect upon spindle structure and/or function. The aneugenic properties of noscapine are less certain and further work is required in this area. Exposure to the drug through its therapeutic use (15mg up to four times daily) could exceed, at least locally within the gastrointestinal (GI) tract, the concentration range shown to be active in these in vitro studies. An immediate topical hazard might exist within the buccal cavity and GI tract, but further confirmation of these in vitro results are required using suitable in vivo systems before definite conclusions can be made regarding any potential hazard associated with the administration of this drug.

Aneuploidy↗