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Biomedical subjects

S Webber

Publications and source records attributed to S Webber.

At least 19 recordsLinked to original sources
PubMed2005

Increase in thyroid follicular cell tumors in nelfinavir-treated rats observed in a 2-year carcinogenicity study is consistent with a rat-specific mechanism of thyroid neoplasia.

The carcinogenic potential of nelfinavir mesylate (nelfinavir) was evaluated in a 2-year oral (gavage) study on Sprague-Dawley rats at dose levels of 0 (control), 0 (vehicle control), 100, 300 and 1000 mg/kg per day. At the end of the treatment, increased incidences of thyroid follicular cell hyperplasia and neoplasms were observed at 300 (males) and 1000 mg/kg per day (both sexes). There were no other treatment-related effects and no tumors at other sites. Results from previous studies indicated a number of effects in the liver and thyroid, as well as metabolic profiles that suggested nelfinavir might cause thyroid hyperplasia/neoplasia secondary to hormone imbalance by altering thyroid hormone disposition. To investigate this hypothesis, the effects of nelfinavir on gene expression in rat hepatocytes and liver slices (in vitro), thyroxine plasma clearance, and thyroid gland function were evaluated. Compared to controls, gene expression analyses demonstrated an increased expression of glucuronyltransferase (UDPGT) and CYP450 3A1 in nelfinavir-treated rat hepatocytes and liver slices. In rats treated with nelfinavir (1000 mg/kg per day) for 4 weeks, liver weights and centrilobular hepatocellular hypertrophy were increased and minimal to mild diffuse thyroid follicular cell hypertrophy and follicular cell hyperplasia were evident in the thyroid gland. Thyroid-stimulating hormone (TSH) levels were significantly increased (three-fold), while tri-iodothyronine (T3)/tetra-iodothyronine (T4) and reverse T3(rT3) levels were unchanged, indicating that a compensated state to maintain homeostasis of T3/T4 had been achieved. Plasma 125I-thyroxine clearance was increased and the plasma thyroxine AUC0-48 was decreased (24%) compared to control. In conclusion, these data indicate that thyroid neoplasms observed in the nelfinavir-treated rats were secondary to thyroid hormone imbalance. Increased thyroxine clearance contributes to the effects of nelfinavir on thyroid gland function and is probably a result of UDPGT induction that leads to elevated TSH levels in the rat and eventual thyroid neoplasia. These results are consistent with a well-recognized rat-specific mechanism for thyroid neoplasms.

Adenocarcinoma, Follicular↗
PubMed2004

The impact of pharmacogenomic factors on acute persistent rejection in adult lung transplant patients.

Persistent rejection in the face of treatment and multiple episodes of rejection are associated with the development of chronic rejection and graft loss in solid organ transplantation. The factors that create an environment for rejection that persists in the face of treatment are as yet not understood. The objective of this study was to evaluate the risk factors, including human multidrug resistance gene (MDR1), cytochrome P4503A5 (CYP3A5) and cytokine gene polymorphisms, associated with acute persistent rejection (APR) in lung transplant patients. One hundred and twenty-five adult lung transplant patients were studied. MDR1 G2677T, C3435T and CYP3A5 polymorphisms were assessed by direct sequencing of the polymorphic region in patient DNA. Cytokine genotyping for five cytokines was performed using the polymerase chain reaction-sequence specific primers (PCR-SSP) technique. Multivariate regression analysis was used to identify the predictors of acute persistent rejection. The dependent variable was the presence or absence of acute persistent rejection based on lung biopsies during the first postoperative year. The independent variables were MDR1 G2677T and C3435T, CYP4503A5 and cytokine polymorphisms, survival status, age, gender, survival days and HLA mismatches. The MDR1 C3435T polymorphism and age were independently associated with acute persistent rejection (p = 0.025, odds ratio = 0.29, 95% CI 0.1-0.86 and p = 0.016, odds ratio = 0.94, 95% CI 0.89-0.98, respectively). For the MDR1 C3435T polymorphism, 72% of patients with the C allele had acute persistent rejection in comparison to 52% for TT patients (p = 0.04). For age, a significant difference was found between the nonrejection group and the rejection group (mean+/-S.D. 52.1+/-11.2 vs. 44.4+/-12.3, p = 0.01). This is the first report of the association of a drug disposition genotype with drug-resistant acute rejection in organ transplant patients. The major predictor of acute persistent rejection in the first postoperative year for lung transplant patients was the MDR1 C3435T genotype. This association could be due to drug resistance, altered drug disposition or other immunologic effects associated with P-glycoprotein (P-gp) function. Future prospective treatment algorithms should be developed that will incorporate the knowledge of gene polymorphisms into treatment regimens to improve the outcome following lung transplantation.

Adult↗
PubMed2004

Hodgkin-like posttransplant lymphoproliferative disorder in children: does it differ from posttransplant Hodgkin lymphoma?

Epstein-Barr virus (EBV)-mediated lymphoid proliferations occur in patients who are immunocompromised and are reported following bone marrow or solid organ transplantation. Most post-transplant lymphoproliferative disorders (PTLD) are polymorphic in appearance; some are monomorphic and can resemble conventional malignant lymphomas. PTLD that resembles Hodgkin lymphoma has been reported infrequently. We herein report seven cases of PTLD that have large numbers of Reed-Sternberg-like (RS-like) cells and highlight differences in the phenotype of these cases that may distinguish Hodgkin-like PTLD (HL-PTLD) from true Hodgkin lymphoma/disease (HD). All patients were in the second decade of life and were 8 months to 13 years following transplant. HL-PTLD involves lymph nodes that contain a mixed population of small to intermediate-sized lymphocytes with large mononuclear and occasionally binucleate RS-like cells. The large cells of HL-PTLD are pleomorphic B cells that react strongly for CD20 and/or CD79a, express CD30, but are usually negative for CD15 and have few mitoses. They are positive for EBV early RNA (EBER) using an EBER-1 probe, as are some of the background small lymphocytes. A single case of true Hodgkin lymphoma has highly atypical RS-like cells that contain numerous mitoses, does not have CD20 or CD79a reactivity, has CD15 and CD30 staining, and the EBER-1 probe is confined to the large cells only. All patients were managed by withdrawal of immunosuppression and variably treated with either antiviral or anti-CD20 monoclonal antibody, or with chemotherapy. A unique instance of evolution from a HL-PTLD to true HD is also illustrated. In conclusion, HL-PTLD and HD appear to be two related but immunophenotypically and biologically distinct forms of lymphoproliferation in post-transplant patients and may require different protocols for their management.

Adolescent↗
PubMed2004

Assessment of functional nasolacrimal duct obstruction--a survey of ophthalmologists in the southwest.

The term 'functional nasolacrimal duct obstruction' describes patients with epiphora where the tear duct is partially or completely patent to syringing. Delayed tear drainage is demonstrated with a fluorescein dye disappearance test (FDDT) or lacrimal scintigraphy. A dacrocystogram is also frequently abnormal. Studies show that selected patients with epiphora because of functional nasolacrimal duct obstruction have an 80-90% success rate with open or endonasal dacryocystorhinostomy. To find out if such patients were being considered for surgery, we sent a questionnaire to all ophthalmologists in the southwest. Of the 198 questionnaires, 163 were completed and returned (82%). In the assessment of epiphora, fewer than half those questioned (41%) regularly used an FDDT and only 51% syringe patients themselves. Most did not use lacrimal scintigraphy or dacrocystography if the drainage system was patent on syringing. This survey shows that many patients with epiphora who are patent to syringing are being incompletely assessed, and hence not considered for dacrocystorhinostomy. We recommend that an FDDT is performed on all patients, syringing is carried out by experienced staff, and more radiological investigations are undertaken, so patients with a highly treatable cause of epiphora can be offered dacrocystorhinostomy.

Attitude of Health Personnel↗
PubMed2002

Dilated pupils and loss of accommodation following diode panretinal photocoagulation with sub-tenon local anaesthetic in four cases.

AIM: To describe pupillary abnormalities associated with diode laser photocoagulation with subTenon's local anaesthetic. METHODS: We describe four cases of tonic pupils following diabetic panretinal photocoagulation with subTenon's local anaesthetic. RESULTS: Six pupils of four patients became dilated and sustained loss of accommodation with denervation hypersensitivity with 0.1% pilocarpine after undergoing panretinal photocoagulation with a subTenon's local anaesthetic. The numbers of burns were not excessive and in one patient it even occurred after only 1200 laser burns. CONCLUSION: Diode laser causes histological changes deeper in the retina and the choroid than in Argon laser. Intense diode laser burns may cause damage to the short ciliary nerves traversing the choroid. In the unanaesthetised patient, pain arises when the laser burn hits these nerves and so may protect the eye from excess damage to the nerves. When the eye is anaesthetised with a subTenon's, local anaesthetic damage to the choroidal nerves may occur without the laser operator being aware that the burns are too intense.

Adult↗
PubMed2001

Sirolimus for rescue and primary immunosuppression in transplanted children receiving tacrolimus.

AIMS: The role of sirolimus (SRL) as a rescue agent (n=42) and as a component of primary immunosuppression (n=8) was evaluated in a mixed population of 50 transplanted children receiving tacrolimus (liver: 26, heart: 5, intestinal: 5, liver-intestine: 9, lung: 1, bone marrow: 1, liver-kidney: 1, multivisceral: 1). Rescue indications for tacrolimus (TAC) failure were recurrent acute rejection and acute rejection complicating withdrawal of immunosuppression in posttransplant lymphoproliferative disorder (PTLD). Rescue indications for TAC toxicity were nephrotoxicity, pancreatitis, seizures, hypertrophic cardiomyopathy, and graft-versus-host disease. RESULTS: Mean age at rescue was 11.5 years and mean follow-up was 204 (range 18-800) days. As primary immunosuppression, SRL+TAC prevented early acute rejection in 7/8 children. The indication for rescue resolved in 33/42 children. In children with TAC toxicity, this was associated with decrease in TAC doses by 50%, significant improvements in renal function, and continuing decline in Epstein-Barr virus (EBV) viral load in PTLD patients. Serious adverse events led to discontinuation of SRL in 9/42 rescue patients, 3 of them also experienced acute rejection. Three additional children also experienced acute rejection on SRL therapy (overall incidence 6/50, 12%). Pharmacokinetic analysis in the first week of SRL administration suggested a short half-life (11.8+/-5.5 hr, n=21). CONCLUSIONS: SRL and reduced-dose TAC may achieve adequate immunosuppression without compromising renal function or enhancing EBV viremia significantly.

Acute Disease↗
PubMed2001

Effects of cyclosporin A administered into the airways against antigen-induced airway inflammation and hyperreactivity in the rat.

The immunosuppressant cyclosporin A given orally has anti-asthma properties but carries an undesirable risk of systemic effects. We administered cyclosporin A to Brown Norway rats either orally (p.o.) or topically by intratracheal (i.t.) instillation into the airways before inhaled antigen. Cyclosporin A suppressed the antigen-induced accumulation of activated (CD25+) CD4+ T lymphocytes and eosinophils in the lung, interleukin-5 mRNA expression in lung tissue and airway hyperreactivity. Intratracheal cyclosporin A suppressed cell accumulation at a 10-fold lower dose than that required orally. Minimum effective doses were 3 mg x kg(-1) i.t. and 30 mg x kg(-1) p.o. Intratracheal administration reduced the plasma concentration and systemic exposure compared with an equieffective oral dose, but the reduction (4-5-fold) was not as large as anticipated. Our data suggests that although topical administration to asthmatics would provide some potential for an improved safety margin, it may not offer any major advantage over existing oral therapy. However, the data clearly demonstrate that a novel immunosuppressant with similar anti-inflammatory properties but reduced potential for systemic effects would offer an attractive therapy for severe asthma.

Administration, Inhalation↗
PubMed2001

The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy.

RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.

Administration, Oral↗
PubMed2001

The effect of cytokine gene polymorphisms on pediatric heart allograft outcome.

BACKGROUND: Cytokines play a major role in the inflammatory and immune responses that mediate allograft outcome. Several studies have shown that the production of cytokines varies among individuals and these variations are determined by genetic polymorphisms, most commonly within the regulatory region of the cytokine gene. The aim of this study was to assess the effect of these allelic variations on acute rejection after pediatric heart transplantation. METHODS: We performed cytokine genotyping using polymerase chain reaction-sequence specific primers in 93 pediatric heart transplant recipients and 29 heart donors for the following functional polymorphisms: tumor necrosis factor-alpha (TNF-alpha) (-308), interleukin (IL)-10 (-1082, -819, and -592), TGF-beta1 (codon 10 and 25), IL-6 (-174), and interferon-gamma (INF-gamma) (+874). The distribution of polymorphisms in this population did not differ from published controls. The patients were classified as either non-rejecters (0 or 1 episode) or rejecters (> 1 episode) based on the number of biopsy proven rejection episodes in the first year after transplantation. RESULTS: Forty-two of the 69 TNF-alpha patients (61%) in the low producer group were non-rejecters, while 9 of the 24 (37.5%) with high TNF-alpha were non-rejecters (p = 0.047). In contrast, IL-10 genotype showed the opposite finding. Forty-two of the 66 patients (64%) in the high and intermediate IL-10 group were non-rejecters, while 9 of the 26 (35%) in the low IL-10 group were non-rejecters (p = 0.011). The combination of low TNF-alpha with a high or intermediate IL-10 genotype was associated with the lowest risk of rejection (34/49 or 69% non-rejecters). Neither the distribution of the IL-6, INF-gamma, and TGF-beta1 genotype in recipients nor the donor genotype showed any association with acute rejection. CONCLUSION: Genetic polymorphisms that have been associated with low TNF-alpha and high IL-10 production are associated with a lower number of acute rejection episodes after pediatric heart transplantation.

Adolescent↗
PubMed2001

Epstein-Barr virus load monitoring: its role in the prevention and management of post-transplant lymphoproliferative disease.

The Epstein-Barr virus load in the peripheral blood at the time of diagnosis of post-transplant lymphoproliferative disease (PTLD) is elevated 1000- to 10,000-fold compared to the level detected in normal latency. With the use of quantitative polymerase chain reaction (PCR), changes in the viral load over time can be measured with a two- to fourfold accuracy. This has allowed early detection of first-time infections and reactivations that may lead to PTLD and has provided an opportunity to intervene before symptomatic disease has occurred. Viral load monitoring has also been used to follow patients with PTLD and, along with other parameters, provided an assessment of the effectiveness of therapeutic protocols. Viral load monitoring has led to the discovery that at least two-thirds of transplant recipients become persistent viral load carriers. While the persistent load appears to be largely carried in latently infected memory B cells, more work is needed to clearly define this type of persistent infection and determine the risks associated with it. New diagnostic tests need to be developed to distinguish the persistent latent viral loads from viral loads that are likely to become symptomatic PTLD.

DNA, Viral↗
PubMed2001

The role of antiviral and immunoglobulin therapy in the prevention of Epstein-Barr virus infection and post-transplant lymphoproliferative disease following solid organ transplantation.

The recognition of the importance of Epstein-Barr virus (EBV) infection, including EBV-associated post-transplant lymphoproliferative disease (PTLD), has led to a new focus on the prevention of this problem. This paper reviews the scientific rationale behind, and clinical experience with, the use of chemoprophylaxis (using acyclovir or ganciclovir) and immunoprophylaxis (using intravenous immunoglobulin) in the prevention of EBV/PTLD. While some centers have already introduced the use of one or both of these agents as standard prophylaxis against the development of this complication, published data in support of these protocols are currently lacking. Well designed clinical trials are necessary to evaluate the potential role of both antiviral and immunoglobulin agents in the prevention of EBV/PTLD in organ transplant recipients.

Antiviral Agents↗
PubMed2001

Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities.

Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor (K(i) = 2 nM) and is being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. The current studies evaluated the presence of metabolites circulating in plasma following the oral administration of nelfinavir to healthy volunteers and HIV-infected patients, as well as the levels in plasma and antiviral activities of these metabolites. The results showed that the parent drug was the major circulating chemical species, followed in decreasing abundance by its hydroxy-t-butylamide metabolite (M8) and 3'-methoxy-4'-hydroxynelfinavir (M1). Antiviral assays with HIV-1 strain RF-infected CEM-SS cells showed that the 50% effective concentrations (EC50) of nelfinavir, M8, and M1 were 30, 34, and 151 nM, respectively, and that the corresponding EC50 against another HIV-1 strain, IIIB, in MT-2 cells were 60, 86, and 653 nM. Therefore, apparently similar in vitro antiviral activities were demonstrated for nelfinavir and M8, whereas an approximately 5- to 11-fold-lower level of antiviral activity was observed for M1. The active metabolite, M8, showed a degree of binding to human plasma proteins similar to that of nelfinavir (ca. 98%). Concentrations in plasma of nelfinavir and its metabolites in 10 HIV-positive patients receiving nelfinavir therapy (750 mg three times per day) were determined by a liquid chromatography tandem mass spectrometry assay. At steady state (day 28), the mean plasma nelfinavir concentrations ranged from 1.73 to 4.96 microM and the M8 concentrations ranged from 0.55 to 1.96 microM, whereas the M1 concentrations were low and ranged from 0.09 to 0.19 microM. In conclusion, the findings from the current studies suggest that, in humans, nelfinavir forms an active metabolite circulating at appreciable levels in plasma. The active metabolite M8 may account for some of the antiviral activity associated with nelfinavir in the treatment of HIV disease.

Blood Proteins↗
PubMed2001

Pediatric solid-organ transplant recipients carry chronic loads of Epstein-Barr virus exclusively in the immunoglobulin D-negative B-cell compartment.

Solid-organ transplant recipients are at risk for development of lymphoproliferative diseases. The purpose of this study was to examine the distribution of Epstein-Barr virus (EBV) load in the peripheral blood of pediatric transplant recipients who had become chronic viral load carriers (>8 copies/10(5) lymphocytes for >2 months). A total of 19 patients with viral loads ranging from 20 to 5,000 viral genome copies/10(5) lymphocytes were studied. Ten patients had no previous diagnosis of posttransplant lymphoproliferative disease (PT-LPD), while nine had recovered from a diagnosed case of PT-LPD. No portion of the peripheral blood viral load was detected in the cell-free plasma fraction. Viral DNA was found in a population of cells characterized as CD19(hi) and immunoglobulin D negative, a phenotype that is consistent with the virus being carried exclusively in the memory B-cell compartment of the peripheral blood. There was no difference in the compartmentalization based upon either the level of the viral load or the past diagnosis of an episode of PT-LPD. These results have implications for the design of tests to detect EBV infection and for the interpretation and use of positive EBV PCR assays in the management of transplant recipients.

Adolescent↗
PubMed2000

Epstein-Barr virus gene expression in the peripheral blood of transplant recipients with persistent circulating virus loads.

Pediatric solid organ transplant recipients are at risk for Epstein-Barr virus (EBV)-driven lymphoproliferative disease. The expression of 5 sentinel EBV genes (EBNA1, EBNA2a, LMP1, LMP2a, and ZEBRA) was examined in solid organ transplant recipients who developed persistent virus loads in their peripheral blood lymphocytes after transplantation. Two distinct groups were identified. LMP2a gene expression alone was detected among 12 of 14 patients carrying EBV loads < or =100 copies/10(5) lymphocytes. The other 2 low-load carriers made LMP2a RNA but also expressed LMP1 RNA. In contrast, LMP2a and LMP1 gene expression was detected among 11 of 13 patients carrying a virus load >100 copies/10(5) lymphocytes. Two high-load carriers made LMP1 RNA but not the RNA for LMP2a or any of the other viral genes. Therefore, persistent low-load carriers appear to maintain an apparently normal state of latent viral infection, whereas high-load carriers display a unique LMP1:LMP2a pattern of viral gene expression that has not been previously described.

Adolescent↗
PubMed2000

Steric Stabilization of Colloids by Poly(dimethylsiloxane) in Carbon Dioxide: Effect of Cosolvents.

Steric stabilization and flocculation of colloids with surface-grafted poly(dimethylsiloxane) (PDMS) chains are examined in liquid and supercritical carbon dioxide with and without hexane as a cosolvent. Neither poly(methyl methacrylate) (PMMA) nor silica particles with grafted 10,000 g/mol PDMS could be stabilized in pure CO(2) at pressures up to 345 bar at 25 degrees C and 517 bar at 65 degrees C without stirring. The addition of 15 wt% hexane to CO(2) led to stable dispersions with sedimentation velocities of 0.2 mm/min for 1-2 µm PMMA particles. The critical flocculation pressure of the colloids in the hexane/CO(2) mixture, determined from turbidity versus time measurements, was found to be the same for silica and PMMA particles and was well above the upper critical solution pressure for the PDMS-CO(2) system. The addition of a nonreactive cosolvent, hexane, eliminates flocculation of PMMA particles synthesized through dispersion polymerization in CO(2) with PDMS-based surfactants. Copyright 2000 Academic Press.

Journal Article↗
PubMed2000

Anti-inflammatory properties of ebselen in a model of sephadex-induced lung inflammation.

Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), is a seleno-organic compound which protects tissues against oxidative stress. Furthermore, recent data has suggested that this compound possesses a range of anti-inflammatory properties. In this study the authors have investigated the effects of ebselen on Sephadex-induced lung oedema and bronchoalveolar lavage (BAL) tumour necrosis factor (TNF)-alpha and endothelin(ET)-1 levels in rats. Sephadex administration induced lung oedema which was accompanied by an increase in BAL TNF-alpha and ET-1 levels. Ebselen administration (1-30 mg x kg(-1), i.p. at 0, 4 and 12 h post Sephadex) significantly inhibited lung oedema (dose that produced 50% of the maximum inhibition of lung oedema 4.6 mg x kg(-1)) and BAL TNF-alpha levels in a dose-related manner with no effect on ET-1 levels. These data suggest that ebselen may be a useful therapy in lung pathologies in which bronchiolar inflammation is a feature.

Animals↗