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Biomedical subjects

T R McGuire

Publications and source records attributed to T R McGuire.

At least 19 recordsLinked to original sources
PubMed2005

Release of TNF-alpha and IL-1beta from porcine brain endothelium corresponds to the pyrogenic potential of three marketed formulations of amphotericin.

BACKGROUND: Formulations of amphotericin include a deoxycholate suspension (d-Amph), an amphotericin-B lipid complex (Ablc), and a liposomal product (L-Amph). Fever is most frequent with d-Amph, intermediate with Ablc, and lowest with L-Amph. OBJECTIVE: To determine if the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1) from brain endothelium corresponds to the incidence of amphotericin fever. RESULTS: Release of TNF-alpha and IL-1beta after L-Amph treatment was similar to negative controls while after d-Amph treatment release was similar to lipopolysaccharide. Ablc treatment produced intermediate pyrogen release.NF-kappaB expression, a transcriptional regulator for TNF-alpha and IL-1beta genes, corresponded to this secretion pattern. TNF-alpha release was elevated 2 hours (p = 0.0021) after treatment while significant elevations in IL-1beta required 6 hours (p = 0.0009). CONCLUSION: Results from this in vitro study suggest that amphotericin fever may be directly mediated by brain endothelium. These experiments also suggest that amphotericin fever is initially mediated by TNF-alpha.

Amphotericin B↗
PubMed2002

Plasma from poorly mobilizing human subjects inhibits cytokine-induced murine blood stem-cell mobilization.

BACKGROUND: Cytokine-induced mobilization of hematopoietic stem/progenitor cells to the circulation facilitates efficient harvest of blood stem cells by leukapheresis. Up to 30% of autologous, and 10-20% of allogeneic blood stem-cell donors respond poorly to mobilizing cytokines and preliminary studies implicated a circulating inhibitor of mobilization. METHODS: In this study, plasma from 11 allogeneic and 23 autologous stem cell donors was assayed for inhibition of mobilization in mice. RESULTS: There were significant correlations between CD34(+) cells collected/kg human donor weight and spleen weight, CD34(+) CD45(+) cells, GMCFC and HPP-CFC per spleen in murine recipients of these plasma samples. Overall, there was a positive association between transforming growth factor beta (TGF-beta) levels and CD34(+) cells per liter of blood processed (LBP). However, when arbitrarily segregated into good versus poor mobilizers, based on less or greater than 15 million CD34(+) cells collected per LBP, the majority (64%) of normal donors were good mobilizers. The majority of the poor mobilizers (83%) were patients. For a subset of 12 individuals whose plasma strongly inhibited mobilization in the mouse, a significant positive correlation of the extent of inhibition with TGF-beta levels was found. For 11 individuals whose plasma, based on colony assays, enhanced mobilization when injected into mice, no correlation with TGF-beta levels was evident. DISCUSSION: Elevated plasma TGF-beta levels in some stem-cell donors may be associated with poor stem-cell mobilization. It remains to be determined whether elevation of TGF-beta levels is a cause of, or a compensatory response to, poor mobilization.

Animals↗
PubMed2001

Organ dysfunction following stem cell transplantation: relationship to plasma cytokine concentrations.

Patients receiving high-dose preparation for stem cell transplantation are at risk for organ dysfunction (OD). Signs of early OD include hypoxia, mental status changes, and liver dysfunction. These early signs have not been correlated with potential cytokine mediators. We compared plasma concentrations of IL-6, TNF-alpha, and IL-10 in OD patients and controls. Cytokines were measured before preparation, 5 days before OD, day of OD, and 5 days after OD. TNF-alpha and IL-10 were not measurable prior to preparation. IL-10 was more likely to be measurable in OD patients than in controls 5 days prior to onset of OD (P = 0.039), on the day of OD (P = 0.023), and 5 days later (P < 0.0001). TNF-alpha was more likely to be measurable only on the day of OD (P = 0.0035). IL-6 was significantly elevated in OD patients at all time points. Patients who had measurable IL-6 on admission were 5.1 times more likely to develop OD (95% CI = 1.4-17.9; P = 0.011). Five days prior to OD for each 100 pg/ml increase in IL-6, patients were 2.75 times more likely to develop OD (95% CI = 1.3-5.8; P = 0.0087). The early elevation of IL-6 in patients who develop OD may help identify a high risk group where preventive therapies can be evaluated.

Acute Kidney Injury↗
PubMed2001

Elevated transforming growth factor beta levels in the plasma of cytokine-treated cancer patients and normal allogeneic stem cell donors.

BACKGROUND: Allogeneic blood stem-cell donors demonstrate more vigorous mobilization of CD34(+) cells to the circulation in response to cytokine administration than do autologous donors. Transforming growth factor (TGF-beta1) has been implicated as a mobilization inhibitor. A study was designed to determine whether plasma TGF-beta1 levels are elevated in cytokine-mobilized autologous cancer donors compared with cytokine-mobilized normal donors. METHODS: Plasma collected from 29 autologous cancer donors and 33 normal allogeneic stem-cell donors following administration of mobilizing cytokines just prior to the first collection was assayed for TGF-beta1 using a sandwich-type ELISA. Plasma from three volunteers not treated with cytokine was also analyzed. Comparisons were made using the Student's t test on log-transformed data. RESULTS: Average TGF-beta1 levels in the plasma of cancer patients were significantly higher than in allogeneic stem-cell donors (4.4 ng/mL versus 7.2 ng/mL; p = 0.038). The allogeneic donors required fewer collections to harvest greater numbers of CD34(+) cells and colony-forming unit granulocyte-macrophage (CFU-GM) than autologous donors. Plasma from three untreated volunteers had mean TGF-beta1 levels of 0.36 ng/mL, with all three levels below the 25th percentile for allogeneic donors and the 5th percentile for cancer patients. DISCUSSION: Cytokine administration was associated with increased plasma TGF-beta1 levels. The levels were higher in cancer patients being mobilized for stem-cell collection than in allogeneic blood stem-cell donors. These differences could underlie the increased number of apheresis procedures required to harvest autologous graft products from cancer patients.

Antigens, CD34↗
PubMed1998

Colorimetric determination of hydroxyurea in human serum using high-performance liquid chromatography.

A high-performance liquid chromatography assay for hydroxyurea in human serum was developed based on a commercial colorimetric assay kit for urea (Sigma Diagnostics). Serum (0.5 ml), spiked with methylurea as an internal standard, was treated with 70% perchloric acid. Supernatant (0.2 ml) was combined with 0.7 ml of BUN acid reagent and 0.6 ml of BUN color reagent. The resulting colored reactant (100 microl) was analyzed on a 300 x 3.9 mm Bondclone 10 C18 column coupled with a UV-Vis detector, at 449 nm. The mobile phase was 13% acetonitrile in water. Retention times of colored derivatives of hydroxyurea and methylurea were 6.5 and 12.2 min, respectively. The log-log calibration curve was linear from 0.0065 to 1.31 mM. Average accuracy was 99.9+/-4.0% and the intra- and inter-day error of assay did not exceed 11%.

Chromatography, High Pressure Liquid↗
PubMed1998

Assay for etoposide in human serum using solid-phase extraction and high-performance liquid chromatography with fluorescence detection.

An HPLC assay for etoposide in human serum was developed. Serum, spiked with podophyllotoxin (internal standard), was treated with sodium dodecyl sulphate prior to solid phase extraction. Analysis was performed on a 300x3.9 mm Bondclone 10 C18 column coupled with a fluorometric detector (lambda(ex) 230 nm, lambda(em) 330 nm). The retention times for etoposide and podophyllotoxin were 14 and 28 min respectively. The range of assay was 0.5 to 20 microg/ml with a detection limit of 0.2 microg/ml. This assay is suitable for use in clinical studies with etoposide.

Antineoplastic Agents, Phytogenic↗
PubMed1995

An in vitro model for endothelial permeability: assessment of monolayer integrity.

An essential component of any in vitro model for endothelial permeability is a confluent cell monolayer. The model reported here utilizes primary human umbilical vein endothelial cells (HUVEC) cultured on recently developed polyethylene terephthalate micropore membranes. Using a modification of the Wright-Giemsa stain, confluent HUVEC monolayers grown on micropore membranes were routinely assessed using light microscopy. Determination of confluence using this method was confirmed by scanning electron microscopy. Transendothelial electrical resistance of HUVEC monolayers averaged 27.9 +/- 11.4 omega.cm2, 10 to 21% higher than literature values. Studies characterizing the permeability of the endothelial cell monolayer to 3H-inulin demonstrated a linear relationship between the luminal concentration of 3H-inulin and its flux across HUVEC monolayers. The slope of the flux versus concentration plot, which represents endothelial clearance of 3H-inulin, was 2.01 +/- 0.076 x 10(-4) ml/min (r2 = .9957). The permeability coefficient for the HUVEC monolayer-micropore membrane barrier was 3.17 +/- 0.427 x 10(-6) cm/s with a calculated permeability coefficient of the HUVEC monolayer alone of 4.07 +/- 0.617 x 10(-6) cm/s. The HUVEC monolayer reduced the permeability of the micropore membrane alone to 3H-inulin (1.43 +/- 0.445 x 10(-5) cm/s) by 78%. Evans blue dye-labeled bovine serum albumin could not be detected on the abluminal side without disruption of the HUVEC monolayer. These results demonstrate a model for endothelial permeability that can be extensively assessed for monolayer integrity by direct visualization, transendothelial electrical resistance, and the permeability of indicator macromolecules.

Cell Membrane Permeability↗
PubMed1995

Evaluation of the pharmacokinetic interaction between cimetidine or famotidine and cyclosporine in healthy men.

OBJECTIVE: To investigate the potential interaction between cimetidine or famotidine and cyclosporine in healthy men. DESIGN: All subjects received oral cyclosporine at baseline, after the first week of 1 histamine2 (H2)-blocker, and a third time after a 1-week washout plus 1 week of the second H2-blocker. Blood samples were collected just before each dose of cyclosporine and for up to 36 hours afterward for pharmacokinetic analysis. SETTING: A college of pharmacy in a university teaching hospital. PARTICIPANTS: The study population consisted of 8 healthy men at least 19 years of age. MAIN OUTCOME MEASURES: Cyclosporine concentrations in whole blood were measured using a polyclonal fluorescence polarization immunoassay. Cyclosporine pharmacokinetic parameters during each of the 3 treatment periods were compared. RESULTS: The average times to maximum cyclosporine concentrations were similar between baseline (3.2 h), cimetidine (2.9 h), and famotidine (3.6 h) dosing periods. There were no significant differences in area under the curve, half-life, or maximum concentration during the 3 dosing periods. CONCLUSIONS: Neither cimetidine or famotidine produced a significant change in the pharmacokinetics of single-dose oral cyclosporine in healthy men.

Adult↗
PubMed1995

Is homosexuality genetic? A critical review and some suggestions.

Genetic analysis of behavioral differences among human beings requires both careful experimental design and appropriate genetic models. Any genetic study must be (1) valid and precise measures of individual differences, (2) appropriate methods to ascertain biological relationships, (3) research subjects who have been randomly recruited, (4) appropriate sample sizes, and (5) appropriate genetic models to interpret the data. In addition, the researchers must exercise caution in interpreting biosocial effects from the observed phenotypic correlations. To date, all studies of the genetic basis of sexual orientation of men and women have failed to meet one or more or any of the above criteria.

Female↗
PubMed1993

Compatibility and stability of ondansetron hydrochloride, dexamethasone, and lorazepam in injectable solutions.

The stability of ondansetron hydrochloride, dexamethasone sodium phosphate, and lorazepam in 5% dextrose injection or 0.9% sodium chloride injection in polyvinyl chloride (PVC) minibags and glass bottles was studied. Triplicate solutions of 8 or 32 mg of ondansetron (as the hydrochloride salt) mixed with 20 mg of dexamethasone phosphate (as the sodium salt) with or without 2 mg of lorazepam were compounded in 50-mL PVC minibags and glass bottles containing either 5% dextrose injection or 0.9% sodium chloride injection and stored at 23-25 degrees C. Duplicate measurements were performed when drugs were added and at 1, 2, 4, 8, and 24 hours after addition. Samples of the 32-mg ondansetron admixtures were collected under aseptic conditions to inspect for precipitation and to count particles with a laser particle analyzer. Samples of all admixtures were evaluated for chemical stability by stability-indicating high-performance liquid chromatography. Ondansetron hydrochloride and dexamethasone were physically compatible and chemically stable for up to 24 hours under the study conditions. The concentration of lorazepam in PVC containers dropped below 90% of the original concentration within four hours. In addition, particle counts in lorazepam-containing solutions were higher when 0.9% sodium chloride injection was the diluent than when 5% dextrose injection was the diluent. In admixtures containing all drugs, ondansetron hydrochloride and dexamethasone sodium phosphate in 5% dextrose injection or 0.9% sodium chloride injection were stable for up to 24 hours when stored in PVC bags or glass bottles.(ABSTRACT TRUNCATED AT 250 WORDS)

Dexamethasone↗
PubMed1992

A biometrical genetic approach to chromosome analysis in Drosophila: detection of epistatic interactions in geotaxis.

Chromosome analysis has been widely used as a first step in elucidating the genetic architecture of several behaviors of Drosophila melanogaster. These chromosome studies have generally used incomplete designs or fairly simple statistical analyses. Here I reanalyze two data sets on geotaxis from Pyle (1978) and Ksander (1966) using a biometrical genetic design. Results from the biometrical genetic reanalysis suggest that individual differences in geotaxis might be due to genes on all three major chromosomes which show extensive epistatic interactions.

Animals↗
PubMed1992

The homeotic gene spineless-aristapedia affects geotaxis in Drosophila melanogaster.

The homeotic mutation spineless-aristapedia (ss(a)) transforms the aristae into second tarsi. Flies with a ss(a) phenotype also show extremely positive geotaxis as measured in a Hirsch-type geotaxis maze. Other antennal mutants and flies with their aristae amputated do not show such extreme positive geotaxis. Deletion analysis has comapped the geotaxis effect with ss(a) in band 89C on the third chromosome. Finally, a biometrical analysis has detected additional genes on the X chromosome that also affects geotaxis.

Animals↗
PubMed1992

Pharmacodynamic studies of cyclosporine in marrow transplant recipients. A comparison of three assay methods.

We investigated the correlation between trough cyclosporine concentration in plasma measured by polyclonal fluorescence polarization immunoassay (FPIA) and polyclonal radioimmunoassay (RIA) or in whole blood measured by high-performance liquid chromatography (HPLC) and the risk of renal dysfunction or acute graft-versus-host disease in 29 patients undergoing allogeneic bone marrow transplantation for leukemia. The FPIA and RIA values were highly correlated (r = 0.93) and on the average CsA concentrations measured by FPIA were 1.56 times higher than those measured by RIA. Ten patients developed renal dysfunction and 10 developed grades II-IV acute GVHD. Although univariate analysis showed that plasma CsA concentrations measured by either FPIA or RIA were significantly correlated with renal dysfunction, the association was stronger with FPIA. Plasma CsA concentrations measured by FPIA but not RIA remained a significant risk factor for renal dysfunction in a multivariate relative risk model. Amphotericin therapy was significantly associated with renal dysfunction in the univariate analysis but not in the multivariate analysis. No significant associations were found between whole blood CsA or CsA M1 concentration, patients' age, gender, or CsA dose and the risk of renal dysfunction. None of the covariates analyzed significantly correlated with the development of acute GVHD. These data suggest that plasma CsA concentrations measured by nonspecific assays may more accurately correlate with renal dysfunction than whole-blood CsA concentrations measured by HPLC in marrow transplant recipients.

Adult↗
PubMed1992

Stability of cyclosporine in dextrose 5%, NaCl 0.9%, dextrose/amino acid solution, and lipid emulsion.

OBJECTIVE: Because of limited intravenous access in patients who have undergone bone marrow transplant (BMT), we undertook a study to determine the safety of mixing cyclosporine in intravenous preparations commonly administered to BMT patients. DESIGN: In a pilot study, we investigated the stability of intravenous cyclosporine (Sandimmune) in four types of intravenous fluids: dextrose 5%, NaCl 0.9%, dextrose/amino acid solutions, and lipid emulsion. Because the pilot study showed highly variable cyclosporine concentrations that suggested inadequate mixing, we undertook another study to determine the effect of the mixing method on cyclosporine concentrations. OUTCOME MEASURE: Cyclosporine was considered stable in the study solutions if concentrations remained above 90 percent of the initial concentrations. RESULTS: Substantial variation in cyclosporine concentrations was observed in lipid emulsion and dextrose/amino acid solutions and gentle swirling of the solutions was insufficient to adequately disperse the drug. The variation was eliminated by vigorous shaking either before each sampling or once after the initial addition of cyclosporine. We used vigorous shaking methods to establish that cyclosporine is stable for up to 72 hours at room temperature in dextrose 5%, 10% amino acid solution with dextrose 50%, and Liposyn 10%, and up to 8 hours in NaCl 0.9%. CONCLUSIONS: These data may be used to simplify cyclosporine administration in patients who have limited intravenous access.

Amino Acids↗
PubMed1991

Improved results of allogeneic bone marrow transplantation for advanced hematologic malignancy using busulfan, cyclophosphamide and etoposide as cytoreductive and immunosuppressive therapy.

Twenty-four patients between the ages of 8 and 48 years (median 27.5) with high-risk for relapse hematologic malignancy received a marrow transplant from an HLA and MLC compatible sibling donor after chemotherapy with busulfan, 4 mg/kg/day for 4 days by mouth, cyclophosphamide 60 mg/kg/day i.v. for 2 days, and etoposide 60 mg/kg i.v. over 4 h on the first day of cyclophosphamide treatment (BU/CY/VP). Toxicity consisted of mucositis, skin rash, and nausea and vomiting in all patients, transient fever thought to be due to etoposide administration in 16/24 (67%) patients, and clinical veno-occlusive disease (VOD) of the liver in 4/24 (17%). There were nine deaths from causes other than recurrent disease in the first 100 days after transplant and two deaths after day 100, a total transplant mortality of 11/24 (46%). Three patients relapsed, but 10/24 (40%) remain alive and disease free 26-182 weeks (median 60 weeks) from transplant. These results compare favorably with results in a group of 12 similar risk patients treated with total body irradiation (TBI) containing regimens during an overlapping time period. Six of the TBI patients have had persistent or recurrent disease and only two (17%) are currently alive and disease free. The probability of disease persistence or relapse is 67% in the TBI group and 20% in the BU/CY/VP group (p less than 0.02).

Adolescent↗
PubMed1990

Pharmacokinetic drug interactions with cyclosporin (Part I).

This article reviews the reported pharmacokinetic interactions between cyclosporin and other drugs. Both rifampicin and the majority of anticonvulsants can decrease cyclosporin concentrations to levels that are at or below the limit of detection for most assays. There have been no reports of any interaction between valproic acid and cyclosporin. Other drugs that have been reported to decrease cyclosporin concentration include sulfadimidine and trimethoprim, nafcillin and octreotide. Erythromycin, ketoconazole and some calcium channel blockers have been clearly shown to increase the concentration of cyclosporin. Other less well documented interactions have been reported with other macrolide antibiotics, other azole antifungal drugs, high dose methylprednisolone, metoclopramide, fluoroquinolones, imipenem/cilastatin, oral contraceptives/danazol, sulindac, methyltestosterone, colchicine, acetazolamide, alcohol and cimetidine. Although the most commonly reported mechanism is inhibition of cyclosporin metabolism, there is increasing evidence that erythromycin, metoclopramide and probably other drugs increase the bioavailability of oral cyclosporin. Two calcium channel blockers which have not been reported to interact with cyclosporin are nifedipine and nitrendipine. With increasing use of cyclosporin, the number of drugs reported to interact will rise. Prudent clinicians should monitor the concentration of this agent more frequently when another drug is added or discontinued and cyclosporin dosage should be adjusted when appropriate. Sustained changes in cyclosporin concentration can result in graft rejection (or graft-versus-host disease) or renal toxicity. Further studies are needed to determine the mechanism of most of these interactions.

Animals↗
PubMed1990

Pharmacokinetic drug interactions with cyclosporin (Part II).

Part I of this article, which appeared in the previous issue of the Journal, considered the potential mechanisms of drug interactions with cyclosporin, and divided the interacting drugs into 2 categories. Drugs that decrease cyclosporin concentrations (e.g. anti-convulsants, rifampicin, etc.) were dealt with first; the authors then moved on to consider the second category, those that increase cyclosporin concentration (macrolide antibiotics, azole antifungal drugs). Part II continues the survey of this category.

Calcium Channel Blockers↗