Search PubMed⌕ Search

Biomedical subjects

T Hamilton

Publications and source records attributed to T Hamilton.

At least 37 records · Page 2Linked to original sources
PubMed1994

Cricothyroidostomy.

Cricothyroidostomy may be a lifesaving procedure when endotracheal intubation is either contraindicated or is impossible as a result of the physical condition of the patient. Commercially available kits have simplified the procedure for the nonsurgeon in the pre-hospital setting.

Airway Obstruction↗
PubMed1993

High binding affinity chimeric anti-colorectal carcinoma antibody correlated to enhanced tumor binding and effector function.

The genetically engineered mouse/human chimeric cB72.3m4 and cB72.3m12 antibodies all recognized the tumor-associated TAG72 antigen. The high affinity cB72.3m4 antibody had an approximately 18-fold higher affinity constant for the TAG72 antigen than the low affinity cB72.3m12 antibody. The relationship amongst antibody binding affinity, tumor binding and effector functions was studied by using these two antibodies. The data showed that the high affinity cB72.3m4 antibody was reactive with, on average, 15% more colon adenocarcinoma cells on tissue sections than the low affinity cB72.3m12 antibody, and it did not produce any cross-reactivities with various normal tissues. The high affinity cB72.3m4 antibody was able to mediate more effective ADCC and CDC to the human ovarian cancer cells in vitro than the low affinity cB72.3m12 antibody. This study provides evidence that this high affinity chimeric cB72.3m4 antibody may be useful in both immunodetection and immunotherapy of cancer.

Adenocarcinoma↗
PubMed1993

Molecular and biological factors in the pathogenesis of ovarian cancer.

BACKGROUND: The classic prognostic parameters are insufficient for predicting the prognosis of the individual patient. Knowledge of molecular and biological factors which are responsible for the development and progression of ovarian cancer may improve the prediction of prognosis. MATERIALS AND METHODS: Recent data both on factors associated with the development and control of ovarian cancer cells and on DNA ploidy have been reviewed. RESULTS: Observations suggest that steroid and peptide hormones have a role in disease etiology and progression, and that peptide growth factors and cytokines, oncogenes and tumor suppressor genes, by their impact on mitosis and cell number may influence the rate of mutations, which could confer malignant transformation. DNA ploidy is an objective independent prognostic factor. DNA aneuploidy indicates high risk, diploidy low risk. Only tumours shown to be DNA diploid by flow-cytometry and image cytometry are considered diploid. S-phase fraction is currently not reliable. CONCLUSION: Understanding the mechanisms involved in ovarian cancer development and growth will allow opportunities for the rational design of effective anti-tumour treatment modalities. More objective and reproducible prognostic variables will improve the predictiveness of prognosis.

DNA, Neoplasm↗
PubMed1992

Preclinical and phase I studies with rhizoxin to apply a pharmacokinetically guided dose-escalation scheme.

BACKGROUND: Rhizoxin is a new macrocyclic lactone isolated from the fungus Rhizopus chinensis which displays broad-spectrum antitumor activity against murine and human tumor xenografts and has activity against a number of vincristine-resistant tumors in vitro and in vivo. PURPOSE: This study describes the preclinical and clinical pharmacology of rhizoxin to apply a pharmacokinetically guided dose-escalation (PGDE) strategy during the phase I trial. METHODS: Rhizoxin was administered by a single intravenous bolus injection to female BALB/c mice over the dose range 7.5-18 mg/m2 from which we derived the dose that was lethal to 10% and 50% of the mice (i.e., LD10 and LD50, respectively). The LD10 was 11.7 +/- 0.7 mg/m2 (mean +/- SD), and the LD50 was 14.7 +/- 0.6 mg/m2. Pharmacokinetic studies were integrated with the toxicity study in female BALB/c mice at one-tenth the LD10, one-half the LD10, and the LD10 (i.e., 1.2, 6, and 12 mg/m2, respectively). From these data, a target area under the plasma drug concentration versus time curve (AUC) (i.e., 40% of the LD10 AUC) was calculated for clinical studies. Phase I studies were initiated at 0.8 mg/m2 (one-tenth the equivalent LD10 in male CD1 mice), with the intent of escalating the dose by an extended factor-of-two method until the target AUC and/or maximum tolerated dose (MTD) was reached. RESULTS: The major drug toxic effects in mice were body weight loss, sluggishness, ataxia, transient changes in hematological parameters, and hematuria. Diarrhea was universal at doses greater than 9 mg/m2, and hind limb paralysis was observed in one of 10 mice, but only at supralethal doses (18 mg/m2). Rhizoxin pharmacokinetics were best described by a two-compartment open model (half-life [t 1/2] alpha = 4.4 minutes +/- 0.9 minute [mean +/- SD], and t 1/2 beta = 84 minutes +/- 20 minutes at 12 mg/m2) and found to be nonlinear with respect to dose. At doses of 1.2, 6, and 12 mg/m2, the respective AUC values were 1.3, 22.4, and 70.6 microM x minute. From these data, a target AUC value of 28 microM x minute (40% of the LD10 AUC) was derived. Rhizoxin was not detectable in patient plasma (less than 5 ng/mL at 0.8 and 1.6 mg/m2), and doses had to be escalated by conventional methods. Myelosuppression was dose limiting in patients: Seven of eight treated at 2.6 mg/m2 experienced World Health Organization grade 3-4 neutropenia, and five of eight developed mucositis. The AUC values at the human MTD (2.6 mg/m2) were in the range of 0.41-1.01 microM x minute, considerably lower than the target AUC of 28 microM x minute. CONCLUSION AND IMPLICATIONS: Although PGDE schemes have been successfully employed for other antitumor agents, this methodology could not be applied during the phase I trial of rhizoxin. PGDE studies in the future may incorporate comparative murine versus human metabolism studies in vitro with phenotyped liver microsomes. It may also be useful to assess the comparative myelotoxicity of a new drug by performing in vitro cytotoxicity studies on mouse and human bone marrow stem cells.

Adolescent↗
PubMed1992

Comparison of urinary 6-beta-cortisol and the erythromycin breath test as measures of hepatic P450IIIA (CYP3A) activity.

The production of 14CO2 in the breath from an intravenous dose of [14C-N-methyl]-erythromycin (the erythromycin breath test [ERMBT]) and the measurement of the ratio of 6-beta-cortisol to free cortisol (6-beta-F/FF) in the urine have each been proposed as means of measuring hepatic P450IIIA catalytic activity in patients. We found that there was a significant correlation between the results of each test (r = 0.59, p less than 0.001) in 47 patients who were without liver disease and who were not taking medications believed to influence P450IIIA catalytic activity. In the 24 of these patients who were subsequently treated with the P450IIIA substrate cyclosporine, the ERMBT result was highly correlated with the mean trough cyclosporine blood level observed; however, there was no correlation between urinary 6-beta-F/FF and the cyclosporine blood levels. In a separate study of a patient during the anhepatic phase of liver transplantation surgery, the ERMBT result decreased by greater than 85%, whereas urinary 6-beta-F/FF decreased by just 50%. We conclude that the ERMBT and urinary 6-beta-F/FF do not always provide similar information about P450IIIA catalytic activity in patients, possibly because of extrahepatic production of 6-beta-F. Of the two tests, the ERMBT appears to provide the most relevant information for cyclosporine administration.

Aryl Hydrocarbon Hydroxylases↗
PubMed1992

The team approach.

Explore the source record for details and available documents.

Breast Neoplasms↗
PubMed1992

Construction and characterization of a high-affinity chimeric anti-colorectal carcinoma antibody ccM4.

We have produced a high-affinity chimeric anti-colorectal carcinoma antibody, ccM4, chimerized in both heavy and light chains by the construction of two expression vectors, the chimeric heavy-chain expression vector mpSV2neo-EP1-Vm4Cr1 and chimeric light-chain vector mpSV2gpt-EP1-VKCK. These vectors contained the neo or gpt gene as a selection marker, the murine immunoglobulin promoter and enhancer (EP1), the genomic DNA fragments of human immunoglobulin constant region (CK and C gamma 1), and murine cDNA fragments of VH and VK region amplified and cloned directly from the B72.3 hybridoma RNA by the polymer chain reaction technique. These two vector DNAs were sequentially transfected into the SP2/0Ag14 cell line. Transfectants were selected in media containing both G418 and mycophenolic acid. The ccM4 antibody was purified from transfectant supernatants with positive binding reactivity for the TAG72 antigen on a protein A column. We demonstrated that ccM4 antibody retained the same high binding reactivity for the TAG72 antigen as its counterpart, the high-affinity chimeric heavy-chain cB72.3m4 antibody. The ccM4 antibody bound specifically to human colon cancer cells, displayed biodistribution patterns similar to cB72.3m4 antibody, and mediated effective antibody-dependent cellular cytotoxicity to human OVCAR3 tumor cells. Therefore, the high-affinity chimeric ccM4 antibody should be useful in cancer immunotherapy.

Animals↗
PubMed1992

Superiority of the University of Wisconsin solution over simple crystalloid for extended heart preservation. A study of left ventricular pressure-volume relationship.

To compare the effects of the University of Wisconsin solution with those of an extracellular crystalloid solution, Krebs-Ringer bicarbonate, as cardiac preservation media, we studied 35 adult dogs in an isolated heart preparation. Four groups of seven hearts were preserved in University of Wisconsin solution for 6 or 12 hours or in Krebs-Ringer bicarbonate solution for 6 or 12 hours. An additional group of seven hearts with no ischemia was used for a control group. In the four preservation groups, hearts were arrested by electrolyte solution (Normosol with potassium chloride, 20 mEq/L, added, 4 degrees C), flushed with 200 ml of the preservation solution, and then stored in the same solution at 1 degree to 2 degrees C. The hearts were mounted on an isolated heart preparation equipped with a computer-controlled servo-pump system that used a mock arterial system to modulate the aortic input impedance presented to the left ventricle. Left ventricular pressure-volume loops were measured on-line for 2 hours of reperfusion with autologous warm oxygenated blood. Elastance was derived from the end-systolic pressure-volume relationship, and diastolic compliance was derived from the end-diastolic pressure-volume relationship. The total left ventricular performance was assessed by the preload recruitable stroke work area, the slope, and its x-intercept, all of which derived from the stroke work (pressure-volume area)-end-diastolic volume relationship. Extended global ischemia had more deleterious effects on the end-diastolic than the end-systolic pressure-volume relationship. In confirmation with other studies, elastance did not accurately reflect the level of ventricular contractile dysfunction because of the significant amount of diastolic dysfunction. The preservation of myocardial systolic and diastolic functions, as demonstrated by the preload recruitable stroke work area and diastolic compliance, was better in the University of Wisconsin solution groups than in the Krebs-Ringer bicarbonate solution groups after 6 and 12 hours of preservation. In addition, 6 hours of preservation with University of Wisconsin solution maintained normal systolic and diastolic functions as compared with those of the control group. Preservation with University of Wisconsin solution prevented any myocardial edema formation; by contrast, this was significantly increased after 12 hours in Krebs-Ringer bicarbonate solution. Groups preserved with University of Wisconsin solution had less reperfusion injury as evidenced by the release of coronary sinus creatine kinase during reperfusion; they also had improved oxygen use during reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗
PubMed1990

Changes in photo-aged human skin following topical application of all-trans retinoic acid.

Although topical applications of retinoids on rodents and humans have been shown to cause epidermal hyperplasia, a detailed study of the influence of retinoids on epidermal differentiation in vivo has not been performed. In order to assess the pharmacologic effects of chronic topical tretinoin application used to improve the appearance of patients with photoaged skin, cutaneous biopsies from 25 patients in a controlled clinical study were examined histologically and immunocytochemically. Chronic application of tretinoin causes epidermal thickening (25 of 25 samples), stratum granulosum thickening (15 of 25), parakeratosis (13 of 25), a marked increase in the number of cell layers expressing epidermal transglutaminase (13 of 25), and focal expression of two keratins, K6 (12 of 25) and K13 (8 of 25), not normally expressed in the epidermis. The morphologic changes correlated with immunohistochemical abnormalities; neither of these correlated with the subjective cosmetic response. Three major epidermal differentiation products, keratins K1, K10, and K14 were not altered, within the limits of the methods used. Thus, chronic topical tretinoin reprograms some, but not all, aspects of human epidermal differentiation in vivo.

Administration, Topical↗
PubMed1989

Therapeutic effect of a radiolabeled monoclonal antibody on human ovarian cancer xenograft in nude mice.

The therapeutic value of 131I-OC125, a radiolabeled monoclonal antibody directed against a human ovarian tumor associated antigen CA125, was examined in an ascites forming intraperitoneal human ovarian carcinoma nude mouse model. Nude mice were injected intraperitoneally with NIH:OVCAR3 cells. Twenty-one days after tumor transplantation, groups of animals were injected intraperitoneally as follows: Group 1 with 200 microCi of 131I-OC125 (n = 20), Group 2 with 200 microCi of 131I (n = 17), Group 3 with 200 microCi of 131I-IgG (n = 21), Group 4 with 60 micrograms of OC125 (n = 18), and Group 5 was left untreated (n = 21). Survival of the tumor-bearing animals was used as the endpoint of the experiment. Mean survivals were found to be 52 +/- 18 days for the 131I-OC125 group, 53 +/- 16 days for the 131I-IgG group, 49 +/- 13 days for the 131I group, 47 +/- 24 days for the OC125 group, and 47 +/- 15 days for the untreated control. These results would indicate no therapeutic advantage of 131I-OC125 over controls in this animal model. However, other approaches using single as well as multiple radiolabeled monoclonal antibodies need to be tested in this model in order to definitely establish the efficacy of this treatment modality.

Animals↗
PubMed1989

Meclofenomate inhibition of UV-induced erythema--a randomized, placebo-controlled, double-blind study.

Systemic intradermal and topical inhibitors of eicosanoid synthesis have been shown to decrease the intensity delay the onset of erythema produced with a single exposure to ultraviolet (UV) light. We studied the effect of single and multiple doses of meclofenomate on erythema induced by single and multiple doses of UV light. Thirty Caucasian subjects took either meclofenomate 100 mg t.i.d. or matching placebo for 5 days, crossing over to the alternative for 5 more days after a 2-day washout period. A statistical analysis was made of erythema response immediately prior to the study and then on 8 successive days during the study. Analysis of single and multiple exposure data revealed a statistically significant inhibition of erythema from meclofenomate therapy as compared with placebo.

Adult↗
PubMed1988

Effect of alpha-difluoromethylornithine (DFMO) on the growth of human ovarian carcinoma.

The antiproliferative effect of alpha-difluoromethylornithine (DFMO) was investigated in a human ovarian cancer cell line (NIH:OVCAR3) both in vitro and in vivo. DFMO at 5 X 10(-5) M, 5 X 10(-4) M and 1 X 10(-3) M concentrations showed growth inhibition of NIH:OVCAR3 cells in culture. Parallel determination of CA 125 in the culture media of these cells show significant decrease in the presence of DFMO compared to controls. Oral administration of DFMO (2% aqueous solution) to nude mice bearing intraperitoneal tumors resulted in a mean survival of 45 days (38-60) versus 25 days (20-35) for control. Both in vitro and in vivo results suggest that DFMO has potential value in the treatment of ovarian carcinoma and should be considered for clinical trials in appropriate cancer patients.

Animals↗
PubMed1987

Radioimaging of human ovarian carcinoma xenograft in nude mice.

Human ovarian carcinomas in nude mice were radioimaged using a well-characterized antibody against a tumor-associated antigen (CA 125) and three transplantable human ovarian carcinoma tumor lines: NIH:OVCAR 3, NIH:OVCAR 5, and NIH:OVCAR 9. Radioiodinated monoclonal antibody OC125 was used in these studies. In order to establish the optimal conditions for imaging, tumor/blood ratios were determined. Gamma scintigraphy of nude mice bearing subcutaneous transplants of human ovarian carcinomas 3-4 days after 131I-OC125 administration demonstrated selective localization of the radiolabeled monoclonal antibody by these tumors without need for any background subtraction techniques.

Animals↗