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Biomedical subjects

E L Gillette

Publications and source records attributed to E L Gillette.

At least 73 records · Page 4Linked to original sources
PubMed1985

Isoeffect curves for radiation-induced cardiomyopathy in the dog.

Canine hearts were irradiated with a range of total doses given in 2, 3, or 4 Gy per fraction. Echocardiography was done before irradiation and at 3 and 6 months after irradiation. Histologic analyses were done of tissues taken at necropsy 6 months after irradiation. The percentage vascular component in the ventricles decreased with increasing total doses. The connective tissue component increased at lower doses and then decreased at higher doses. There was more fibroblastic proliferation and collagen production in the lower dose range and there may have been more cell killing by the higher doses. There was some evidence of myocardial hypertrophy at higher doses, which would have caused an apparent decrease in the connective tissue component. In either case, surviving fibroblasts would be expected to continue proliferating and producing collagen. At longer time intervals after irradiation the connective tissue component would likely continue to increase as observed clinically. That increase would be proportional to dose, but might not be closely related to initial killing of fibroblasts. Many factors such as changes in blood supply, continued loss of myocardium, and other stresses on the heart could influence the degree of fibrosis at later times. A relationship of response to cell killing appeared to exist based on alpha/beta ratios that were less than 3 Gy whether determined at the mid-range or for the greatest response of vasculoconnective tissues. Alpha/beta ratios ranged from 2.7 to 5 Gy for increases in diastolic wall thickness of the left ventricle at 3 and 6 months after irradiation. The low alpha/beta ratios reflect relatively steep isoeffect curves and have important implications for use of coarser fractionation schedules for treatment volumes that include the heart. The risk of cardiac damage could be significantly increased.

Animals↗
PubMed1985

Physiological studies of whole-body hyperthermia of dogs.

Whole body hyperthermia to 42 degrees C was induced in five normal beagles, using a humidity- and temperature-controlled chamber. Core temperatures of 41.2-43.0 degrees C were achieved in 50 min and maintained for 60 min. Cardiopulmonary responses included marked tachypnea and tachycardia. Blood gases underwent progressive drops in both PO2 (mean, 117 torr) and PCO2 (mean, 22 torr), suggesting the possibility of the development of a diffusion barrier during heating. Increased anion gaps in the face of respiratory alkalosis indicated that a metabolic acidosis developed in the heated dogs. Transient but significant drops in serum potassium and phosphorus were also observed during hyperthermia. Other physiological data, including serum chemistries, complete blood count, colony-forming units, and urine electrolyte excretion, did not change significantly.

Animals↗
PubMed1985

The pathogenesis of radiation nephropathy in the dog.

Canine kidneys were biopsied at 2-week intervals from 3 to 13 weeks after a single 15-Gy dose of intraoperatively delivered 6 MeV electrons to determine the pathogenesis and dose-limiting tissue for radiation nephropathy. The data suggest that the dose and time after irradiation determine the dose-limiting tissue. The early functional survival of canine kidneys appeared to be dependent on parenchymal cell killing. Histologic changes in epithelial cells were seen as early as 3 weeks after irradiation. The parenchyma decreased to 50% of the preirradiation volume by 9 weeks but repopulated to near normal by 11 weeks. A second wave of depopulation, possibly due to perivascular fibrosis, was evident at 13 weeks. Previous investigators have demonstrated progressively extensive changes in renal vessels after irradiation. In this study, permanent vascular damage was seen at 3 weeks; however, most early changes in vessel walls proved to be temporary and probably resulted from atrophic vasoconstriction following parenchymal depopulation. Vessel dimensions returned to near normal as the parenchyma repopulated; however, a "histohematic barrier" created by progressively increasing perivascular fibrosis may cause a reduction in oxygen and nutrient support of the parenchyma and permanent loss of renal function.

Animals↗
PubMed1984

Clinical use of thermal enhancement and therapeutic gain for hyperthermia combined with radiation or drugs.

Values for thermal enhancement and therapeutic gain are useful for deciding future directions of hyperthermia combined with other cancer therapy modalities. Evidence of thermal enhancement of effects on normal tissues is important as it indicates the need for dose modification. Specific values cannot be used generally to determine the degree of dose modification for clinical applications. A range of values accounting for many variables, including method of dose delivery for heat and the other modalities and knowledge of the normal tissues at risk, would be required for such specific application. There is frequently hyperthermic enhancement of radiation damage to acutely responding tissues. That may be avoided if tumors can be selectively heated, but extensive temperature monitoring is necessary to avoid hot spots. Irradiation and heating of spontaneous canine tumors resulted in an increased probability for tumor control with no apparent increase in late complications. Human clinical studies have shown that, with care, tumor response can be enhanced without significantly increasing normal tissue damage and that a therapeutic gain can be achieved. Caution must be exercised because, with few exceptions, follow-up was not long, and the tissues at risk were limited. Most human studies have been of relatively superficial tumors of small volume. Little information is available on whole-body or regional hyperthermia for assessment of thermal enhancement or therapeutic gain. Also, there is little information about chemotherapy combined with heat, although studies of heat with perfusion chemotherapy for malignant melanomas of the extremity have shown significantly increased survival rates.

Animals↗
PubMed1983

Effect of heat, radiation and pH on mouse mammary tumor cells.

Experiments were done in vitro with cells derived from a C3H mouse mammary adenocarcinoma (MADCAP-37) to determine the influence of pH and sequencing on hyperthermia induced radiosensitization. The heat treatment was one hour at 42.5 degrees C in a precision controlled water bath. The heat treatment did not significantly reduce cell survival. Five Gy of x radiation was given at variable intervals from two hours before to two hours following heating. Survival curves under acid pH (6.4-6.7) and alkaline pH (7.2-7.4) were obtained for selected intervals, corresponding to points of interest in the sequencing study. Survival was greater for irradiation alone at acid pH than at alkaline pH. The greatest cell killing occurred when irradiation and hyperthermia were given simultaneously at either alkaline or acid pH. At alkaline pH, survival increased as the interval increased between heating and irradiation. At acid pH, radiation survival remained low for as much as two hours following heating. If tumors are at acid pH, the greatest differential effect should be obtained for irradiation following heating because cells at alkaline pH (normal) had approximately 10 times greater survival. Vascular changes caused by heating might alter that response.

Adenocarcinoma↗
PubMed1982

Hyperthermia effects in animals with spontaneous tumors.

Hyperthermia caused complete regression of various animal tumors. Preliminary indications are that hyperthermia combined with irradiation increased the probability for tumor control with no increase in normal tissue complications. Dose-response assays planned will make comparisons of hyperthermia and irradiation alone and combined more meaningful. Whole-body hyperthermia alone and combined with chemotherapeutic agents is being studied in dogs. Of great interest is the toxicity observed in older animals bearing tumors. Their response is more relevant to that expected in humans with cancer than is that of young healthy animals.

Animals↗
PubMed1981

Metronidazole: a method for its determination in biological fluids and its disposition kinetics in the dog.

A method for the analytical determination of metronidazole concentrations in biological tissues was developed using high performance liquid chromatography. The procedure was employed to investigate the pharmacokinetics of metronidazole in dogs following intravenous and oral administration (44 mg/kg). The overall elimination rate constant beta was 0.0027 +/- 0.0005 min-1, the apparent specific volume of distribution (V'd) was 0.948 +/- 0.096 L/kg overall clearance (ClB) was 2.49 +/- 0.54 ml/kg/min and the rate constant for absorption Kab was 0.0456 +/- 0.0353 min-1. Oral bioavailability was high but variable (59%-100%). Implications of these data for chemotherapy of infections caused by anaerobic bacteria, trichomonads, and Giardia and for the sensitization of hypoxic neoplastic cells to radiotherapy are discussed.

Administration, Oral↗
PubMed1981

Warfarin in the dog: pharmacokinetics as related to clinical response.

Warfarin was administered intravenously (i.v.) as a single dose of 1.5 mg/kg to healthy dogs and the pharmacokinetic parameters were investigated. Elimination could be described by a one-compartment open model. Values for the elimination half-life and apparent specific volume of distribution were 14.5 +/- 4.1 h and 0.22 +/- 0.04 litre/kg, respectively. Oral maintenance doses were calculated from the data collected following i.v. administration and administered every 12 h for a total of five doses after an initial i.v. loading dose of 1.5 mg/kg. Prothrombin times increased from a control value of 8.6 +/- 0.3 sec to 55.2 +/- 5.2 sec over a period of 96 h. Prothrombin time returned to control values by 62 h after withdrawal of the drug. We propose a dosage regimen of warfarin for anticoagulant therapy in the dog of 0.22 mg/kg to be given orally every 12 h. Prothrombin time should be monitored during therapy and the dose of warfarin modified according to the degree of suppression of coagulation factors desired.

Administration, Oral↗
PubMed1981

Ploidy and DNA distribution analysis of spontaneous dog tumors by flow cytometry.

Ploidy and DNA content distributions were measured for 68 biopsy specimens of spontaneous (solid) dog tumors using flow cytometry analysis of mithramycin-stained cells. The tumor ploidy (i.e., DNA index values) ranged from 1.0 to 4.0 (diploid = 1.0), with a mean of 1.4. More than 80% of the tumors had elevated G0-G1 peak DNA contents and were classified heteroploid, similar to human solid tumors. Six mammary carcinomas and osteosarcomas had bimodal G0-G1 peaks. Based on flow cytometric data and pathology criteria, it was observed that: (a) the percentage of tumor S-phase cells tended to increase with increasing DNA index; and (b) for a given DNA index, the percentage of S-phase cells was lower for well-differentiated tumors and higher for poorly differentiated tumors. The inherent scattering of the DNA content and DNA distribution data between different tumor types limited the usefulness of these data for classifying tumors. The results suggest that improved classification of cytologically different tumors and tumor subsets might be achieved by simultaneous flow measurement of DNA content and DNA distribution information with an additional parameter that detects the cytological differentiation state.

Animals↗
PubMed1980

Flow cytometric applications to tumour biology: prospects and pitfalls.

A brief review of cytometry instrumentation and its potential applications in tumour biology is presented using our recent data. DNA distribution measurements of cells from spontaneous dog tumours and cultured cells after exposure to X-rays, alpha particles or adriamycin are shown. The data show that DNA fluorescence measurments have application in the study of cell kinetics after either radiation or drug treatment. Extensive and careful experimentation is needed, however, to utilize the sophisticated developments in flow cytometry instrumentation.

Animals↗
PubMed1979

Response of canine mast cell tumors to radiation.

Twenty-three dogs completed a fractionated course of ionizing radiation therapy for mast cell tumors. In 10 dogs the response was satisfactory, and the tumors were considered controlled 12 months after completion of the prescribed course of therapy. Treatment was considered unsatisfactory for the remaining 13 dogs due to failure to control the tumor locally, generalized metastasis, or both. A dose effect was noted in the response of the tumors to radiation. Of 6 dogs, 5 responded satisfactorily when the tumor dose was 4,000 rads or greater. When the tumor dose was less than 4,000 rads, 5 of 17 dogs responded satisfactorily. The dose calculated to control 50% of the meat cell tumors was 3,625 rads (95% confidence interval: 3,265-4,024 rads). Adverse normal tissue reactions, which consisted of moist desquamation in 10 animals and necrosis in 4, were recorded. The dose calculated to cause desquamation in 50% of the dogs was 3,750 rads (95% confidence interval: 3,348-4,200 rads).

Animals↗
PubMed1979

Irradiation of the microvasculature with fast neutrons.

Single- and split-dose irradiation of the eyes of dogs was performed with cyclotron-produced polyenergetic neutrons at a rate of about 0.2 Gy (20 rad) per minute. Neovascularization was subsequently induced surgically in the avascular corneas and stimulated for 7 days to study the response of slowly proliferating capillary endothelial cells. Corneal tissue samples were evaluated quantitatively by morphometric methods. A dose-response curve was drawn by plotting per cent capillary volume versus dose. D0 was 2 Gy (200 rad), and the recovery ability was determined to be equivalent to 1.3 Gy (130 rad). Depending on the level of damage, relative biological effectiveness (RBE) values were 1.9 to 2.3.

Animals↗
PubMed1979

Large animal studies of hyperthermia and irradiation.

Investigators who have studied hyperthermic response of spontaneous animal tumors have reported complete remission for variable periods of 15 to 38% of tumors treated. Normal tissue complications were minimal. Long-term control appears more likely if irradiation is combined with hyperthermia, but information is lacking to date to confirm this. Dose-response assays of radiation alone have been done which would make comparisons with hyperthermia and radiation more meaningful. Probabilities for increasing tumor control without significantly increasing normal tissue response can be estimated better from such assays. Spontaneous tumors in companion animals have advantages over rodent tumor systems of relatively larger treatment fields; longer follow-up times are possible, and serial monitoring of a variety of clinical data can be done. Experience of investigators using these tumors has shown that animal owners and referring veterinarians are most cooperative in reasonable, humane approaches to experimental cancer therapy.

Animals↗