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G Shelton

Publications and source records attributed to G Shelton.

At least 19 recordsLinked to original sources
PubMed2000

Dexamethasone does not significantly contribute to the response rate of docetaxel and estramustine in androgen independent prostate cancer.

PURPOSE: We evaluated the independent response rate of dexamethasone before docetaxel and estramustine administration as measured by changes in serum prostate specific antigen (PSA) in patients with androgen independent prostate cancer. MATERIALS AND METHODS: A total of 12 patients received 20 mg. dexamethasone orally every 6 hours for 3 doses repeated every 3 weeks before starting cytotoxic therapy with estramustine and docetaxel. After progression on dexamethasone 280 mg. estramustine orally 3 times daily on days 1 to 5 and 70 mg./m.2 docetaxel intravenously for 1 hour on day 2 were given. RESULTS: None of the patients initially treated with dexamethasone monotherapy (median 1 cycle, range 1 to 5) had a PSA decline of 50% or greater. Median PSA increase on monotherapy was 47% (range 0% to 22%). On estramustine and docetaxel therapy PSA decreased 50% or greater in 11 patients (92%, 95% confidence intervals [CI] 60 to 99) and 80% or greater in 7 (58%, 95% CI 29 to 84), and normalized in 5 (42%, 95% CI 16 to 71), with a median duration of response of 153 (range 42 to 371), 132 (range 84 to 287) and 84 (range 21 to 174) days, respectively. Median times to reach 50% and 80% decreases in baseline PSA were 21 (range 21 to 209) and 63 (range 21 to 138) days, respectively. In 9 patients (75%, 95% CI 43 to 93) PSA decreased at least 50% by week 9. Of 4 patients with bidimensionally measurable disease 3 had a partial response. Median time to progression was 263 days (range 91 to 378). CONCLUSIONS: Administration of 20. mg. dexamethasone orally every 6 hours for 3 doses every 3 weeks does not significantly contribute to the PSA response rate of estramustine and docetaxel.

Adenocarcinoma↗
PubMed1999

Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer.

PURPOSE: To evaluate the toxicity, efficacy, and pharmacokinetics of docetaxel when combined with oral estramustine and dexamethasone in a phase I study in patients with progressive metastatic androgen-independent prostate cancer. PATIENTS AND METHODS: Thirty-four men were stratified into minimally pretreated (MPT) and extensively pretreated (EPT) groups. Estramustine 280 mg PO tid was administered 1 hour before or 2 hours after meals on days 1 through 5, with escalated doses of docetaxel from 40 to 80 mg/m2 on day 2. Treatment was repeated every 21 days. RESULTS: Thirty-four patients were assessable for toxicity and 33 for response. In the MPT patients, dose-limiting myelosuppression was reached at 80 mg/m2, with six patients experiencing grade 3/4 granulocytopenia. In EPT patients, escalation above 70 mg/m2 was not attempted. Fourteen MPT (70%) and six EPT (50%) patients had a > or = 50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. The overall 50% PSA response rate was 63% (95% confidence interval [CI], 28% to 81%). Of the 18 patients with bidimensionally measurable disease, five (28%; 95% CI, 11% to 54%) achieved a partial response. At the time of entry onto the study, 15 patients required narcotic analgesics for bone pain; after treatment, eight (53%) discontinued their pain medications. The area under the curve for docetaxel increased linearly from 40 to 70 mg/m2. At 80 mg/m2, the measured area under the curve was 8.37 (standard deviation, 0.724), which was significantly higher than the previously reported values. CONCLUSION: The recommended phase II dose of docetaxel combined with estramustine is 70 mg/m2 in MPT patients and 60 mg/m2 in EPT patients. This combination is active in men with androgen-independent prostate cancer.

Aged↗
PubMed1999

Phase I/II studies of docetaxel (Taxotere) combined with estramustine in men with hormone-refractory prostate cancer.

Evaluation of the combined regimen of estramustine and docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) in men with hormone-refractory prostate cancer is in its early stages. While this combination is promising in terms of efficacy, adverse events associated with estramustine are a concern. Estramustine has been associated with side effects such as nausea, vomiting, edema, and serious vascular events. Reported here are the results of phase I and phase II trials in which 280 mg estramustine was given three times daily on days I to 5 in 21-day treatment cycles with docetaxel at varying doses. Data from patients evaluable thus far support the efficacy of this combination, both in chemotherapeutically naive patients and in those who have had prior therapy. A survival benefit from this combination appears achievable from these early studies. As significant antitumor activity can be achieved with docetaxel alone, future studies need to define the minimal dose of estramustine for this combination.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Aerobic and anaerobic correlates of mechanical work by gastrocnemius muscles of the aquatic amphibian Xenopus laevis.

Isolated, saline-perfused gastrocnemius muscles of Xenopus laevis were used to assess the relationships between aerobic and anaerobic metabolism during conditions of rest, isotonic contraction and recovery. The major part (85%) of the energy used during 25 min of isotonic contractions in the saline-perfused muscles was from anaerobic rather than aerobic sources. However, the small contribution made by oxidative metabolism during activity can be attributed, in part at least, to limitations imposed by the rate of perfusion and the low O2 capacity of the perfusate. The respiratory exchange ratio (R = VCO2/VO2) of saline-perfused gastrocnemius muscles of Xenopus was 0.82 at rest, increasing to values well above 1.0 during activity. The elevated R value is consistent with liberation of CO2 by metabolic acid titration of the bicarbonate buffer system of the saline perfusate. Recovery from exercise was characterized as a period of net CO2 retention (R values of 0.4) presumably reflecting a replenishment of depleted CO2 stores. Depending on the acid-base status of the venous outflow from the isotonically contracting muscles, hydrogen ions were found to be released at either a greater rate (alkalosis) or slower rate (acidosis) than that of lactate.

Aerobiosis↗
PubMed1986

Gas exchange, storage and transport in voluntarily diving Xenopus laevis.

A closed, extracorporeal loop, containing oxygen and carbon dioxide electrodes, was developed in order to make continuous measurements of lung gas PO2 (PAO2) and PCO2 (PACO2) in undisturbed Xenopus laevis. Pulmonary R values (delta PACO2/delta PAO2) are about 0.8 during periods of lung ventilation in resting animals, but they fall very rapidly as a voluntary dive proceeds. In fact, the instantaneous R values for lung eventually fall to zero during a voluntary dive, since PAO2 continues to decline whilst PACO2 (after an initial increase) comes into a steady state as transcutaneous CO2 losses balance metabolic production. These relationships change during spontaneous underwater activity, aquatic hypercapnia or enforced diving, with significantly higher PACO2 levels being found at any PAO2 value than in resting animals. Emergence from such dives is marked by a considerable hyperventilation, leading to lung R values which are 2-3 times higher than those seen during lung ventilation of animals at rest. The lungs of Xenopus are therefore important in eliminating the CO2 stored during a period of breath-holding but not of major importance in forming part of that store themselves. The lungs of Xenopus are, however, important sources of stored oxygen during voluntary dives, the rate of use being clearly related to activity levels and dive durations. There could be sudden changes in the rate of PAO2 depletion during a dive, suggesting that factors additional to the metabolic rate of the cells may be important in determining the way in which the lung store is used. In a parallel series of experiments, O2 and CO2 partial pressures were determined in lung gas samples and in simultaneously drawn samples of blood from the femoral artery (systemic arterial) and left auricle (pulmonary venous) of animals making voluntary dives. These blood/gas data, together with results of previous experiments on Xenopus, have been used to develop an idealized model of O2 exchange, storage and transport during a 30-min voluntary dive. The volume of the O2 stores held in the lungs and various subdivisions of the circulation are shown in the model by plotting the PO2 of the store against its respective O2 capacitance. The model illustrates the overall importance of the lung as a source of oxygen during breath-holding and that early use of a large systemic venous O2 store may be an important basic function for cardiovascular adjustments seen in a dive.

Animals↗
PubMed1980

Cardiovascular dynamics and adrenergic responses of the rainbow trout in vivo.

Cardiac output and dorsal aorta, ventral aorta, caudal artery, caudal vein, and subintestinal vein pressures have been directly measured in intact unanaesthetized trout. Cardiac output (Q) averaged 36.7 ml/kg.min. The pressure drop across the systemic vascular resistance (Rs) was approximately twice that across the gill resistance (Rg), and a significant positive pressure persisted in the venous system. alpha-Adrenergic blockade revealed a considerable endogenous vasomotor tone resulting from latent adrenergic constriction of Rs. Intravenous adrenaline caused a pressor response throughout the circulatory system which has been analysed in detail with the aid of previous studies on isolated parts of the trout circulation. The complex and variable form of the pressor response reflected differential contributions from changes in Q, Rg, and Rs. Increases in Rs (alpha-receptor activation) were the principal cause of all pressor responses. Rg usually declined slightly due to passive dilation and/or beta-receptor stimulation, but occasionally increased due to alpha-receptor activation. The cardiac response reflected a varying balance between a direct beta-stimulatory effect of adrenaline on Q and an indirect passive inhibition of Q by the increase in peripheral resistance. Both effects were mediated through changes in stroke volume. Occasional tachycardia or more frequent reflex bradycardia were minor components of the cardiac response. The in vivo actions of other adrenergic agents have been similarly analysed.

Animals↗
PubMed1980

The reflex control of heart rate and cardiac output in the rainbow trout: interactive influences of hypoxia, haemorrhage, and systemic vasomotor tone.

In cannulated trout there was no cholinergic vagal tone as revealed by atropine blockade during normal heart rates. Reductions in heart rate occasionally occurred under normoxia without apparent external stimuli ('spontaneous' bradycardia) and always occurred under environmental hypoxia (hypoxic bradycardia) due to the imposition of significant vagal tone. Direct measurements of cardiac output (Q) during these bradycardias showed that increases in cardiac stroke volume compensated for the falls in heart rate so that total Q remained unchanged or increased slightly. Sudden experimental reductions in arterial blood pressure via blockade of systemic vasomotor tone with yohimbine or via haemorrhage had no effect on heart rate during normal rates, but caused cardioacceleration during both types of bradycardia. These increases in heart rate never exceeded the point of zero vagal tone (normal heart rate) and were largely or wholly due to reductions in endogenous vagal tone. These cardioaccelerations were temporary; spontaneous bradycardia could re-occur at any time, while hypoxic bradycardia always re-occurred if the hypoxic stimulus were maintained. The results are interpreted in terms of a central interaction between the baroreceptor and chemoreceptor reflexes.

Animals↗
PubMed1979

Acid-base relationships in the blood of the toad, Bufo marinus. I. The effects of environmental CO2.

An abrupt increase in ambient CO2 resulted in a marked respiratory acidosis which took place within 30 min. During this time there was a considerable reduction in the PCO2 difference between arterial blood and inspired gas caused by an increase in ventilations. Prolonged CO2 exposure (24 h) showed that there was some compensation for the acidosis in that plasma bicarbonate concentrations increased substantially. At the same time, however, the PCO2 of arterial blood always rose so that the net result was usually only a small increase in pH. Upon return to air, the blood was backtitrated along a buffer line elevated above and parallel to that seen during the initial response to hypercapnia. The fall in arterial blood PCO2 during the early stages of recovery often led to pH values higher than those seen in the untreated animal. After 48 h in air, recovery had gone further with PCO2, pH and [HCO3-] levels approaching but rarely reaching the pre-exposure values.

Acid-Base Equilibrium↗
PubMed1979

Acid-base relationships in the blood of the toad, Bufo marinus. II. The effects of dehydration.

Cutaneous CO2 excretion is reduced as the skin dries during dehydration but an increase in breath frequency acts to regulate the arterial blood PCO2 and thus pHa. Moreover, the toad does not urinate and water is reabsorbed from the bladder to replace that lost by evaporation at the skin and lung surfaces. The animal does, however, produce a very acid bladder urine to conserve circulating levels of plasma [HCO3-] and this together with an increased ventilation effectively maintains the blood acid-base status for up to 48 h of dehydration in air. Water loss and acid production are presumably also reduced by the animal's behaviour; animals remain still, in a crouched position or in a pile if left in groups. Dehydrated toads are less able than hydrated toads to regulate blood pH during hypercapnia: they hyperventilate and mobilize body bicarbonate stores in much the same fashion as hydrated animals but due to the restrictions on cutaneous CO2 excretion and renal output, there is comparatively little reduction in the PCO2 difference between arterial blood and inspired gas thereby resulting in a more severe respiratory acidosis. These factors further contribute to the persistent acidosis which continues even when the animals are returned to air.

Acid-Base Equilibrium↗
PubMed1979

Acid-base relationships in the blood of the toad, Bufo marinus. III. The effects of burrowing.

When Bufo marinus burrows, the skin becomes intimately surrounded by substrate but the nares always remain exposed to the surface air. Upon entering into a state of dormancy the animal hypoventilates and this together with the loss of the skin as a respiratory site results in a rise in arterial blood PCO2 despite a probable decline in metabolism. Even though lung ventilation falls, the toad regulates blood pH and the respiratory acidosis is progressively compensated for by a progressive increase in plasma [HCO3-] along the course of an elevated PCO2 isopleth. At steady state, the acidosis is fully compensated for by a new equilibrium ratio of HCO3- to PCO2 at the same pH as the non-burrowed animal. Arousal from the dormant state at this time results in a marked lung hyperventilation and a sharp decline in body CO2 stores.

Acid-Base Equilibrium↗
PubMed1978

Some response characteristics of CO2 electrodes.

Radiometer carbon dioxide electrodes and probably other electrodes of similar design do not give the same readings, except under certain very limited conditions, when used to measure carbon dioxide concentrations in solution and the gas phase with which the liquid is in equilibrium. Blood samples of high P(CO2), when introduced into the sample chamber of an electrode at low P(CO2), lose CO2 to the electrode resulting in a reduction of sample P(CO2) and hence, because the sample size is very small, a recorded value much below the real P(CO2) of the sample is obtained. The reverse occurs if the P(CO2) of the sample is below that of the electrode. To avoid these problems the electrode should be held at the same P(CO2) as the sample, or sample replacement should be used to establish the real P(CO2). The differences in response of the electrode to gases and liquids should also be taken into account.

Animals↗
PubMed1976

Cardiovascular dynamics of the chelonia during apnoea and lung ventilation.

1. In both Pseudemys and Testudo, blood pressures are identical in all chambers of the ventricle. Systolic pressures are not measurably different in the ventricle and systemic arteries but are 0-5-2-0 cm H2O lower in the pulmonary artery due to the resistance of the pulmonary outflow tract. Diastolic pressures are the same in all systemic arteries but are substantially lower in the pulmonary artery. It is concluded that the systemic and pulmonary circulations are perfused by a single pump during both apnoea and lung ventilation. 2. Flow profiles in pulmonary and systemic arteries are characteristicallly different. Substantial changes in cardiac output may occur during intermittent breathing and apnoea, especially if there are large fluctuations in heart rate. Pulmonary flow increases during lung ventilation due to vasodilation of the lung vasculature. Systemic is also affected though the increase is usually smaller. 3. Any separation in the blood pumped by the single ventricle must be maintained by laminar flow patterns and the composition of the blood in each of the major arteries should reflect their relationship to these patterns.

Animals↗
PubMed1975

Physical and adrenergic factors affecting systemic vascular resistance in the rainbow trout: a comparison with branchial vascular resistance.

The passive distensibility and adrenergic reactivity of the systemic vascular resistance (Rs) in Salmogairdneri have been studied using perfused trunk preparations, and the data compared with previous results on the branchial resistance (Rg). At normal levels of efferent blood pressure, Rs is relatively more distensible than Rg in response to afferent pressure increases, but this difference may not be important in vivo. alpha-adrenegic constrictory receptors predominate in Rs, in contrast to beta-adrenergic dilatory receptors in Rg; a significant alpha-adrenergic tone in Rs is lost during perfusion. Rs is far less sensitive than Rg to circulatory catecholamine levels. It is suggested that the sympathetic nervous system, rather than plasma catecholamines, provides the effective adrenergic control of Rs in vivo.

Animals↗