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R M Walker

Publications and source records attributed to R M Walker.

At least 55 records · Page 3Linked to original sources
PubMed1989

The illusion of futility in clinical practice.

The claim that a treatment is futile is often used to justify a shift in the physician's ethical obligations to patients. In clinical situations in which non-futile treatments are available, the physician has an obligation to discuss therapeutic alternatives with the patient. By contrast, a physician is under no obligation to offer, or even to discuss, futile therapies. This shift is supported by moral reasoning in ancient and modern medical ethics, by public policy, and by case law. Given this shift in ethical obligations, one might expect that physicians would have unambiguous criteria for determining when a therapy is futile. This is not the case. Rather than being a discrete and definable entity, futile therapy is merely the end of the spectrum of therapies with very low efficacy. Ambiguity in determining futility, arising from linguistic errors, from statistical misinterpretations, and from disagreements about the goals of therapy, undermines the force of futility claims. Decisions to withhold therapy that is deemed futile, like all treatment choices, must follow both clinical judgments about the chance of success of a therapy and an explicit consideration of the patient's goals for therapy. Futility claims rarely should be used to justify a radical shift in ethical obligations.

Attitude of Health Personnel↗
PubMed1989

Medical ethics education: coming of age.

Medical ethics education is instruction that endeavors to teach the examination of the role of values in the doctor's relationship with patients, colleagues, and society. It is one front of a broad curricular effort to develop physicians' values, social perspectives, and interpersonal skills for the practice of medicine. The authors define medical ethics education as more clinically centered than human values education and more inclusive of philosophical, social, and legal issues than is interpersonal skills training. The authors review the history of the emergence of medical ethics education over the last 20 years, examine the areas of consensus that have emerged concerning the general objectives and premises for designing medical ethics programs, and describe teaching objectives and methods, course content, and program evaluation used in such programs on both preclinical and clinical levels. The four interrelated requirements for successful institutionalization of medical ethics education programs are defined and discussed, and the paper ends with an overview of the uncertain future of medical ethics education, an accepted but still not fully mature part of physician training in the United States. An extensive reference list accompanies the article.

Bioethical Issues↗
PubMed1989

Development of a teaching program in clinical medical ethics at the University of Chicago.

The University of Chicago Pritzker School of Medicine has developed and evaluated an extensive teaching program in clinical ethics coordinated primarily through the Center for Clinical Medical Ethics. The program provides medical students with a foundation in medical ethics during the four years of medical school and augments the clinical ethics knowledge and teaching skills of the housestaff and clinical faculty at the University of Chicago. Together, medical student teaching and clinical faculty development have made clinical ethics an integral part of medical education at the University of Chicago. Through these efforts, the teaching program aims to incorporate clinical ethics considerations into medical decisions and in this way contribute to improving patient care. (A detailed overview of all clinical ethics instruction at the school is provided.)

Bioethical Issues↗
PubMed1988

Chronic toxicity of the anticonvulsant zonisamide in beagle dogs.

The chronic toxicity of the new anticonvulsant drug zonisamide (1,2-benzisoxazole-3-methanesulfonamide) was evaluated in a detailed 52-week study in which dose levels of 0, 10, 30 and 75 mg/kg/day were administered orally in gelatin capsules to groups of five Beagle dogs per sex. Potential toxicity was based on the effects of zonisamide on body weight and food consumption; clinical and ophthalmic examinations; electrocardiography and heart rates; clinical biochemistry, hematology and urinalysis determinations; organ weights and gross and histopathologic evaluations; electron microscopy of high dose and control male dogs; and plasma zonisamide concentrations. Zonisamide was relatively well tolerated during the study. In animals given 75 mg/kg/day, early body weight losses occurred and therefore, from Weeks 2 and 3 until study termination, for males and females respectively, the high dose was given as two equal portions (i.e., 37.5 mg/kg each) approximately 3-4 hr apart. Clinical laboratory analyses in the dogs given 75 mg/kg revealed a small but statistically significant decrease in plasma albumin concentration and a small increase in alkaline phosphatase activity. In animals given 75 mg/kg, liver weights were increased and a brownish discoloration of the liver was noted grossly at necropsy. No significant light microscopic changes were evident; however, electron microscopic evaluation of the liver tissue from the 5 male dogs given 75 mg/kg revealed the presence of concentric lamellae of paired smooth membranes which were not seen in control animals. At the 10 and 30 mg/kg dose levels, plasma zonisamide concentrations reached steady-state and were proportional to dose, but at 75 mg/kg, plasma levels were disproportionately higher and never achieved steady-state. The results of this study indicated that at the high dose level of 75 mg/kg, chronic administration of zonisamide had a mild effect on the liver, particularly the endoplasmic reticulum.

Administration, Oral↗
PubMed1987

Furosemide toxicity in isolated mouse hepatocyte suspensions.

Incubation of freshly isolated mouse hepatocytes with 0.5 or 1.0 mM furosemide caused a depletion of cellular acid soluble sulfhydryls to approximately 20-30% of control over the course of 4.5 h. The depletion was accompanied by a reduction in cell viability (indicated by the lactate dehydrogenase latency test) which was significant (P less than 0.05) for 0.5 mM but not for 1.0 mM furosemide at 4.5 h. Ultrastructurally, 0.5 or 1.0 mM furosemide caused cytoplasmic changes including loss of glycogen, disaggregation of polyribosomes, vesiculation of endoplasmic reticulum, and occasional appearance of lamellar bodies consisting of concentric arrays of paired smooth membranes. These concentrations of furosemide also caused cell surface changes, including loss of microvilli, development of an irregular shape compared to the spherical appearance of untreated hepatocytes, and the development of occasional blebs. The appearance of pale staining hydropic cells was indicative of the final stages of cell death. N-Acetylcysteine (6.0 mM) was effective at preventing the depletion of soluble sulfhydryls, the loss of viability, and the ultrastructural effects of 0.5 or 1.0 mM furosemide, suggesting a role for soluble sulfhydryls in the pathogenesis of furosemide hepatotoxicity.

Acetylcysteine↗
PubMed1984

Prophylactic antibiotics in appendicectomy: a prospective double blind randomized study.

Our double blind prospective randomized trial comparing intravenous cefoxitin with rectal metronidazole in appendicectomy reveals both groups to be similar regarding basic data, with no significant difference in the results between the two drugs. Nearly all the wound infections occurred after the patient went home. Most were minor infections and the overall infection rate was 6%. The intravenous route was the more certain but the more expensive. Bacteriology suggests that the same flora were present in the appendiceal wall of normal and acute non-perforated appendices. This would suggest bacteriologically that the same risks exist with non-inflamed appendicectomy as occurs with inflamed non-perforated appendices. These findings support the use of short course prophylaxis in appendicectomy.

Adolescent↗
PubMed1983

Ultrastructural effects of acetaminophen in isolated mouse hepatocytes.

The ultrastructure of isolated mouse hepatocytes shows good correlation with that of cells from intact liver. Incubation of isolated mouse hepatocytes with 1.0 mM acetaminophen causes a variety of cytoplasmic and cell surface lesions, as well as cell death. The changes are similar or equivalent to those caused by acetaminophen in vivo. The most prominent feature of damage in isolated hepatocytes is bleb formation, which is also seen occasionally in control incubations. The protective compound alpha-mercaptopropionylglycine and the antidote N-acetylcysteine both prevented the acetaminophen-induced changes. It is suggested that the in vivo counterpart to the blebs are endocytic vacuoles which form at cell margins due to the intravascular pressure of the sinusoids. It is suggested that the cell surface changes both in vivo and in isolated hepatocytes are caused by some dysfunction to the microfilament component of the cytoskeleton.

Acetaminophen↗
PubMed1983

Increased acetaminophen-induced hepatotoxicity after chronic ethanol consumption in mice.

The effect of chronic ethanol consumption on acetaminophen (200, 400, and 600 mg/kg) toxicity was determined by maintaining mice for 10 days on diets consisting of chow and one of the following drinking solutions: 10% ethanol + 10% sucrose, 8% sucrose, or tap water. Toxicity as manifested by mortality, liver enlargement, and liver congestion was greatest in the ethanol-treated group. We suggest that the greater mortality was a result of the increased liver congestion and consequent hypovolemia. Despite the increased levels of cytochrome(s) P-450, covalent binding of [3H]acetaminophen reactive metabolite(s) to liver protein was not higher in ethanol-treated animals. This can be explained by the higher initial glutathione concentration and/or ability to replenish glutathione in the ethanol-treated group. We suggest that the enhancement of acetaminophen toxicity by ethanol is the result of an effect of ethanol on hepatocyte membranes which renders the cells more susceptible to toxic injury.

Acetaminophen↗
PubMed1983

Scanning electron microscopic examination of acetaminophen-induced hepatotoxicity and congestion in mice.

Acetaminophen-induced hepatotoxicity and associated hepatic congestion were investigated by scanning and correlative transmission electron microscopy. Acetaminophen (750 mg/kg orally) causes changes in cell surface morphology and the relationship between hepatocytes and sinusoidal lining cells. There is endocytic vacuolation at lateral and sinusoidal margins of centrilobular hepatocytes, loss of microvilli, Disse space enlargement, dilation of bile canaliculi, and disappearance of the studlike projections from hepatocyte lateral surfaces. Erythrocytes enter the enlarged Disse space and endocytic vacuoles via enlarged pores in sinusoidal lining cells, thereby collapsing the sinusoids. Lining cells are not lost, but apparently held in position by preservation of intercellular junctions, cytoplasmic projections from hepatocytes, and anchorage by fat-storing cells within the Disse space. Congestion can abate by 24 hours, indicating that erythrocytes can return to the general circulation from the Disse space.

Acetaminophen↗
PubMed1982

Acetaminophen-induced hypothermia in mice: evidence for a central action of the parent compound.

Pretreatment of mice with phenobarbital, an inducer of oxidative drug metabolism, had no effect on the early hypothermic effect of a toxic dose of acetaminophen, while pretreatment with metyrapone, SKF-525A, or piperonyl butoxide (inhibitors of mixed-function oxidase) enhanced the hypothermia. In mice treated with acetaminophen alone, brain parent drug levels correlated with the degree of hypothermia, while liver drug levels did not. Also, intracerebroventricular injection of acetaminophen resulted in significant hypothermia within 20 min. These results indicate that the early hypothermia caused by acetaminophen in mice is due to the parent drug, not to its toxic reactive metabolite, and that the effect is mediated centrally. The observation that piperonyl butoxide and SKF-525A themselves caused significant hypothermia indicates that the use of these compounds should be avoided when body temperature is being followed in drug metabolism experiments.

Acetaminophen↗
PubMed1982

Role of renal prostaglandins during antidiuresis and water diuresis in man.

The relationship of renal prostaglandins to antidiuretic hormone action and water diuresis was examined in 13 normal subjects and 2 subjects with diabetes insipidus. Following overnight water deprivation, a oral water load caused a prompt and sustained rise in the rate of urinary PGE2 excretion from 7.7 +/- 1.2 to 81.6 +/- 26.4 ng/hr (P less than 0.0001) in 7 normal subjects. Because the simultaneous increase in urinary excretion of urea was only 17% of the rise in urinary PGE2, passive wash-out of renal PGE2 probably accounts for only a small fraction of the increment in PGE2 excretion. Administration of the antidiuretic hormone analogue DDAVP to 6 normal subjects during sustained water diuresis resulted in a decrease in PGE2 excretion and urine flow rate comparable to that of dehydrated subjects. Thus, PGE2 excretion varied directly with urine flow rate over a wide range of states of hydration in all 13 normal subjects. One patient with central diabetes insipidus and one with nephrogenic diabetes insipidus demonstrated a similar positive correlation of PGE2 excretion rate and urinary flow rate in states of hydration, dehydration, and after administration of DDAVP. In the patient with nephrogenic diabetes insipidus, this relationship of PGE2 excretion rate to urine flow rate was unaffedted by DDAVP over a broad range of urine flow rates. Inhibition of prostaglandin synthesis with indomethacin in 6 normal subjects resulted in a significant decline in free water clearance (7.7 +/- 1.0 to 4.7 +/- 0.9 ml/min. P less than 0.001) and an increase in the minimal UOsm (61 +/- 4 to 93 +/- 19 mOsm/kg. P less than 0.01) achieved during water diuresis without a change in creatinine or osmolar clearances. Furthermore, the tightly linked relationship of PGE2 excretion rate to urine flow rate was reduced in 5 of 6 subjects during indomethacin treatment. We conclude that urinary PGE2 excretion varies directly with urine flow rate and is not directly dependent on ADH activity or state of hydration in man. The rise in PGE2 excretion during water diuresis may enhance the excretion of free water since indomethacin treatment blunted free water clearance while suppressing the rise in PGE2 excretion.

Adult↗
PubMed1982

Acetaminophen toxicity in fed and fasted mice.

Acetaminophen (750 mg/kg) toxicity and its modification by N-acetylcysteine (NAC, 1200 mg/kg) have been compared in fed and fasted mice. There was no significant difference between fed and fasted animals with respect to microsomal protein content, cytochrome(s) P-450 content, and aryl hydrocarbon hydroxylase activity. Glucuronyl transferase activity was significantly higher in fasted mice. Hepatotoxicity, as determined histologically and by liver enlargement was greater in fasted than fed mice. Covalent binding of [3H]acetaminophen metabolite(s) to liver proteins was also greater in fasted animals. NAC administration prevented acetaminophen-induced microscopic changes and liver enlargement and reduced the magnitude of covalent binding of acetaminophen metabolites. Fasting caused a marked fall in liver reduced sulfhydryl concentration. The incidence of acetaminophen-induced hypothermia was greater in fasted than in fed animals. NAC administration reduced hypothermia in fasted mice and abolished it in fed animals. It is concluded that enhanced acetaminophen toxicity in fasted mice compared with fed mice is unlikely to be a consequence of increased reactive metabolite formation, but rather a result of reduced inactivation of reactive metabolite(s) due to reduced hepatic glutathione stores in fasted mice.

Acetaminophen↗
PubMed1981

Furosemide induced hepatotoxicity.

Furosemide-induced (400mg/kg ip) hepatotoxicity progressing to centrilobular necrosis was studied by light and electron microscopy in Swiss white mice. Centrilobular glycogen depletion and cytoplasmic foaminess, usually accompanied by extensive vacuolation, were detectable by light microscopy 1 1/2 hr after furosemide. Centrilobular congestion and hydropic single cell necrosis developed after 3 hr. Electron microscopy revealed disaggregation of polyribosomes, vesiculation of endoplasmic reticulum, an endocytic origin for the vacuolation, and a definite sequence in the development of congestion. Vacuolation coincided with loss of microvilli and resulted in detachment of sinusoidal lining cells from hepatocytes. Small vacuoles apparently formed at the sinusoidal margin of hepatocytes by fusion of microvilli. Congestion and occlusion of sinusoidal lumens developed as a consequence of erythrocytes entering the enlarged Disse space, possibly through pores in the lining cells, and thence entering endocytic vacuoles. The vacuolation, loss of microvilli and terminal hydropic degeneration suggest an important role for the plasma membrane in the development of furosemide-induced hepatotoxicity. Comparisons with known membrane toxins support this concept.

Animals↗