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Biomedical subjects

K M Anderson

Publications and source records attributed to K M Anderson.

At least 73 records · Page 4Linked to original sources
PubMed1996

Economic assessment of platelet glycoprotein IIb/IIIa inhibition for prevention of ischemic complications of high-risk coronary angioplasty. EPIC Investigators.

BACKGROUND: In the EPIC trial, c7E3 Fab, an antiplatelet IIb/ IIIa receptor antibody, reduced 30-day ischemic end points after high-risk coronary angioplasty by 35% and 6-month ischemic events by 23% but increased in-hospital bleeding episodes. METHODS AND RESULTS: Of the 2099 patients randomized in EPIC, data were collected on 2038 (97%) for prospective hospital cost and major resources. Physician fees were estimated from the Medicare Fee Schedule. Regression analysis was used to examine the economic tradeoff between reduced ischemic events and increased major bleeding during the initial hospitalization. A potential cost savings of $622 per patient during the initial hospitalization from reduced acute ischemic events with c7E3 Fab was offset by an equivalent rise ($521) in costs as the result of an increase in bleeding episodes. Baseline medical costs for the bolus and infusion c7E3 Fab arm averaged $13,577 (exclusive of drug cost) compared with $13,434 for placebo (P = .42). During the 6-month follow-up, c7E3 Fab decreased repeat hospitalization rates by 23% (P = .004) and repeat revascularization by 22% (P = .04), producing a mean $1270 savings per patient (exclusive of drug cost) (P = .018). With a cost of $1407 for the bolus and infusion c7E3 Fab regimen, the cumulative net 6-month cost to switch from standard care to routine c7E3 Fab averaged $293 per patient. CONCLUSIONS: In high-risk coronary angioplasty, aggressive platelet inhibition with c7E3 Fab, by significantly reducing ischemic events and repeat revascularization, recoups most of the cost of therapy and has the potential to pay for itself.

Abciximab↗
PubMed1996

Effects of platelet glycoprotein IIb/IIIa receptor blockade by a chimeric monoclonal antibody (abciximab) on acute and six-month outcomes after percutaneous transluminal coronary angioplasty for acute myocardial infarction. EPIC investigators.

Percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction is an attractive alternative to thrombolysis, but is still limited by recurrent ischemia and restenosis. We determined whether adjunctive platelet glycoprotein IIb/IIIa receptor blockade improved outcomes in patients undergoing direct and rescue PTCA in the Evaluation of c7E3 for Prevention of Ischemic Complications (EPIC) trial. Of the 2,099 patients undergoing percutaneous intervention who randomly received chimeric 7E3 Fab (c7E3) as a bolus, a bolus and 12-hour infusion, or placebo, 42 underwent direct PTCA for acute myocardial infarction and 22 patients had rescue PTCA after failed thrombolysis. The primary composite end point comprised death, reinfarction, repeat intervention, or bypass surgery. Outcomes were assessed at 30 days and 6 months. Baseline characteristics were similar in direct and rescue PTCA patients. Pooling the 2 groups, c7E3 bolus and infusion reduced the primary composite end point by 83% (26.1% placebo vs 4.5% c7E3 bolus and infusion, p = 0.06). No reinfarctions or repeat urgent interventions occurred in c7E3 bolus and infusion patients at 30 days, although there was a trend toward more deaths in c7E3-treated patients. Major bleeding was increased with c7E3 (24% vs 13%, p = 0.28). At 6 months, ischemic events were reduced from 47.8% with placebo to 4.5% with c7E3 bolus and infusion (p = 0.002), particularly reinfarction (p = 0.05) and repeat revascularization (p = 0.002). We conclude that adjunctive c7E3 therapy during direct and rescue PTCA decreased acute ischemic events and clinical restenosis in the EPIC trial. These data provide initial evidence of benefit for glycoprotein IIb/IIIa receptor blockade during PTCA for acute myocardial infarction.

Abciximab↗
PubMed1996

Does an inability to eradicate normal stem cells preclude the cure of some cancers?

Presently, identified signal transduction pathways do not alter normal stem-cell survival. With prostate cancer as a model, the argument is advanced that an inability to eradicate normal androgen-dependent prostate stem-cells precludes successful treatment of transformed, androgen-independent and metastatic progeny. While applying this idea to cancers of non-essential organs or to endocrine cancers seems feasible, the inutility of this approach for most other malignancies appears likely, although not certain.

Animals↗
PubMed1996

Increased risk of non-Q wave myocardial infarction after directional atherectomy is platelet dependent: evidence from the EPIC trial. Evaluation of c7E3 for the Prevention of Ischemic Complications.

OBJECTIVES: We sought to determine the effects of platelet glycoprotein IIb/IIIa receptor blockade on adverse outcomes, especially non-Q wave myocardial infarction, in patients undergoing directional atherectomy in the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial. BACKGROUND: Randomized trials comparing directional atherectomy with percutaneous transluminal coronary angioplasty (PTCA) have demonstrated modest benefits favoring atherectomy but at a cost of increased acute ischemic complications, notably non-Q wave myocardial infarction. The mechanism for this excess risk is unknown. METHODS: Of 2,038 high risk patients undergoing coronary intervention in the EPIC trial, directional atherectomy was performed in 197 (10%). Patients randomly received the chimeric glycoprotein IIb/IIIa antibody 7E3 (c7E3), as a bolus or a bolus and 12-h infusion or placebo. Study end points included death, myocardial infarction, repeat intervention or bypass surgery. RESULTS: Patients undergoing directional atherectomy had a lower baseline risk for acute complications but had a higher incidence of any myocardial infarction (10.7% vs. 6.3%, p = 0.021) and non-Q wave myocardial infarction (9.6% vs. 4.9%, p = 0.006). Bolus and infusion of c7E3 reduced non-Q wave myocardial infarctions by 71% after atherectomy (15.4% for placebo vs. 4.5% for bolus and infusion, p = 0.046). Non-Q wave myocardial infarction rates after PTCA were not affected by c7E3, although Q wave myocardial infarctions were reduced from 2.6% to 0.8% (p = 0.017). CONCLUSIONS: The EPIC trial confirmed the increased risk of non-Q wave myocardial infarction with directional atherectomy use compared with PTCA. A bolus and 12-h infusion of the glycoprotein IIb/IIIa receptor inhibitor c7E3 abolished this excess risk. Directional atherectomy-related non-Q wave myocardial infarction appears to be platelet aggregation dependent.

Abciximab↗
PubMed1996

The anti-GPIIb-IIIa agents: fundamental and clinical aspects.

The platelet GPIIb/IIIa receptor mediates platelet aggregation induced by all physiologic agonists. Blockade of the receptor, either by monoclonal antibodies or small molecules patterned after the arginine glycine-aspartic acid (RGD) cell recognition domain, prevents arterial thrombosis in animal models much better than does aspirin. c7E3 Fab, the Fab fragment of the mouse/human chimeric antibody 7E3 (abciximab: ReoPro), was shown to reduce ischemic events after angioplasty when given in conjunction with heparin and aspirin to patients at high risk in the EPIC study, but its was associated with an increase in bleeding. Preliminary data from the subsequent EPILOG study, in which a lower dose of heparin was used, demonstrated efficacy in low risk as well as high risk patients and no significant increase in major bleeding. Preliminary data from the CAPTURE study support the use of c7E3 Fab in patients with unstable angina who are candidates for PTCA within 24 hours. Positive trends toward decreased thrombotic events have also been observed in patients treated with small molecule inhibitors of GPIIb/IIIa receptors. This new class of agents thus holds promise for improving the therapy of angioplasty as well as perhaps other thrombotic phenomena.

Abciximab↗
PubMed1995

Impact of echocardiographic left ventricular mass on mechanistic implications of exercise testing parameters.

Electrocardiographic left ventricular (LV) hypertrophy has long been known to be associated with an abnormal ST-segment response to exercise; this association has been considered to represent a false-positive finding. There is a paucity of data relating echocardiographic LV mass to exercise ST-segment responses and other exercise parameters. As part of a routine evaluation, 1,408 men and 1,618 women from the Framingham Heart Study who were free of clinical cardiac disease underwent echocardiography and exercise treadmill testing according to the Bruce protocol at the same clinic visit. Abnormal ST-segment responses were defined both by standard criteria and the delta ST/heart rate index. LV mass was calculated from M-mode echocardiography. Echocardiographic LV hypertrophy was associated with an abnormal delta ST/heart rate index (in men, odds ratio [OR] 1.78, 95% confidence interval [CI] 1.05 to 3.01, p = 0.03; in women, OR 2.13, 95% CI 1.31 to 3.44, p = 0.002) but not with an abnormal response according to standard criteria. Echocardiographic LV hypertrophy was also associated with a lower likelihood of achieving an age-predicted target heart rate (in men, OR 0.45, 95% CI 0.31 to 0.65, p < 0.001; in women, OR 0.53, 95% CI 0.37 to 0.76, p < 0.001) and with a lower exercise capacity. Despite these associations, echocardiographic LV hypertrophy was associated with a higher peak heart rate-systolic blood pressure double product. In conclusion, echocardiographic LV hypertrophy is associated with an abnormal ST-segment response, a lower likelihood of achieving target heart rate, decreased exercise capacity, and an increased double product, which is a reflection of myocardial oxygen demand.

Adult↗
PubMed1995

Reversal of multidrug resistance phenotype by surfactants: relationship to membrane lipid fluidity.

Previous studies have suggested that multidrug resistance (MDR) reversal by polyoxyethylene surfactants involves alterations in plasma membrane lipid physical state of resistant cells as one of the possible mechanism(s). To date, however, a detailed and critical examination of the relationship between membrane lipid fluidity and MDR reversal by these surfactants has not been performed. In the present studies, therefore, a series of experiments were conducted to critically examine the role of membrane lipid physical state in MDR reversal by employing a unique class of clinically important nontoxic lipophilic surfactants and the KB-8-5-11 drug-resistant cell line. MDR reversal was assessed by rhodamine-123 uptake. The effect of surfactants on plasma membrane lipid fluidity of these cells was assessed utilizing a fluorescence polarization technique with fluorophores DPH, TMA. DPH, 2-AS, and 12-AS. Our studies demonstrated that: (i) in vitro addition of active MDR-reversing surfactants (Solutol HS-15, Tween 40, and Cremophor EL, 10 micrograms/ml each) decreased lipid fluidity of isolated crude plasma membranes of resistant cells; (ii) the inactive surfactants (octylglucoside, hecameg) failed to influence membrane lipid fluidity; (iii) cells grown in the presence of active surfactants also exhibited a decreased plasma membrane lipid fluidity as measured with intact cells utilizing the probe TMA.DPH; and (iv) active surfactants did not influence lifetimes of the excited state of the fluorophores. These findings demonstrate that decrease of the plasma membrane lipid fluidity of KB 8-5-11 resistant cells may be one of the important mechanism(s) of MDR reversal by polyoxyethylene surfactants.

Cell Line↗
PubMed1995

Selective inhibitors of 5-lipoxygenase reduce CML blast cell proliferation and induce limited differentiation and apoptosis.

Inhibitors of the arachidonic acid metabolizing enzyme, 5-lipoxygenase, reduce the rate of proliferation of chronic myelogenous leukemia blast cells. The inhibitory agents studied were ETYA, A63162 and SC41661A. These reagents induced differentiation of cultured chronic myelogenous leukemia cells from blast to promyelocytic morphology. Promyelocytic cells then underwent apoptosis, which was identified by nuclear and cytoplasmic morphological features and by DNA laddering. Proliferation of monoblastoid U937 and myelomonocytic HL60 cell lines, known to contain 5-lipoxygenase and synthesize leukotrienes, was reduced by these inhibitors. U937 cells cultured with ETYA, A63162 or SC41661A for 48 h exhibited apoptosis as assessed by DNA laddering and morphology. Characteristic ultrastructural changes of apoptosis were seen at 120 h. MK886, an inhibitor of 5-lipoxygenase with a mechanism of action distinct from oxidation/reduction reagents, at 20-40 microM also inhibited CML and U937 cell proliferation and induced apoptosis, as shown by DNA laddering and ultrastructure.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1995

Water-clear cell adenoma of the parathyroid. A case report with immunohistochemistry and electron microscopy.

We report a water-clear cell adenoma of the parathyroid gland, a lesion which to our knowledge has not been described previously. Like its rare but well-described hyperplastic counterpart, water-clear cell hyperplasia, this adenoma is composed of cells with abundant foamy-to-granular cytoplasm and mild nuclear pleomorphism. The cells form glandular structures and cell nests separated by fine fibrovascular septae. The tumor cells stain positively with anti-parathyroid hormone and show characteristic glassy and flocculate material by electron microscopy. Unlike water-clear cell hyperplasia, water-clear cell adenoma is a solitary lesion that compresses the residual nonneoplastic parathyroid gland.

Adenoma↗
PubMed1994

A new method for indexing left ventricular mass for differences in body size.

Left ventricular (LV) mass is determined to a large extent by body size. This has created controversy regarding the optimal method of defining normal values in the clinical setting. Previous groups have advocated indexing LV mass for body surface area, lean body mass, or height, which is an obesity-independent measure of body size. This study describes a new approach that involves dividing LV mass by height raised to a noninteger power. In a sample of 387 men and 714 women who were between 20 and 45 years of age and who were free of cardiovascular disease, the height exponent was determined by logarithmic regression models to be 2.12 in men and 1.91 in women; in a pooled analysis, the height exponent was 1.97. This approach reduced male versus female differences in the mean and 95th percentile values for LV mass; mean value differences who reduced from 52% among raw values to 29% among adjusted values. Compared with height or body surface area indexation, it was found to slightly increase the correlation between LV mass and systolic blood pressure. In contrast, body surface area indexation reduced the association between LV mass and obesity. The current method of indexation is independent of obesity, reduces LV mass variability associated with body size and gender, and may therefore be a useful method for defining normal and abnormal values of LV mass in the clinical setting. The findings of this study also suggest that indexation of LV mass for body surface area is inappropriate.

Adult↗
PubMed1994

Potential applications of apoptosis in modifying the biological behavior of therapeutically refractory cancers.

Recent information about apoptosis or programmed cell death, the anti-apoptotic gene, BCL2, its interaction with reactive oxygen species and the role of these agents in senescence and apoptosis, suggests a discussion of their relationships could be of interest. Such information may eventually provide alternative approaches to modifying the biological behavior of therapeutically resistant cancers. Some of these comments probably are self-evident, others may be less so and provide ideas for further studies.

Apoptosis↗
PubMed1994

New models for predicting cardiovascular events.

Data from the Framingham Heart Study are used to derive equations for long-term predicted probabilities for death and a variety of cardiovascular endpoints. An accelerated failure method is employed, first the standard Weibull model and then a useful extension. The extension relaxes the assumption of proportional hazards implied by the standard Weibull model. Models differ markedly in form for the various endpoints, but in every case the varying scale model provided a significantly better fit. The resulting differences in predicted probability may be important in planning community health projects or clinical trials and in carrying out cost-benefit analyses.

Cardiovascular Diseases↗
PubMed1994

Spontaneous chemiluminescence of ETYA (5,8,11,14-eicosatetraynoic acid) is inhibited by catalase or peroxidase.

5,8,11,14-eicosatetraynoic acid (ETYA), an isomorphic competitive analogue of arachidonic acid, spontaneously generates a chemiluminescence signal detected with a liquid scintillation spectrometer operated at ambient temperature in the out-of-coincidence mode. The intensity of the signal was 10- or more-fold above background, required oxygen for its generation, was inhibited by antioxidants, and approximately doubled in D2O. Arachidonic acid, which contains 4-alkene rather than alkyne bonds did no more than double the chemiluminescent signal above background. When examined at 37 degrees C in a Berthold AutoLumat 958 luminometer, DBA (lucigenin) was required to detect a signal above background. Catalase or peroxidase, and to a lesser extent mannitol or histidine but not superoxide dismutase, strongly diminished the signal intensity. These observations provide a baseline for interpreting the functional and electron microscopic changes produced by ETYA in PC3 prostate and A172 glioblastoma cell lines, consistent with a contribution from oxidative stress associated with free radicals, and the absence of these morphological changes in U937 monoblastoid cells.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1994

Determinants of change in total cholesterol and HDL-C with age: the Framingham Study.

OBJECTIVE: The purpose of the study was to assess the determinants of change of total cholesterol and high density lipoprotein cholesterol (HDL-C) change in an adult population. METHODS: The prospective cohort was examined at baseline and eight years later. A total of 2,222 men and 2,677 women age 20-79 years at baseline were included. Analyses were performed in 15-year age groups, and persons with cardiovascular disease or cancer during the observation period were excluded. RESULTS: In longitudinal analyses, body mass index (BMI) and plasma total cholesterol levels of each rose in concert among younger age groups, whereas levels declined in older individuals. Mean levels of BMI and total cholesterol peaked at a later age in women than in men. The corresponding changes in HDL-C were negative at all ages, and greater declines were seen in the elderly. A decrease in plasma total cholesterol was highly associated with greater age and a decrease in body mass index over the study interval, whereas the decline in HDL-C was proportional to change in body mass index. These changes remained significant after adjustment for baseline age and change in alcohol intake, cigarette consumption, diuretic use, and oral estrogen use. CONCLUSIONS: The rise in plasma total cholesterol among apparently healthy young men and women and its fall in the elderly are significantly associated with similar trends for obesity. The key determinants of a decline in HDL-C are an increase in obesity and advancing age itself. A decline in total cholesterol and in HDL-C is particularly common among the elderly, and it can be expected to occur without specific dietary or pharmacologic intervention.

Adult↗
PubMed1994

Morphologic changes of apoptosis induced in human chronic myelogenous leukemia "blast" cells by SC41661A (Searle), a selective inhibitor of 5-lipoxygenase.

Several inhibitors of the arachidonic acid-metabolizing enzyme, 5-lipoxygenase reduce proliferation of hematopoietic and non-hematopoietic cells and cell lines and some cells undergo limited differentiation. Cells were cultured from patients with chronic myelogenous leukemia in "blast" crisis with the selective inhibitor of 5-lipoxygenase, SC41661A[3-(3,5-bis(1,1-dimethyl)-4-hydroxyphenyl)hiol]-N-me thyl-N-[2-(2- phridinyl-propanamide)]. Cells cultured for 3 to 5 days with 40 microM SC41661A exhibited reduced cellular numbers along with ultrastructural changes and DNA laddering characteristic of apoptosis. Similar culture conditions reduced proliferation of U937 monoblastoid cells. In U937 cells, the ultrastructural features of apoptosis were not observed at 72 hours, when DNA laddering was present and cell numbers were reduced, but was present after 144 hours of culture. Dissociation between certain morphologic and biochemical sequelae of apoptosis has been described in other systems. These observations are of interest since the induction of apoptosis in dividing chronic myelogenous leukemia (CML) cells by a non-cytotoxic agent suggests paradigmatically new sites for therapeutic intervention.

Amides↗
PubMed1994

Reduced drug resistance in a multidrug resistant cell line by 5,8,11,14-eicosatetraynoic acid.

We examined whether the arachidonic acid competitive antagonist, ETYA (5,8,11,14-eicosatetraynoic acid), modulated drug sensitivity in a cell line that over-expresses the multiple drug resistance protein, MDR1. ETYA was nontoxic to drug-sensitive parental KB3-1 cells or drug-resistant MDR KB8-5-11 cells, with an IC50 of 190 microM for both lines. ETYA (20 microM) increased rhodamine 123 accumulation in KB8-5-11 MDR cells but not in KB3-1 sensitive cells. Arachidonic acid at 20 microM did not alter rhodamine accumulation in either cell line. Increasing the concentration of ETYA from 40 to 160 microM or incubation beyond 30 min did not increase KB8-5-11 dye retention. Forty microM or more ETYA increased KB3-11 dye retention. In a 6 day proliferation assay of KB8-5-11 cells, a nontoxic (40 microM) concentration of ETYA reduced the IC50 for doxorubicin 4-fold, the IC50 for colchicine 2-fold, but had no effect on the IC50 for vinblastine. ETYA at 40 microM did not alter the IC50 for any drug tested with KB3-1 cells. Therefore: (a) ETYA (20 or 40 microM) modulated resistance of KB8-5-11 cells to several drugs to a limited extent, without potentiating toxicity in the parental line, while arachidonic acid did not. (b) Since cationic rhodamine 123 is concentrated in mitochondria, the extent is dependent upon the transmembrane potential, and increased dye retention due to ETYA may in part be related to altered ETYA-induced cell membrane potential.

5,8,11,14-Eicosatetraynoic Acid↗