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Biomedical subjects

E Coronado

Publications and source records attributed to E Coronado.

27 records · Page 2Linked to original sources
PubMed1989

Tumor and serum tamoxifen concentrations in the athymic nude mouse.

The athymic nude mouse has been used as an in vivo model for pharmacologic studies of the antiestrogen, tamoxifen. Serum and tumor tamoxifen and metabolite concentrations were examined during and after 100 and 1000 micrograms/day doses injected s.c. Tamoxifen and tamoxifen metabolites were quantitated by high-performance liquid chromatography. Tamoxifen was detected in tumors after a dose of 100 micrograms/day, although serum concentrations were not detected. At a dose of 1000 micrograms/day, tumor tamoxifen and its active metabolites were detected in high concentrations ranging up to greater than 6 mmol/g tissue. Serum tamoxifen metabolites were not detected at either dose. In summary, high doses of tamoxifen were required in the nude mouse to obtain clinically relevant serum concentrations, and significant tumor levels were achieved at doses that resulted in undetectable serum levels. The relationship between serum tamoxifen concentrations, tumor tamoxifen levels, and the biologic activity of the drug requires further study.

Animals↗
PubMed1989

Role of total parenteral nutrition in the treatment of Crohn's disease.

We studied 49 patients with severe nonresponsive Crohn's disease receiving 73 courses of total parenteral nutrition (TPN) for a total of 2,153 days (30 +/- 18 days/admission). Forty-five percent of all courses of TPN resulted in patients not being operated on, whereas 55 percent resulted in surgical intervention. Fifty percent of patients who did not undergo operation initially as a result of a successful course of bowel rest and TPN had surgery within 15.4 +/- 13.9 months, whereas 75 percent of patients operated on immediately after a course of TPN did not need additional surgery during a follow-up of 36.1 +/- 31.2 months. Thus, a total of 80 percent of patients underwent gastrointestinal surgery sometime during the study and follow-up periods. TPN has an important role in replenishment of nutritional deficits and perioperative nutritional support; however, from the results of the present study, it is difficult to advocate it as the sole primary therapy for Crohn's disease.

Adolescent↗
PubMed1989

Effect of hemorrhagic hypotension on endotoxin-induced lung injury in awake sheep.

Pulmonary insufficiency is a major cause for mortality and morbidity following shock and sepsis. We studied the effect of hemorrhagic shock and retransfusion on endotoxin-induced lung dysfunction. Eighteen unanesthetized sheep with chronic lung lymph fistulae were divided into 3 groups. In Group I (n = 5) hemorrhagic shock of 50 torr was induced by arterial bleeding. Shed blood was retransfused after 4 h, and the animals were observed for 5 h. In Group II (n = 7) 1 microgramg/kg E. coli endotoxin was injected intravenously, and the animals were observed for 5 h. In Group III (n = 6) hemorrhagic shock was induced similarly to Group I. After 2 h of hypotension, E. coli endotoxin was injected similarly to Group II. Blood was retransfused after 4 h. During hemorrhagic shock arterial oxygen tension (PaO2) increased from 78.0 to 94.0 torr (P less than 0.005), lymph flow (QL) decreased from 7.2 to 5.2 ml/h (P less than 0.05) and lymph protein clearance (L/P.QL) from 4.6 to 3.3 ml/h (P less than 0.05). Calculated pulmonary microvascular pressure (Pmv) decreased from 11.1 to 7.0 torr (P less than 0.05). Plasma TXB2 increased from 197 to 967 pg/ml (P less than 0.05) and lymph TXB2 from 272 to 833 pg/ml (P less than 0.05). Endotoxin infusion was followed by a fall in WBC to 2,900/microliters (P less than 0.001), rise in pulmonary artery pressure (Ppl) from 17.5 to 49.7 torr (P less than 0.005), and Pmv from 12.1 to 23.7 torr (P less than 0.01). PaO2 decreased from 78.0 to 61.0 torr (P less than 0.01), QL increased to 36.9 ml/h (P less than 0.001), and L/P.QL to 24.3 ml/h (P less than 0.001). Plasma TXB2 increased to 7,600 pg/ml (P less than 0.005) and 6-Keto PGF1 alpha to 1,519 pg/ml (P less than 0.01). Infusion of endotoxin during hemorrhagic shock was followed by a comparable fall in WBC, pulmonary hypertensive response and hypoxemia, while Pmv increased only to 19.2 torr which was significantly lower than Group II (P less than 0.05). The rise in QL to 17.4 and L/P.QL to 10.6 ml/h in response to endotoxin was also significantly lower than Group II (P less than 0.05 and P less than 0.05, respectively). Plasma and lymph TXB2 and 6-Keto PGF1 alpha were unchanged. It is concluded that hemorrhagic shock reduced endotoxin-induced pulmonary microvascular pressure, pulmonary lymph production and protein flux, while the fall in WBC, early pulmonary hypertensive phase, hypoxemia, and prostanoid production were not altered by the hypotensive insult.

Animals↗
PubMed1988

Blockade of the epidermal growth factor receptor inhibits transforming growth factor alpha-induced but not estrogen-induced growth of hormone-dependent human breast cancer.

Transforming growth factor alpha (TGF alpha), a polypeptide that binds to the epidermal growth factor (EGF) receptor, is expressed and secreted by human breast cancer cells and has been proposed as an autocrine growth factor and as a mediator of the mitogenic effect of estrogen. We investigated the potential importance of secreted TGF alpha in estrogen-responsive MCF-7 human breast cancer cells using monoclonal (528ab and 225ab) and polyclonal antibodies that block the EGF/TGF alpha receptor. Confirming other studies, these MCF-7 cells expressed TGF alpha with mRNA transcripts of 4.8 kilobases identified by Northern analysis, and they secreted TGF alpha activity measured by normal rat kidney colony-forming assay and an EGF RRA of conditioned medium. This activity was increased 3-fold by 1 nM 17 beta-estradiol and decreased by 1 microM tamoxifen. 528ab and 225ab bound to EGF receptors in MCF-7 cells with high affinity [dissociation constant (Kd) 0.1-0.5 nM] and blocked the binding of EGF/TGF alpha. These antibodies failed to inhibit baseline DNA synthesis or growth of MCF-7 cells although they were potent inhibitors of EGF/TGF alpha-induced growth of these cells. We hypothesized that if secreted TGF alpha mediates estrogen-induced growth, then EGF/TGF alpha receptor blockade should inhibit estrogen stimulation. MCF-7 cells were first treated with tamoxifen to inhibit growth and to reduce TGF alpha expression. Under these conditions, estrogen replenishment induced a marked dose-dependent rescue of TGF alpha secretion, DNA synthesis, and cell proliferation. Exogenous TGF alpha also partially restored growth of tamoxifen-inhibited cells. Although the simultaneous addition of 528ab or 225ab blocked TGF alpha-induced rescue of MCF-7 cells, it had no effect on rescue by estradiol.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1988

Cardiopulmonary response to intraperitoneal instillation of autologous unclotted blood in hemorrhagic shock.

Adult respiratory distress syndrome has been described in patients following multiple trauma and hemorrhagic shock. Pure hemorrhagic shock in sheep does not lead to pulmonary dysfunction. To settle this seeming discrepancy, we hypothesized that an additional factor such as intraperitoneal blood was necessary to produce pulmonary dysfunction. Twenty-two sheep prepared by hemodynamic and lung lymphatic cannulation were divided into three groups. In group I (n = 7) hemorrhagic shock of 50 torr for 2 hr was induced by arterial bleeding. In group II (n = 12) hemorrhagic shock was induced as in group I, and 200 ml of autologous unclotted blood was infused into the peritoneal cavity. In group III (n = 3) 200 ml of unclotted shed blood was infused intraperitoneally and 200 ml NaCl 0.9% infused intravenously. Intraperitoneal infusion of 200 ml of shed blood in normal animals did not alter pulmonary hemodynamics, pulmonary shunting, lymph flow, or lymph protein clearance. Hemorrhagic shock was followed by a fall in cardiac index (CI) to 104 ml/min.kg (P less than 0.005), CVP to 0.4 torr (P less than 0.01) and rise in pulse rate to 127 per min (P less than 0.01). Blood hemoglobin decreased to 7.6 g/dl (P less than 0.0001) and platelets to 309,000/microliter (P less than 0.05). Pulmonary microvascular pressure fell to 6.7 torr (P less than 0.01) and pulmonary wedge pressure to 1.2 torr (P less than 0.005). These parameters were not altered by instillation of unclotted blood into the peritoneal cavity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Serum tamoxifen concentrations in the athymic nude mouse after three methods of administration.

The athymic nude mouse has been used as an in vivo model for pharmacologic studies of the antiestrogen, tamoxifen. We have examined the steady-state serum tamoxifen concentrations achieved in mice with s.c. slow-release pellets, s.c. injections, and i.p. injections, in an attempt to identify a method that would yield serum levels similar to those observed in patients receiving tamoxifen therapy. Tamoxifen and tamoxifen metabolites were examined by a high-performance liquid chromatography assay which has a sensitivity of 8 ng/ml. Tamoxifen metabolites were not observed with any dose or schedule. After slow-release pellets containing 5 or 25 mg tamoxifen no tamoxifen was detectable, even after 2 weeks of treatment. Very low levels (0.07 microM) were found with 50-mg pellets. Tamoxifen was also not detected either with daily s.c. injections of 500 micrograms/mouse or with i.p. injections of 2.5 mg/kg. However, daily s.c. injections of 1000 micrograms or i.p. injections of 25, 50, or 100 mg/kg resulted in tamoxifen concentrations ranging from 0.21 to 0.51 microM which are similar to those observed in patients. Thus, clinically relevant tamoxifen concentrations can be achieved in the nude mouse with either of these methods of administration.

Animals↗