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Biomedical subjects

J Cassidy

Publications and source records attributed to J Cassidy.

At least 199 records · Page 11Linked to original sources
PubMed1987

Phase I and pharmacokinetic study of flavone acetic acid.

Flavone acetic acid is the second in a series of compounds based on the flavonoid aglycone ring structure to be clinically evaluated in malignant disease. Preclinical studies have indicated that a minimum plasma level of 150 micrograms/ml is required before therapeutic efficacy (in a wide range of experimental tumors) is seen in mice; both in vitro and in vivo studies also suggest that the duration of drug exposure is crucial in determining activity. Thus a Phase I trial has been performed in a total of 54 patients using 3 schedules, i.e., a 1-, 3-, and 6-h infusion. In each case, treatment was given once weekly for a minimum of 3 weeks. The maximum tolerated doses were 6.4, 6.4, and 10.0 g/m2, respectively. Dose limiting toxicity was denoted by an intense feeling of warmth and flushing with a 1-h infusion, hypotension with a 3-h infusion, and hypotension and diarrhea with a 6-h infusion. No objective responses were seen in this Phase I trial. The recommended doses for Phase II trials of flavone acetic acid in Europe are 4.8 g/m2 over 1 h or 8.6 g/m2 over 6 h. At these doses the peak plasma concentrations obtained are 650 and 388 micrograms/ml, respectively. Total drug exposure (assessed by an area under the curve greater than 100 micrograms/ml) was approximately 50% greater for the 6-h schedule. This Phase I trial indicates that peak plasma concentrations associated with experimental activity are achievable in humans, although optimal drug exposure times have not yet been defined.

Adult↗
PubMed1986

Phase I and pharmacokinetic study of LM985 (flavone acetic acid ester).

We have conducted a Phase I and initial clinical pharmacological evaluation of LM985, the first of a series of compounds based on the flavone ring structure to be considered for clinical trial in malignant disease. The drug was administered i.v. to 26 patients with advanced cancer on an every-21-day schedule. Patients were treated at 14 dosage levels ranging from 10 to 1500 mg/m2. Dose limiting toxicity was identified as acute reversible hypotension occurring during drug infusion; no leukopenia, alopecia, hepatic toxicity, or renal toxicity was observed, but at the higher dose range, mild sedation was apparent. Twenty patients had measurable disease and were evaluable for response. One patient with colorectal carcinoma had stable disease after three courses of LM985; however, no other responses were seen. Pharmacokinetic and in vitro drug degradation studies imply that the ester LM985 is hydrolyzed to LM975 (flavone acetic acid) rapidly in vivo. LM975 is active in a variety of animal tumor models, but it does not have the cardiovascular side effects seen with LM985 (hypotension and bradycardia) in pithed or anesthetized rats. We would recommend that LM975 be considered for clinical trial, because it seems likely that substantially higher doses of LM975 than of LM985 can be given without dose limiting cardiovascular toxicity.

Adult↗
PubMed1985

Increasing the response rate to cytotoxic chemotherapy by endocrine means.

Cloned cell lines of human breast cancer can be growth inhibited by tamoxifen and this inhibition can be reversed by estrogen. We wondered whether tamoxifen inhibition of breast cancer followed by estradiol reversal would increase the efficacy of chemotherapy by increasing the fraction of rapidly cycling cells. We describe a clinical trial in which 110 patients were prospectively randomized to chemotherapy consisting of cytoxan 750 mg/m2 and adriamycin 30 mg/m2 on Day 1 plus 5-FU 500 mg/m2 and methotrexate 40 mg/m2 on Day 8 vs the same chemotherapy plus tamoxifen 20 mg/m2 Days 2-6 and premarin 0.625 mg Q 12-H X 3 on Day 7. Chemotherapy was given in 21-day cycles. 108 patients were evaluable. No difference exist for any important prognostic variables. The first 55 patients were randomized to a regimen in which 5-FU preceded methotrexate by 24 h; thereafter, all patients received methotrexate followed in 1 h by 5-FU. No difference in any response parameter was seen between these two 5-FU methotrexate schedules. No differences in percent of protocol chemotherapy administered or observed toxicity was seen between the 2 regimens. Objective response rate was nearly identical--57% without and 64% with additional hormones. Prior adjuvant chemotherapy with L-PAM had no observable effect on response rate, response duration or survival. In a limited number of patients with inflammatory breast cancer we saw a significantly higher response rate (93 vs 61%; P = 0.03) than in patients with recurrent metastatic disease. Time to progression (13 vs 17 months) and survival (17 vs 23 months) of responders significantly favored the treatment arm including tamoxifen and premarin. Greater benefits of additional tamoxifen and premarin were seen in partial vs complete responders. This may have resulted from lower doses of chemotherapy given to patients achieving a complete remission. An additive effect of hormones plus chemotherapy cannot be entirely excluded as the explanation for the improved results seen with the addition of tamoxifen for 4 days plus 1 day of premarin. We believe that our results suggest that further efforts to increase the efficacy of chemotherapy by perturbing tumor growth rates may be worthwhile.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Dynamic variability of binding of antiarrhythmic drugs during the evolution of acute myocardial infarction.

We tested the hypothesis that the changes in free fatty acid and alpha 1-glycoprotein concentrations, which occur during acute myocardial infarction, exert asynchronous and opposing influences on the serum protein binding of selected drugs. Free drug fractions of two antiarrhythmic agents with contrasting binding characteristics, quinidine and procainamide, were related to free fatty acid and alpha 1-glycoprotein concentrations on days 1 through 5 and 10 in 20 patients with acute myocardial infarction. The mean free quinidine fraction was elevated on day 1 (9.0 +/- 4.4% vs 6.7 +/- 2.7% in patients with stable heart disease; p less than .05) and fell progressively to day 10 (4.0 +/- 2.8%; p less than .0002) as free fatty acid concentration decreased (day 1 = 464 +/- 272 meq/liter; day 10 = 264 +/- 155 meq/liter; p less than .01) and alpha 1-glycoprotein concentration increased (day 1 = 98 +/- 31 mg/dl; day 10 = 141 +/- 47 mg/dl; p less than .02). Multiple stepwise regression showed a major influence of changing alpha 1-glycoprotein concentration on the observed sequential changes in the free quinidine fraction (p less than .005). In contrast, no serial changes in procainamide binding were noted. In conclusion, metabolic changes during the course of acute myocardial infarction sequentially alter free quinidine fraction and, consequently, may influence pharmacodynamics.

Aged↗
PubMed1984

A randomized attempt to increase the efficacy of cytotoxic chemotherapy in metastatic breast cancer by hormonal synchronization.

Human breast cancer cells in tissue culture can be growth inhibited by tamoxifen, an inhibition that can be reversed by estrogen. The question of whether tamoxifen inhibition of breast cancer followed by estradiol reversal would increase the efficacy of chemotherapy was asked. One hundred ten patients were prospectively randomized to chemotherapy consisting of cytoxan (750 mg/m2) and Adriamycin (30 mg/m2) on day 1 plus 5-fluorouracil (5-FU) (500 mg/m2) and methotrexate (MTX, 40 mg/m2) on day 8 versus the same chemotherapy plus tamoxifen (20 mg/m2) on days 2-6 and premarin (0.625 mg every 12 hours for three days) on day 7. Chemotherapy was given in 21-day cycles. The first 55 patients were randomized to a regimen in which 5-FU preceded MTX by 24 hours; thereafter, all patients received MTX followed in one hour by 5-FU. No difference in any response parameter was seen between these two 5-FU/MTX schedules. A limited number of patients with inflammatory breast cancer had a significantly higher response rate (93% versus 61%; p = 0.03) than patients with recurrent metastatic disease. Time to progression (13 versus 17 months) and survival (17 versus 23 months) of responders significantly favored the treatment arm including tamoxifen and premarin. Whereas an additive effect of hormones plus chemotherapy cannot be entirely excluded as the explanation for the improved results with the addition of tamoxifen for four days plus one day of premarin, results suggest that further efforts to increase the efficacy of chemotherapy by perturbing tumor growth rates may be worthwhile.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1982

Phase II trial of 13-cis-retinoic acid in metastatic breast cancer.

Studies have suggested that both natural and synthetic retinoids have extensive chemopreventive activity against a variety of carcinogens in vivo and in vitro. We have previously shown that growth of human breast cancer cells can be inhibited by retinoids, and retinoic acid-binding proteins have been demonstrated in these cell lines and tumor biopsies. We studied the activity of 13-cis-retinoic acid in the treatment of 18 patients with advanced breast cancer refractory to standard cytotoxic and/or endocrine therapy. Patients began on 0.5 mg/kg and escalated to 8 mg/kg over a one-month period unless toxicity (dry skin, dry mucosa, cheilitis, conjunctivitis) forced dose reduction. All these toxicities responded promptly to dose reduction. Four patients exhibited drug related hypercalcemia, 2 complained of severe earache and several had nausea, vomiting and abdominal cramping. There were no objective responses as defined by standard criteria. One patient with thrombocytopenia secondary to documented marrow involvement demonstrated a recovery of platelet count from 9000 to 110,000. 13-cis-Retinoic acid is not of apparent value in women with heavily pretreated breast cancer.

Breast Neoplasms↗
PubMed1977

Correlation of mean pulmonary artery wedge pressure, left atrial dimention, and PTF-V1 in patients with acute myocardial infarction.

The mean pulmonary artery wedge pressure (PAWP), left atrial dimension (LAD) by echocardiography, and PTF-V1 in the electrocardiogram were correlated with each other in 16 patients with acute myocardial infarction in the control period and after therapeutic intervention with either Dextran or furosemide and/or nitroprusside. No significant correlation was found between a normal control PAWP and the LAD. An increased control PAWP correlated well with an increased LAD (r = 0.98). No significant correlation was found between the LAD and the PAWP whether normal or elevated after therapeutic intervention. No significant correlation was found between the PAWP whether normal or elevated and the PTF-V1. No significant correlation was found between the LAD and the PTF-V1. We conclude in acute myocardial infarction 1) the PTF-V1 is not useful in assessing PAWP before or after therapeutic intervention, 2) the LAD correlates poorly with a normal control PAWP but correlates well with an elevated control PAWP, and 3) the LAD cannot be used to assess PAWP after therapeutic intervention.

Acute Disease↗
PubMed1977

High reversion of atrial flutter to sinus rhythm after atrial pacing in patients with pulmonary disease.

The effect of atrial pacing on atrial flutter was evaluated in 36 consecutive episodes in 33 patients. Seventeen episodes occurred in a pulmonary setting, 14 of these in patients with chronic pulmonary disease. Twenty-four (67 percent) of the 36 episodes converted to sinus rhythm within one minute after atrial pacing. In nine (25 percent) of the 36 episodes, atrial fibrillation developed after atrial pacing. Atrial flutter was not affected by atrial pacing in three (8 percent) of the 36 episodes.n 12 (86 percent) of the 14 patients with chronic pulmonary disease and in 14 (82 percent) of the 17 patients in whom a pulmonary setting was responsible for atrial flutter, atrial pacing caused conversion to sinus rhythm. Atrial pacing may be the treatment of choice for atrial flutter in patients with pulmonary disease because of its excellent rate of success in this subgroup whose risk of cardioversion is increased by poor anesthetic tolerance and hypoxia.

Aged↗