Phase II study of iproplatin in metastatic breast carcinoma

Thirty patients with progressive metastatic breast cancer and one prior chemotherapy regimen were treated with iproplatin at a starting dose of 300 mg/m2 iv every 3 weeks. After the first 11 patients, the starting dose was decreased to 270 mg/m2. There were one complete remission, three partial remissions, and two minor responses. Responses were observed in soft tissue and osseous and visceral areas. Grade 3 nausea and vomiting were observed in 38% of patients, and grade 3 diarrhea occurred in 31%. The dose-limiting toxicity was thrombocytopenia, which required dose de-escalation in 15 patients. No nephrotoxicity, neurotoxicity, or ototoxicity was observed. Iproplatin has modest antitumor activity in this group of previously treated patients with metastatic breast cancer.     

Stroke in coronary artery bypass graft surgery: an analysis of the CASS experience. The participants in the Coronary Artery Surgery Study.

An analysis of the Coronary Artery Surgery Registry (CASS) was performed to determine the occurrence of stroke after coronary artery bypass surgery in patients entered into the Coronary Artery Surgery Study Registry. Of the 10,098 patients having coronary artery bypass surgery at the Coronary Artery Surgery Study participating sites during the period July 1974 through May 1979, a total of 348 patients (or 3.4%) sustained a stroke during the first year after coronary bypass surgery. Fifty-nine strokes occurred on the day of surgery, and an additional 129 strokes occurred during hospitalization for coronary bypass surgery. Thus, 188 patients (1.9%) of the entire surgical group sustained a stroke during initial hospitalization for coronary artery bypass surgery. Logistic regression analysis was used to predict stroke on the day of surgery, during the hospitalization for surgery, and during the first year after surgery. The most powerful predictors of stroke on the day of coronary artery bypass surgery were: 1) older age (n = less than 0.0001); 2) use of alpha-adrenergic drugs after bypass (n = 0.0001); and 3) longer duration of cardiopulmonary bypass (n = 0.002). For those strokes occurring at least 1 day after coronary artery bypass but during the initial hospitalization, age and duration of cardiopulmonary bypass were the most powerful predictors of stroke. An analysis of predictors of stroke within 1 yr after hospital dismissal for initial coronary bypass surgery revealed that the most powerful predictor was a history of previous cerebrovascular disease (n less than 0.0001) and a history of hypertension (n less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of cigarette smoking on survival of patients with angiographically documented coronary artery disease. Report from the CASS registry

Through a multicenter registry of patients in the Coronary Artery Surgery Study, we prospectively evaluated morbidity and mortality in 4,165 smokers with angiographically proved coronary artery disease, 2,675 of whom continued to smoke and 1,490 of whom quit. At five years, mortality (adjusted by Cox analysis for baseline differences) was 22% for those who continued smoking and 15% for quitters. The relative risk (also from the Cox analysis) for mortality in continuers vs quitters was 1.55 (95% confidence interval, 1.29 to 1.85). The adverse effect of smoking mainly took the form of higher frequencies of myocardial infarction--associated death and sudden death: the frequencies of these events during follow-up in continuers vs quitters were 7.9% vs 4.4% for myocardial infarction--associated death and 2.8% vs 1.5% for sudden death. This study supports the recommendation that patients with coronary artery disease should stop smoking.     

Evidence for a non-genomic action of progestins on sexual receptivity in hamster ventral tegmental area but not hypothalamus.

Progestogenic stimulation of both the ventromedial nucleus of the hypothalamus (VMH) and the ventral tegmental area (VTA) is critical for normal receptivity in estrogen-primed hamsters. However, anatomical and biochemical studies have identified very few estrogen-induced progestin receptors in the rodent ventral midbrain. To determine whether progesterone might be working on the membrane of neurons in the VTA, progesterone 3-CMO BSA (P-3-BSA) was applied intracranially. The size of P-3-BSA makes it relatively impermeable to the cell membrane. Ovariectomized hamsters were implanted with 2 chronic cannulae, one aimed at the VMH and the other at the contralateral VTA. These animals were then estrogen-primed and tested for sexual receptivity after progesterone-containing tubes were inserted just dorsal to the VMH and P-3-BSA inserts were applied above the VTA. The following week, the hamsters were tested again with the contents of the inserts reversed. Animals with progestogenic stimulation to the VMH and P-3-BSA to the VTA were receptive yet those with P-3-BSA to the hypothalamus and progesterone to the VTA were not receptive. These data suggest that progesterone is capable of facilitating sexual receptivity within the VTA by actions on the cell membrane. The non-genomic effects in the VTA require concurrent genomic activation by progesterone within the hypothalamus.     

Muscimol facilitates sexual receptivity in hamsters when infused into the ventral tegmentum.

Progestogenic stimulation of both the ventral medial nucleus of the hypothalamus (VMH) and the ventral tegmental area (VTA) within the midbrain is critical for normal receptivity in female hamsters. However, few estrogen-induced progestin receptors have been found in the midbrain. In addition, recent evidence suggests that progestin's action in the VTA is mediated nongenomically at the membrane. The present experiment investigated the possible role of GABAA receptors in mediating the effects of progesterone in this brain region. Ovariectomized female hamsters were bilaterally implanted with chronic cannulae aimed toward the ventral mesencephalon. Five days after surgery, animals were injected with 10 micrograms estradiol benzoate SC. Forty hours later, the same animals were injected with either 25 or 100 micrograms progesterone and at hour 43.5, 50 ng muscimol was infused in 0.5 microliters. Control animals received 0.5 microliters vehicle, sterile saline, or no infusion. At hour 44, animals were tested for sexual receptivity by placing them in an observation arena with a sexually experienced male for 10 min, during which lordosis duration was recorded. The following week, the same regimen was given with the alternate dose of progesterone. Histology revealed that only those animals that were infused with muscimol into the VTA had total lordosis durations that were significantly longer than the controls. Implants that missed the ventral tegmental area were much less effective. These results indicate that GABA might play a facilitatory role in enhancing the efficacy of threshold doses of progesterone. Whether this interaction is due to a direct effect of progestins on the GABAA receptor complex awaits further study.     

Effects of the positive inotropic agents milrinone and pimobendan on the development of lethal ischemic arrhythmias in conscious dogs with recent myocardial infarction

The effects of milrinone and pimobendan upon the initiation of programmed ventricular stimulation-induced ventricular tachycardia (VT) and the incidence of lethal ischemic ventricular arrhythmias were assessed in conscious dogs with recent anterior myocardial infarctions. Based upon the results of previous studies, the animals which were entered into this investigation were nonresponsive to baseline programmed stimulation and, therefore, considered to be at "low risk" toward the development of subsequent lethal ischemic arrhythmias. Milrinone (200 micrograms/kg/h continuous i.v. infusion) and pimobendan (300 micrograms/kg i.v.) were administered in dosing regimens shown to produce equivalent and sustained increases in left ventricular (LV) + dP/dt. At the time of repeat electrophysiologic testing, 9 of 9 pimobendan-, 9 of 10 milrinone-, and 12 of 12 concurrent vehicle-treated animals remained nonresponsive to programmed ventricular stimulation. Compared to a total control population of 39 "low risk" postinfarction dogs; however, both milrinone and pimobendan administration increased the incidence of sudden ventricular fibrillation occurring in response to the development of acute posterolateral ischemia (milrinone 4 of 10 [40%] and pimobendan 4 of 10 [40%] versus "low risk" control population 4 of 39 [10.3%]; p = 0.038). The incidence of ischemic mortality at 24 h after the development of posterolateral myocardial ischemia was increased in the milrinone-treated group (6 of 10 [60%]) compared to the "low risk" control population (6 of 39 [15.2%]; p = 0.007), whereas the incidence of 24-h ischemic mortality in the pimobendan-treated group (4 of 10 [40%]) was only of borderline statistical significance when compared to that of the "low risk" control population (p = 0.083). Milrinone, but not pimobendan, delayed the onset of acute posterolateral myocardial ischemia in the postinfarction dogs. The predominant electrophysiologic effects of both milrinone and pimobendan were decreases in ventricular refractoriness in both non-infarct (NZ) and in infarct zones (IZ), as well as reductions in electrocardiographic QTc or QT intervals. These findings suggest that with both positive inotropic agents, including milrinone which may possess protective antithrombotic action, sudden death may be increased via a reduction in ventricular refractoriness in the ischemically injured heart. The enhanced susceptibility toward the development of ischemic ventricular arrhythmias in the presence of the inotropic interventions is not predicted by programmed ventricular stimulation testing prior to the ischemic event.     

Phase I-II study: triciribine (tricyclic nucleoside phosphate) for metastatic breast cancer

Triciribine is a purine analogue which inhibits DNA and protein synthesis. We performed two studies to define its activity against metastatic breast cancer. The first study was a phase II study in 14 patients with metastatic breast cancer who had received two or fewer chemotherapy treatments. The treatment schedule was triciribine 20 mg/m² per day by 24-h infusion (CI) daily for 5 days every 6 weeks as recommended by a previous open phase I trial. When neither response nor toxicity was seen in the phase II trial, we assumed the starting dose was too low for this group of patients with good performance status and repeated the phase I trial in patients with metastatic breast cancer with good performance status. The starting dose was 35 mg/m² per day using the same 5-day CI schedule, and starting doses were increased in subsequent cohorts of three patients in increments of 5 mg/m² until toxicity occurred. In the initial (phase II) study, one patient had stable disease for 18 weeks (three courses), the remainder progressed. There were no significant toxic effects. In the subsequent phase I study, ten patients were treated until the study was closed The maximum dose was 40 mg/m². Two patients died, one each at the 35 and 40 mg/m² levels, respectively, 3 months and 6 weeks after their last course, one without interveing disease progression. Both had severe hypertriglyceridemia (18- and 21-fold elevation) and severe fatigue. At postmortem examination, one had congestive cardiomyopathy, and the other had severe pancreatitis and hypothyroidism. One patient had severe exacerbation of psoriasis which made her bedridden for more than 30 days. Four patients had hyperglycemia. Plasma pharmacology studies showed erratic drug levels, presumably related to enterohepatic circulation. Postmortem pharmacology studies showed residual drug present as long as 12 weeks after the last dose. We conclude that triciribine is ineffective at all doses tested and at doses of 35 mg/m² has unacceptable toxic effects.This work was performed under National Cancer Institute contract 1-CM-57739