Gossypol has demonstrated in vitro effects on cell cycle regulation and anti-tumor activity against mammary carcinoma cell lines. This Phase I/II study assesses both the effect of gossypol on cell cycle regulatory proteins in vivo and the clinical effect. Twenty women with refractory metastatic breast cancer received oral gossypol at daily doses between 30 and 50 mg per day. Gossypol plasma levels were measured (n = 8) and the modulation of the retinoblastoma (Rb) gene protein and Cyclin D1 was assessed by serial biopsies (n = 4). Grade I-II toxicities with gossypol treatment included nausea in 30% of patients, fatigue 15%, emesis 15%, altered taste sensation 15% and diarrhea in 10% of patients. Two of the three patients receiving 50 mg/day experienced dose limiting dermatologic toxicity (grade III). One patient had a minor response and two patients had stable disease with > 50% decline in serial assessments of the serum tumor markers. Immunohistochemical analysis of cyclin D1 and Rb expression in serial biopsies of four patients revealed both a concurrent decrease in cyclin D1 expression and an increase in nuclear Rb expression in three patients. The maximal tolerated dose (MTD) of gossypol was 40 mg/day. Gossypol appears to affect the expression of Rb protein and cyclin D1 in breast cancer metastases at doses achievable, yet had negligible antitumor activity against anthracycline and taxane refractory metastatic breast cancer. The cell cycle regulatory effects of gossypol suggest a potential role for gossypol as a modulating agent in conjunction with other cell cycle specific compounds.
The analgesic meperidine has been reported to produce signs of central nervous system excitation in human beings. To determine the relationship between signs and symptoms of central nervous system excitation and plasma levels of meperidine and normeperidine, we studied 67 patients receiving meperidine for the relief of postoperative or chronic pain. In 48 patients, excitatory effects ranging from mild nervousness to tremors, twitches, multifocal myoclonus, and seizures were directly correlated with accumulation of normeperidine in plasma. Evidence of compromised renal function occurred in only 14 of the 48 symptomatic patients, suggesting that renal dysfunction may contribute to but is not the sole factor in the accumulation of normeperidine or its relation to adverse neurological signs. In a second study we surveyed mood alterations in 47 patients receiving meperidine and 29 receiving other narcotic analgesics for postoperative pain. The repeated administration of meperidine was associated with adverse alterations in various elements of mood (e.g., apprehension, sadness, restlessness).
To investigate the relation between acetvlator phenotype and the development of procainamide-induced lupus, we determined the rate of development of antinuclear antibodies in 20 patients of known acetylator phenotype receiving chronic procainamide therapy. The duration of therapy required to induce antibodies in 50 per cent of slow (11) and rapid (nine) acetylators was 2.9 and 7.3 months respectively. The median total dose that produced ant;bodies was 1.5 g per kilogram and 6.1 g per kilogram respectively. After one year antibodies had developed in 18 patients. Retrospective studies of patients in whom procainamide lupus had developed revealed that the duration of therapy required for induction in 14 slow and seven rapid acetylators was 12 +/- 5 and 48 +/- 22 months respectively (P less than 0.002). We conclude that acetylator phenotype influences the rate at which procainamide induces antinuclear antibodies and probably the lupus syndrome. Antibody production is probably related to the parent compound or a non-acetylated metabolite.
N-Acetylprocainamide (NAPA) and procainamide plasma and urine concentrations were determined by thin-layer chromatography (TLC) densitometry in people of known acetylator phenotype (dapsone phenotyping) taking procainamide for more than 3 days. The plasma NAPA/procainamide ratio 3 hr after the last dose for fast acetylators (mean plus or minus SD) is 1.8 plus or minus 0.59 (N equal to 8) and for slow acetylators, 0.61 plus or minus 0.09 (N equal to 6) P smaller than 0.001). The renal clearance of NAPA averaged 1.2 times the simultaneously measured endogenous creatinine clearance, whereas procainamide clearance was approximately double the creatinine clearance. There was no difference between slow and rapid acetylators in the renal clearance of either drug or the urine pH, indicating that the difference in plasma NAPA/procainamide ratios between these two groups is due to differences in their rates of acetylation. Therefore, procainamide is probably acetylated by the polymorphic N-acetyltransferase in man. Reflecting the blood level differences, the NAPA/procainamide ratio in urine (collected 99 to 180 min after last dose) was found to be higher in rapid than in slow acetylators. The plasma protein binding of NAa and of procainamide are similar. Since NAPA seems to have an antiarrhythmic potency similar to procainamide, NAPA probably contributes to the antiarrhythmic activity of procainamide therapy, especially in genetic rapid acetylators.
Pain is often inadequately treated. To evaluate a common method of assessing pain and to identify some barriers to improving pain control, 50 hospitalized patients in pain, their nurses, and their physicians were interviewed about the pain experienced by the patients. The patients' "pain behavior" was assessed and literature was reviewed to identify the risk for developing iatrogenic drug addiction in patients with no prior history of drug abuse. Doctors and nurses tended to assess pain intensity as less than the patients' assessments. The doctor's and nurse's assessment of the same patient correlated poorly ( r ϭ 0.21). Pain behavior correlated weakly ( r s ϭ 0.36) with patients' pain scores. Twenty-one patients wanted more pain medicine but often staff would not give more. A common reason was fear of addiction, notwithstanding a literature that iatrogenic addiction hardly ever occurs in usual hospitalized patients. Barriers to better pain control in acutely hospitalized patients include: (1) exaggerated fear of iatrogenic addiction, (2) an attitude among staff that patients exaggerate the intensity of their pain, (3) poor correlation between pain behavior and pain intensity that can mislead staff who rely on pain behavior to assess pain intensity, and (4) a lack of agreement between doctor and nurse in estimating the intensity of a patient's pain. A new way of thinking about patients in pain, assessing pain as either present or absent, is proposed for evaluation. If pain is present, one should attempt to ameliorate it in a manner consistent with the desire of the patient and the acceptability of adverse effects.
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