Pharmacology and toxicology of a seven-day infusion of 1-beta-D-arabinofuranosylcytosine plus uridine in dogs.

In vitro studies of certain lymphoid tumor cells show potentiation of 1-beta-D-arabinofuranosylcytosine (ara-C) effects by uridine because it elevates intracellular uridine triphosphate, resulting in increased ara-C triphosphate levels. Seven-day continuous i.v. infusions of uridine at 123 mg/kg/h (2.5 g/sq m/h) were studied in 5 male beagles. Steady state levels of uridine were reached within 4 to 6 h and ranged from 2 to 5 X 10(-4) M over the course of the infusion. Steady state uracil levels ranged from 4 to 10 X 10(-4) M. After the end of infusion, uridine and uracil levels fell with a half-life of approximately 15 and 18 min, respectively. Toxicity in 2 dogs treated at this dose was limited to minimal diarrhea and a transient rise of alkaline phosphatase to 2 to 3 times normal. No drug toxicity was evident at sacrifice on Days 7 or 72. Three dogs received a 7-day infusion of ara-C plus uridine followed approximately 4 weeks later by an infusion of ara-C alone (or the same drugs in the reverse sequence). Coinfusion of 2.5 or 5.0 mg/kg/day (50 or 100 mg/sq m/day) of ara-C had no significant effects on uridine plasma levels or postinfusion half-lives. Similarly, no consistent effect was seen of uridine on ara-C plasma levels. Uridine coinfusion with ara-C resulted in a definite potentiation of myelosuppression; at 5.0 mg/kg/day X 7 of ara-C white blood cell and platelet nadirs (X 10(3)/microliters) were 0.8 and 15 as compared to 3.6 and 66, respectively, with ara-C alone. One-third of the dogs developed reversibly elevated transaminases with the combination treatment. The results show that a minimally toxic dose of uridine enhances bone marrow and probably hepatic toxicity of coadministered ara-C.

Kaposi's sarcoma in a young homosexual man. Association with angiofollicular lymphoid hyperplasia and a malignant lymphoproliferative disorder.

Recent reports have described an unexpected number of cases of a virulent form of a Kaposi's sarcoma (KS) as well as acquired immunodeficiency in young homosexual men. A 31-year-old man initially had a benign disorder, angiofollicular lymphoid hyperplasia. Kaposi's sarcoma then developed, and he died of a malignant lymphoproliferative disorder. We believe that this is unique among the recently described cases of KS in homosexual men because of the occurrence of this second malignancy. It may be that similar cases will be recognized in this population.

Finding time, stopping the frenzy.

While the deleterious consequences of long hours of work for individuals, families and communities have previously been documented, the assumption that long hours are necessary to get the work done, especially in a world where speed is becoming increasingly critical to corporate success, has prompted little challenge. So Leslie Perlow, an assistant professor of business at the University of Michigan, Ann Arbor, set out to explore the necessity for the seemingly endless workdays that so many postindustrial settings require. Her study of a group of software engineers at a Fortune 500 company--identified only as the Ditto Corp--is detailed in her book, Finding Time: How Corporations, Individuals, and Families Can Benefit from New Work Practices (Cornell University Press, 1997). Perlow's research reveals a "sad and all too common tale" of workers harried by competing demands, frequent interruptions and shifting deadlines. To meet the firm's expectations, the engineers she studied sacrificed home life, focused on individual tasks to the detriment of group goals and, in many cases, eventually lost any enthusiasm they'd had for working for the company. There has been some recognition that stress and burnout may be bad for a corporation as employees become less committed, decide to leave or get fired and that this kind of turnover can hurt the firm in the longer term. But Perlow documented the additional, and quite significant, shorter-term costs to the corporation of the current way of using time at work. What she found was a "vicious time cycle:" Time pressures led to a crisis mentality, which led to "individual heroics." That is, I'll do whatever it takes to do my job--even if it means interrupting you while you try to do yours. For the engineers Perlow studied, the lack of helping, the constant interruptions and the perpetual crises--clearly illustrated by the daily log that appears on page 34--made it harder to develop products. Ultimately, they worked long hours to complete tasks they'd been too busy to do earlier because of the constant interruptions. Worse, because everyone was busy responding to crises, no one had time to prevent future crises, thus perpetuating the cycle. But as dire as the situation sometimes seemed, change was possible. The "quiet time" phase of the author's nine-month study indicated that productivity could be enhanced by structuring work time to allow the engineers intervals to work alone, uninterrupted. After this first phase, about two out of three of the 17 people involved said their productivity during quiet time was above average. Nearly as many said overall productivity was above average as well. This implies that the costs of the current way of using time exceed the benefits. The data further show that change must be collective, addressing all elements of the vicious cycle. The promising implication is that collective change could benefit everyone--corporations, individuals and families. The work process could be made more efficient and effective. At the same time, individuals could succeed at work and still have time for responsibilities outside of work; people might not have to choose so definitively between their work and their home lives. To make the necessary changes, however, will require a shift from a system that rewards individuals heroics and long hours to one that rewards individuals' contributions to their teams--without the accompanying emphasis on visible work hours. That is, there must be a shift in emphasis from individual to collective achievement. And there must be a sharing of the resulting gains in efficiency between employees and employers. In the following excerpt from her book, Perlow describes what is needed to turn a vicious time cycle into a "virtuous" one:

Chemotherapy of breast cancer.

Carcinoma of the breast will prove fatal to over 37,000 women in the United States in 1983, despite attempts at early diagnosis. Hormonal manipulation, known to provide effective palliation for many years, can now be effectively aimed at receptor positive women who have a 50-70% chance of responding. Newer agents, such as tamoxifen and aminoglutethimide offer the benefits of older treatments with less morbidity. Investigations of drugs acting at the level of the central nervous system are ongoing. Single agent chemotherapy is clearly effective in causing tumor regression, but effective combination chemotherapy provides more responses and a longer duration of response. The most effective combination regimens at present contain doxorubicin. Pharmacologic studies at the cellular level can be expected to provide more effective combinations. The most effective way to combine hormonal and chemotherapeutic treatments is not known. In receptor positive women without life-threatening disease, beginning with hormonal treatment may be effective in providing palliation at low toxic cost without jeopardizing overall survival. New efforts to cure clinically manifest metastatic breast cancer may eschew palliation as a prime goal. Techniques of synchronizing and of stimulating breast cancer to increase its susceptibility to cytotoxic drugs are under investigation. Immunotherapy is not established as a beneficial modality in the treatment of breast cancer, although levamisole has led to suggestive benefit in small controlled trials. The use of chemotherapy, and possibly of some hormonal treatments in appropriate patients, as an adjuvant to surgery prolongs disease-free survival. This approach, using established chemotherapeutic and hormonal agents when the metastatic disease is subclinical, is consonant with abundant evidence from experimental systems and other human cancers that are curable. Expectation of curing human breast cancer will likely require aggressive action at the time when the total body tumor burden is at a minimum.