A phase I study of bortezomib and temozolomide in patients with advanced solid tumors.

PURPOSE: The primary objective was to determine the maximum tolerated doses (MTDs) of the combination of bortezomib and temozolomide in patients with solid tumors. The secondary objective was to evaluate the pharmacokinetics (PK) of bortezomib with and without concurrent hepatic enzyme-inducing anticonvulsants (HEIAs). METHODS: Bortezomib was administered on days 2, 5, 9, and 12; temozolomide on days 1-5 of a 28-day cycle. Dose escalation proceeded using a standard 3+3 design. Patients with primary or metastatic brain tumors were eligible and were stratified based on whether they were taking HEIAs or not. RESULTS: Of the 25 patients enrolled, 22 were not taking HEIAs. MTDs were only given to patients not receiving HEIAs. Dose-limiting toxicities (DLTs) consisted of grade-3 constipation, hyponatremia, fatigue, elevated hepatic enzymes, and grade-4 neutropenia, thrombocytopenia, constipation, and abdominal pain. Stable disease (>8 weeks) was observed in 5 patients. Bortezomib systemic clearance (CL(sys)) on day 9 was 51% of the CL(sys) on day 2 (P < 0.01) Similarly, the normalized area under the concentration-time curve (norm AUC) on day 9 was 1.9 times the norm AUC on day 2 (P < 0.01). The median bortezomib CL(sys) on days 2 and 9 was significantly higher (P < 0.04) in patients taking HEIAs, and the median norm AUC was correspondingly lower (P < 0.04). CONCLUSIONS: The MTDs for the combination of bortezomib and temozolomide in patients not taking HEIAs are 1.3 and 200 mg/m(2), respectively. The rate of bortezomib elimination in patients taking HEIAs was increased twofold. Additional trials are needed to better define the optimal dosing in such patients.

Assistive technology in the home.

Emerging technologies for home use may ease long-term costs for patients. More important, they may be applied to home care to improve patient quality of life and outcomes. What will the increasing role of physicians be in this arena?

Multidisciplinary home rehabilitation. A practical model.

The home is the most natural setting for rehabilitation. At home, the patient and family become active team members and the plan of care is created and carried out in the environment in which the patient will live. Home rehabilitation enhances the patient's autonomy, independence, and community reintegration.

Home care of the elderly diabetic patient.

As the anticipated growth of sophisticated diabetic services continues to accelerated in homes across America, physicians must first be educated as to the potentially unlimited spectrum of diabetic home care products and services that will become increasingly available to the patients whom they serve. Second, much research must be completed to critically examine the safety, quality, and cost issues of diabetic home care, to provide the necessary data to assure that home care services will be neither under- or over-utilized and will meet the necessary acute and long-term health care needs of our diabetic patients. Third, physicians must take a leadership role in examining the pitfalls of our existing expensive and often fragmented acute care-oriented health care model, which has not effectively addressed the increasing costs and incidence of chronic diseases, such as diabetes, in our society. With computerization and the explosive mobilization of high-technology health care products and services, we are witnessing an exponential growth in the list of services available in the home setting for diabetic patients. There has never been a time in the history of medicine that we, as physicians, have needed to create new, innovative, high-quality approaches to necessary, accessible, and cost-effective alternative health care delivery systems as is the case now. I believe that the renewal of home care, with physician vision, direction, and review, will be a major step toward the highest-quality medical care provided to our diabetic patients at home.

Medically induced drug addiction.

Iatrogenic, or medically induced, drug addiction is a problem affecting both patients and physicians. We describe the function of a new center devoted solely to managing iatrogenic addiction. The center accepts patients on physician referral only. The addiction usually arises as a complication of a medical disorder that is accompanied by pain and requires comprehensive and multidisciplinary evaluation and treatment. Detoxification from the offending medication, provision of chronic analgesia, and maintenance are managed with methadone. All appropriate modalities of treatment including psychotherapy, physical therapy, and relaxation techniques are employed.

Chronic pain: an addiction.

Chronic pain is distinguished from persistent pain and it is proposed that chronic pain involves addiction to the endogenous opioid system. Even when the organic lesions responsible for pain are removed, chronic pain can be maintained as an internal state preventing the withdrawal or abstinence syndrome associated with endorphins and enkephalins.

Simulation of oviductal ovum transport.

The present note describes a Monte Carlo simulation of ovum transport in the rabbit oviduct. Ova execute a random walk through a one-dimensional oviduct and the jump probabilities at each point are obtained from in vitro electrical recordings of smooth muscle activity. Simulated transport are compared with experimental findings at 18 and 66-68 h after human chorionic gonadotropin injection.