Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar.

Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20-25 mg m(-2) intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m(-2) and escalated in an accelerated titration design to 25 mg m(-2). Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m(-2). The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10-73) ml h(-1) m(-2) in cycle 1 to 18 (3-37) ml h(-1) m(-2) with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m(-2) in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.

Phase I study of rubitecan and gemcitabine in patients with advanced malignancies.

BACKGROUND: Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in advanced malignancies. PATIENTS AND METHODS: Twenty-one patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of rubitecan at 0.75 mg/m(2)/day administered orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) administered intravenously on days 1 and 8 of a 21-day cycle. RESULTS: The MTD was defined as rubitecan 1 mg/m(2) administered orally days 1-5 and 8-12, and gemcitabine 1000 mg/m(2) administered intravenously over 30 min days 1 and 8, given every 21 days. Dose-limiting toxicity was myelosuppression including neutropenia and thrombocytopenia. Other side effects included diarrhea, nausea, vomiting and fatigue. Five patients with stable disease were observed among 18 evaluable patients. CONCLUSIONS: The recommended phase II dose is rubitecan 1 mg/m(2) given orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) as a 30-min intravenous infusion on days 1 and 8 of a 21-day cycle.

Safe handling practices of cytotoxic drugs: the results of a chapter survey.

PURPOSE/OBJECTIVES: To describe how nurses from a local Oncology Nursing Society (ONS) Chapter Implement Occupational Safety and Health Administration (OSHA) guidelines for handling cytotoxic drugs (CDs) in their individual practices and to identify barriers to implementing these guidelines. DESIGN: Mailed survey. SETTING: ONS chapter in a large midwestern city. SAMPLE: 103 nurses, 83 of whom handle CDs. Mean years in oncology nursing was 7.5. METHODS: Mailed survey consisting of 48 questions on seven topics, as well as demographic questions. MAIN RESEARCH VARIABLES: Roles in preparation and administration of CDs, management spills, patient care, and use of protective equipment in patient and family education practices; barriers to use of protective practices. FINDINGS: Subjects used some protective equipment when preparing and administering CDs, but the type of equipment and its frequency of use did not specifically meet OSHA Guidelines. Rates of compliance with guidelines were better for management of spills and disposal of equipment. Verbal instructions for patients and families were employed but very few provided written instructions or explanations. Barriers to using protective equipment included a lack of time, problems with availability, and concerns about patient reactions. CONCLUSIONS: Barriers must be overcome and better safe-handling practices incorporated into practice to ensure the safety of nurses. More education is needed for family members who come into contact with patients receiving CDs. IMPLICATIONS FOR NURSING PRACTICE: Future research to document the extent of the problem, including stratification of responses according to the quantity and frequency with which a nurse administers CDs. Better, and perhaps more frequent, staff and family education efforts are needed.

Review of the etiology and treatment of premenstrual syndrome.

Premenstrual syndrome (PMS) is a diagnostic enigma that causes significant morbidity in many woman. Numerous theories have been proposed in an attempt to explain the varied symptoms that occur cyclically in women with PMS. Suggested etiologic theories of PMS include psychological abnormalities, nutritional deficiencies, aberrations in the renin-angiotensin-aldosterone axis, altered prostaglandin activity, hormonal imbalances, and changes in endogenous opioid peptide activity. Because of the lack of standardized diagnostic criteria, clinical drug trials for PMS have been severely compromised. For every proposed cause of PMS, there exists a drug or drug class that has been investigated for treatment of the associated symptoms. Many clinical studies are uncontrolled, a significant deficiency in study design for a disorder that is associated with a high placebo response rate. At the present time, no definitive treatment for PMS exists and therapy must be individualized according to clinical response. This review article defines PMS, describes one of the current approaches to the diagnostic work-up, discusses the proposed etiologies of PMS, and reviews the various proposed treatment modalities.