Phase I clinical and pharmacological study of merbarone.

Merbarone, a nonsedating derivative of thiobarbituric acid, has demonstrated excellent activity against certain murine tumors, including L1210 and P388 leukemias, B16 melanoma, and M5076 sarcoma. Preclinical studies suggested that the antitumor effects of this drug were schedule dependent, since repeated dosing increased killing of tumor cells when compared to intermittent injections. We have completed a Phase I clinical and pharmacological study of merbarone in which the drug was administered both as a 2-h infusion and as a continuous i.v. infusion over 24 h. In view of the increased toxicity observed in animals following bolus injections and the possibility of schedule-dependent anticancer activity, a schedule of drug administration daily for 5 days was selected. Fifty patients with advanced cancer were treated at dose levels that ranged from 100 to 1500 mg/m2/day. When the drug was administered by peripheral vein, phlebitis was observed at the infusion site at daily doses greater than or equal to 150 mg/m2. Therefore, all patients who received drug doses greater than or equal to 200 mg/m2 were treated by continuous i.v. infusion using central venous catheters. Renal insufficiency, initially observed at a dose of 1000 mg/m2/day, was the dose-limiting toxic reaction at 1500 mg/m2/day. Three of five patients treated at the highest dose level were unable to complete the infusion due to this effect. Marked hypouricemia was observed in all patients. Other toxic effects were mild and included nausea, fatigue, leukopenia, thrombocytopenia, and anorexia. Alopecia was noted in several patients who received doses greater than or equal to 1000 mg/m2/day. No major antitumor effects were observed. Dose-dependent, steady-state plasma concentrations of merbarone were reached within 24-48 h after beginning the continuous i.v. infusion. Elimination of drug from plasma followed a two-compartment model, with a t1/2 alpha of 4.2 h and a t1/2 beta of 15.3 h. Renal excretion of merbarone and its major metabolites accounted for less than 30% of the administered dose. We conclude that merbarone is relatively well tolerated with few constitutional symptoms. The current formulation of the drug causes phlebitis when administered by peripheral vein, and renal insufficiency is commonly observed at daily doses which exceed 1250 mg/m2. The recommended dose for extended Phase II evaluation is 1000 mg/m2/day daily for 5 days administered by central venous catheter.

Phase I evaluation of a combination of monoclonal antibody R24 and interleukin 2 in patients with metastatic melanoma.

A combination of recombinant human interleukin 2 (rhIL-2) and mouse monoclonal antibody R24 (recognizing the ganglioside GD3) was evaluated in patients with metastatic melanoma in a phase I trial. rhIL-2 was given at a constant daily dose of 1 x 10(6) units/m2 i.v. over 6 h on days 1-5 and 8-12. R24 was given on days 8-12 at four dose levels (1, 3, 8, and 12 mg/m2 daily). Twenty patients were evaluable for toxicity and response, five at each dose level. The toxicity of the combination was not overlapping and generally mild. There was a rebound peripheral blood T-lymphocytosis at the end of treatment increasing with the dose of R24. The median lymphocyte count on day 12 of treatment was 3108 +/- 554/ml in patients treated at R24 doses of 8 and 12 mg/m2 versus 2239 +/- 672/ml at doses of 1 and 3 mg/m2. This evidence and other data suggested that R24 enhanced IL-2-mediated T-cell activation in vivo. Two patients demonstrated increases in R24-mediated antibody-dependent cellular cytotoxicity for GD3-expressing cells during treatment. rhIL-2 appeared to accelerate the development of human anti-mouse antibody; three patients developed human anti-mouse antibody by the fifth day of R24 treatment, earlier than observed in prior studies using R24 alone and one patient during the first week of rhIL-2 alone, prior to R24 treatment. One patient had a partial response in soft tissue sites lasting 6 months and two patients had minor responses. This clinical trial extends the previous observation that R24 enhances lymphocyte proliferation in vitro.

Educating psychiatry residents about death and dying. A national survey.

A national survey was conducted to assess the prevalence of teaching about death and dying issues in psychiatric training programs. Responses from 142 program directors indicated that 56% of responding programs offer specific lectures or didactics on this topic. Of residents surveyed (N = 286), 25.8% reported such lectures. Residents' feelings and experiences regarding death and dying are also explored. Psychiatric residency training programs are challenged to enhance their educational efforts on this topic in view of the demand for this knowledge resulting from many factors, which include the AIDS epidemic, issues of assisted suicide, and expectations from medical colleagues.

Phase II trial of amonafide in patients with stage III and IV non-small-cell lung cancer.

Amonafide (benzisoquinolinedione, nafidimide, NSC 308847) is an anticancer agent that functions as a DNA intercalator. Sixteen patients with stage III or IV non-small-cell lung cancer who had not previously received chemotherapy were given amonafide at an initial dose of 300 mg/m2 i.v. daily for 5 days every 21 days. No major objective responses were observed among the 14 patients adequately treated (95% confidence limits 0-20%). Local reactions at the injection site or phlebitis were seen in 14 of the 16 patients. Leukopenia (44%), nausea or vomiting (38%), and thrombocytopenia and rash (each 25%) were also noted. With the low response rate and the toxicity observed, amonafide at this dosage and schedule has limited use in the treatment of non-small-cell lung cancer.

Bicorrectional horizontal V-osteotomy of the first metatarsal head.

This article discusses the Reverdin-Laird procedure for the surgical correction of hallux abducto valgus. This procedure, also known as the "distal L", is presented as an alternative to the technically difficult bicorrectional Austin procedure. Excellent visualization allowing for accurate wedge resection is a primary benefit of the procedure.

Hallucinations and ifosfamide-induced neurotoxicity.

BACKGROUND: Hallucinations as a symptom of central neurotoxicity are a known but poorly described side effect of ifosfamide. Most cases of ifosfamide-induced hallucinations have been reported with other mental status changes. METHODS: The authors interviewed six persons with ifosfamide-induced hallucinations in the presence of a clear sensorium. All patients were receiving high-dose ifosfamide as part of their bone marrow transplant procedure. RESULTS: Hallucinations occurred only when the patient's eyes were closed and, in all but one case, were reported as disturbing or frightening. Underreporting of these hallucinations by patients is likely. CONCLUSIONS: Hallucinations may be the sole or first manifestation of neurotoxicity. The incidence may be dose and infusion-time related. The clinician should be alerted for possible ifosfamide-induced hallucinations, which may occur without other signs of neurotoxicity. "Eyes-closed" hallucinatory experiences appear to be an unusual feature of this presentation. Patients anxious about this experience respond well to support and education about this occurrence. Optimal pharmacologic management of disturbed patients is unclear. If agitation becomes marked, high-potency neuroleptics (i.e., haloperidol) may be effective.

The request for assistance in dying. The need for psychiatric consultation.

BACKGROUND: Public initiatives and legislative proposals have increased the likelihood that some states will legalize euthanasia and assisted suicide as a means of ending the suffering of patients with terminal illness. However, suggested safeguards that would guide physicians in such cases have not properly addressed the need to evaluate psychosocial factors that could motivate patients' requests for premature death. METHODS: Four cases of patients with cancer who expressed a wish to end their lives prematurely are described. These cases were evaluated with regard to mental and emotional functioning. RESULTS: Pain and suffering, organic mental disease, depression, and personality issues play significant roles in patients' requests for assistance in dying. CONCLUSION: Comprehensive psychosocial assessment is needed when evaluating requests for assistance in dying. This assessment may reveal hidden problems or conflicts that affect rational decision making, a prerequisite to informed consent for any procedure or intervention.

Experimental lead paint poisoning in nonhuman primates. II. Clinical pathologic findings and behavioral effects.

Oral administration of lead-containing paint to rhesus monkeys induced anemia, more profound in older primates. Erythrocytes were microcytic and hypochromic, but tended to become macrocytic terminally. Stippled erythrocytes were increased in all poisoned monkeys, especially in those with high blood lead levels and anemia. Proteinuria, glycosuria, casts and sloughed tubular cells containing acid-fast inclusion bodies were found on urinalysis. Terminal elevations of blood urea nitrogen were associated with profound anemia and renal tubular damage. Repeated blood lead values over 200 microgram/dl were associated with a moribund termination while monkeys which had levels under 100 microgram/dl remained apparently healthy. Behavioral studies in a small number of subclinically poisoned juveniles and neonates failed to reveal deficiencies of visual acuity or cognitive ability, nor was there evidence of alterations in levels of activity.