Feasibility study of combining metronidazole with chemotherapy.

Metronidazole, 1.5 g/sq m, was administered p.o. to patients with advanced malignancies 12 hr and 1 hr before and 6 hr and 24 hr after each of adriamycin, BCNU, and mitomycin-C. Doses of adriamycin varied from 50 to 90 mg/sq m. At an adriamycin dose of 75 mg/sq m, the median granulocyte nadir was 900/microliters and the median platelet nadir was 240,000/microliters. No enhancement of stomatitis or cardiotoxicity was noted at the doses studied. Doses of BCNU varied from 145 to 265 mg/sq m. At a BCNU dose of 240 mg/sq m, the median granulocyte nadir was 2600/microliters and the median platelet nadir was 102,000/microliters. Two patients developed hypotension that may have been due to a metronidazole-alcohol interaction. Doses of mitomycin-C varied from 10 to 20 mg/sq m. At a mitomycin-C dose of 20 mg/sq m, the median granulocyte nadir was 1300/microliters and the median platelet nadir was 81,000/microliters. Four of 40 patients developed pulmonary toxicity and one developed renal toxicity. Of 11 evaluable patients treated on the adriamycin regimen, 4 responded and 5 stabilized. With BCNU, 7 of 17 responded and 2 stabilized. With mitomycin-C, 2 of 32 responded and 12 stabilized. Overall, 4 of 8 patients with squamous cell carcinoma or adenocarcinoma of the lung attained partial remissions and one had a minor response. Using this metronidazole dose schedule, phase II studies are being conducted with adriamycin, 75 mg/sq m, in squamous cell and adenocarcinomas of the head and neck; with BCNU, 240 mg/sq m, in glioblastomas and squamous cell and adenocarcinoma of the lung; and with mitomycin-C, 20 mg/sq m, in adenocarcinomas of the breast and colon.

Antipsychotics in bipolar disorder.

Antipsychotics are commonly added to lithium for relief of severe psychotic symptoms and behavioral disruption during an acute manic episode. In general, lithium is superior in stabilizing mood and ideation, whereas neuroleptics are better in controlling hyperactivity, and the course of clinical response is faster to antipsychotics than to lithium. The effects of neuroleptics on bipolar depression need further study. Traditional neuroleptics carry the risk of extrapyramidal symptoms, and concern exists over neurotoxicity from the combination of lithium and a neuroleptic. Roles for clozapine, risperidone, and newer atypical neuroleptics, which may carry a lower risk of associated extrapyramidal side effects, will become clear with additional study and clinical experience. Long-term antipsychotic therapy in the maintenance phase of bipolar disorder is common; the efficacy, however, remains unclear and the risk of tardive movement disorders is substantial. Otherwise treatment-resistant patients who receive maintenance antipsychotic therapy to prevent recurrent episodes of mania should be followed closely, with regular screening for early signs of movement disorders.

Treatment of bipolar disorder: how far have we come?

Research on bipolar disorder continues to indicate that recurrent episodes of mania and depression have a deteriorative effect on patient functioning, response to treatment, and prognosis. Lithium is the treatment of choice for both acute affective episodes and long-term maintenance, but not all patients respond adequately to lithium therapy. Alternatives or adjuncts to lithium in acute mania include carbamazepine, valproate, electroconvulsive therapy (ECT), and clozapine. For acute depression, antidepressants often are added to lithium treatment or used alone; nonpharmacologic options include ECT and light therapy. Studies suggest that carbamazepine and valproate may be as effective as lithium in maintenance therapy and that thyroid supplementation may increase response in rapid-cycling patients. Using psychosocial intervention in addition to maintenance pharmacologic treatment may increase medication compliance, decrease hospitalizations, and increase overall functioning.

Serum lithium levels and the outcome of maintenance therapy of bipolar disorder.

A literature review was conducted to locate studies that compared different serum lithium levels in the long-term treatment of patients with bipolar disorder and articles about factors that may affect serum lithium levels. Patients with bipolar disorder on long-term treatment with lithium are typically maintained at serum lithium concentrations between 0.6 and 1.0 mEq/L. Although there are individual exceptions, serum lithium levels below 0.6 mEq/L have been shown in controlled clinical trials to be less effective in preventing relapses than levels within this range, whereas levels much above 1.2 mEq/L can lead to toxicity. Differences in efficacy between levels within the accepted range have not been established. However, higher levels are associated with greater side effects, which can lead to poor compliance. Interindividual variation in pharmacokinetics and pharmacodynamics, as well as such external factors as diet and concomitant medications, can affect serum lithium levels.

Report on efficacy of treatments for bipolar disorder.

Nearly one percent of adults in the United States suffer from bipolar disorder, a severe, chronic, and life-threatening disease. This disorder involves periodic episodes of mania and depression. At least 80 percent of patients who have an initial episode of mania will have one or more subsequent episodes. Because recurring episodes have a cumulative deteriorative effect on functioning and treatment response, the sooner bipolar patients are diagnosed and treated, the better their changes are for recovery. With optimal treatment, a bipolar patient can regain approximately 7 years of life, 10 years of effective major activity, and 9 years of normal health, which otherwise would have been lost due to the illness. For treatment purposes, bipolar disorder is divided into three stages: acute mania, acute depression, and maintenance. Lithium is the standard treatment for acute mania, and its effectiveness is solidly supported by experimental evidence. Rigorous studies over the past 40 years involving hundreds of patients have repeatedly shown the efficacy of lithium therapy, with approximately 80 percent of subjects responding favorably. For those who do not, several other drugs and nonpharmacologic therapies are available that have shown high success rates in well-standardized trials. The anticonvulsant drug carbamazepine has been associated with improved symptoms in approximately 60 percent to 70 percent of subjects in double-blind trials comparing it against placebo, neuroleptics, and/or lithium. Valproate, another anticonvulsant, has been shown to be comparable to lithium and superior to placebo in treating acute mania in several double-blind, placebo-controlled trials. Electroconvulsive therapy (ECT) is another effective treatment for acute mania, with a positive response rate of approximately 80 percent. Acute bipolar depression has been successfully treated with a number of agents, including monoamine oxidase inhibitors (e.g., tranylcypromine), lithium, tricyclic antidepressants, and second-generation antidepressants (e.g., bupropion). Nonpharmacologic approaches such as ECT, sleep deprivation, and light therapy have been effective as supplemental therapy in many patients. For maintenance therapy, lithium is again the drug of choice. Clinical research has shown that maintenance lithium lessens the frequency and severity of episodes of mania and depression in bipolar patients and helps stabilize mood between episodes. Long-term lithium treatment also reduces the risk of mortality for bipolar patients: without treatment, mortality is two to three times higher than that of the general population; with treatment, it is not significantly different. Several other drugs have been studied as alternatives or adjuncts to lithium therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Penetration of teniposide (VM-26) into human intracerebral tumors. Preliminary observations on the effect of tumor type, rate of drug infusion and prior treatment with amphotericin B or oral glycerol.

Thirty-four consenting patients received VM-26 50-100 mg/m2 I.V. before surgical resection of intracerebral tumor, and drug was measured using a high pressure liquid chromatographic technique. Sufficient tumor for analysis was obtained from 29 patients. Brain metastases (13 patients) had higher concentrations of VM-26 than did gliomas (13 patients). Concentrations were comparable in brain metastases and meningiomas (3 patients). Prolonged (24 h) infusion of VM-26 did not appear to result in higher tumor drug concentrations in 5 patients than did rapid (1 h) infusion in 24 patients. Pretreatment with Amphotericin-B 10 mg/m2 12 h and 1 h before VM-26 did not appear to have any effect on VM-26 uptake into 4 intracerebral tumors, although data were limited, and VM-26 concentrations were very high in 1 metastasis. Pretreatment with oral glycerol 500 mg/kg 18 h, 12 h, 6 h, and immediately before I.V. VM-26 may have resulted in increased penetration of VM-26 into 9 tumors, although confirmation is required. Amphotericin-B, glycerol, and operative conditions did not appear to alter VM-26 plasma pharmacokinetics.

Penetration of VP-16 (etoposide) into human intracerebral and extracerebral tumors.

VP-16 100 mg/m2 was given intravenously to 10 patients undergoing surgical resection of intracerebral tumors, and the drug was assayed in resected tumor using high pressure liquid chromatography. VP-16 concentrations varied from undetectable (less than .1 microgram/g) to 5.9 micrograms/g (mean, 1.4 microgram/g). VP-16 concentrations in tumors were lower than concurrent plasma concentrations. In addition, intracerebral tumors had a lower concentration of VP-16 than did extracerebral tumors (mean VP-16 concentration, 3.9 micrograms/g) from 7 patients receiving VP-16 50-100 mg/m2 intravenously. Plasma pharmacokinetics of VP-16 were different in our patients with intracerebral tumors than in previously studied patients with extracerebral tumors and it is unclear what role this may played in variability of tumor VP-16 concentrations. VP-16 concentrations were similar in glioblastomas and brain metastases. Specimens from patients with small cell undifferentiated carcinoma of the lung had the highest VP-16 concentrations. A patient who had both viable and necrotic tumor resected during an occipital lobectomy had a higher drug concentration in the necrotic than in the viable area of tumor. In addition, VP-16 concentration decreased as a function of distance into brain from the tumor. Based on our data, VP-16 might be expected to have less activity against intracerebral than against extracerebral human tumors.

Phase I study of intracarotid PCNU.

A phase I study of the intracarotid administration of PCNU was conducted in patients with intracerebral tumors recurring after cranial radiation. Seventeen patients were treated including 16 with recurrent gliomas or glioblastomas and 1 with recurrent brain metastases from adenocarcinoma of the lung. An additional patient received a vertebral artery infusion of PCNU for a recurrent glioblastoma. Seven of 17 patients receiving intracarotid PCNU responded for a response rate of 41%. If only evaluable patients with gliomas are considered, the response rate was 44%. Tumor grade at time of initial diagnosis, exposure to prior chemotherapy, and dose of PCNU did not appear to have a major impact on response rate. Zubrod performance status 3 patients had a lower response rate (25%) than did patients with performance status 1 or 2 (response rate 63%). Thrombocytopenia and reversible central nervous system toxicity were dose limiting at a PCNU dose of 110 mg/m2. Two patients had possible permanent central nervous system toxicity. Three patients had permanent ipsilateral visual impairment, including one at the lowest dose used into the carotid artery (60 mg/m2). Orbital pain appeared to be substantially less than that seen with intracarotid BCNU but headaches may have been somewhat more common. The single patient receiving a vertebral artery infusion developed marked headaches and restlessness after receiving 25 mg/m2 of a planned 75 mg/m2 treatment into the vertebral artery and the treatment had to be discontinued. Symptoms were rapidly reversible upon stopping the medication. Our overall impression is that intracarotid PCNU causes less ocular pain but more transient central nervous system toxicity than does intracarotid BCNU.(ABSTRACT TRUNCATED AT 250 WORDS)