Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Streptozotocin (STZ) has shown antitumor activity against various tumors in man, but the clinical usefulness of this drug has been limited, mainly because of renal and gastrointestinal toxicity. Nineteen patients with advanced cancer of various types were given a mean dose of 3.4 g/m2 of STZ by continuous iv infusion over 5-6 days each month for one or two monthly cycles. Basic serum and urine studies were performed immediately before and after each treatment cycle. Following STZ treatment, no significant changes in BUN or creatinine were seen. Four patients in whom initial tests for proteinuria were negative developed grade 1 or 2+ proteinuria after completion of the treatment cycle. No myelosuppression or renal failure was observed. Six patients had no nausea or vomiting, seven patients had nausea only, three patients had nausea and vomiting which were well-controlled with antiemetics, and three patients had uncontrollable nausea and vomiting. Confusion, lethargy, and depression were noted in five patients who had no prior central nervous system abnormalities; these effects appeared during treatment or in the immediate posttreatment period. Two patients with diffuse non-Hodgkin's lymphoma had complete remission, while several other patients had documented improvement. Although central nervous system toxicity may be a limiting factor, prolonged STZ infusions may have significant clinical promise.
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PMID:Continuous streptozotocin infusion: a phase I study. 16 Aug 36

High-dose infusions of methotrexate with citrovorum factor rescue were evaluated in 27 patients with advanced recurrent breast cancer who had previously been treated with various Adriamycin-containing regimens. Eight of 27 patients (29%) achieved objective tumor regression with a median duration of response of 26 weeks. Nineteen patients had previously received standard doses of methotrexate (less than 50 mg/m2/dose), while eight patients had had no prior exposure to methotrexate. The response rates observed in these two groups of patients were similar. Except for two drug-related deaths, toxic effects were acceptable. Myelosuppression was mild, transient, and noncumulative. Gastrointestinal toxic effects did not appear to be dose-related and were mild in most instances. Central nervous system dysfunction with lethargy, fatigability, confusion, and disorientation was the most significant toxic effect of this high-dose methotrexate therapy and was observed in six (22%) of the patients. In two patients treatment with this program was discontinued because of the development of renal dysfunction. High-dose methotrexate with citrovorum factor rescue appears to be an effective regimen in patients with advanced refractory breast cancer. However, in view of the enormous cost necessitated by this treatment approach, we do not feel further studies would be worthwhile.
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PMID:High-dose methotrexate for advanced breast cancer. 31 46

A phase II evaluation of anguidine was carried out in 30 patients with advanced refractory breast cancer. A dose of 5.0 mg/m2 daily for 5 days was explored. The main toxic effects were nausea and vomiting, fever and chills, hypotension, skin erythema, somnolence, confusion, and lethargy. Myelosuppression was minimal. Among these extensively pretreated patients, there was one partial responder and one additional patient who showed improvement (less than a partial response); both responses occurred in soft tissue sites.
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PMID:Phase II study of anguidine in advanced breast cancer. 45 16

This phase I study investigated flavone acetic acid (FAA) given as a 12-h intravenous infusion every 3 weeks in the absence of urinary alkalinisation. Cohorts of three patients were treated at doses of 7, 10 and 13 g/m2. One subject had colon cancer; 5, renal cancer; and 3, lung cancer. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in four patients, 1 in two subjects and 2 in three cases. The maximum tolerated dose was 13 g/m2. The dose-limiting toxicities were WHO grade 3 hypotension and grade 3 diarrhoea. Other toxicities included lethargy and dizziness, nausea, temperature fluctuation, myalgia and dry mouth, but no significant myelosuppression was encountered. One patient receiving 10 g/m2 for renal cancer showed a partial response that lasted for 3 months and included the resolution of pulmonary and cutaneous metastases. The pharmacokinetics showed large interpatient variability. At 12-16 h post-infusion, the plasma elimination profile entered a plateau phase, with frequent increases in concentration suggesting enterohepatic recycling. Neither peak FAA levels nor AUC values were dose-dependent at the doses studied. Peak plasma levels were 101-402 micrograms/ml and AUC (0-48 h) values were 75-470 mg ml-1 min. Plasma protein binding varied with total concentration. Two metabolites were detected in the plasma, and both also underwent apparent enterohepatic recycling. Repeat dosing resulted in decreases of up to 48% in peak levels and AUC values for FAA in three of six patients. Of the total FAA dose, 39%-77% was excreted in the urine as FAA or metabolites within 2 days. The dose recommended for further phase II studies is 10 g/m2.
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PMID:A phase I and pharmacokinetic study of 12-h infusion of flavone acetic acid. 155 Nov 73

The NCI Canada Clinical Trials Group conducted a phase II study of menogaril given intravenously every 4 weeks in low-grade non-Hodgkin's lymphoma. Fifteen of 26 eligible patients had had no prior therapy. Partial responses were seen in 9 patients (35%). Toxicity was moderate including myelosuppression, nausea, phlebitis, alopecia, and lethargy. This drug has only modest activity in this potentially responsive group of patients.
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PMID:A phase II study of menogaril in low-grade non-Hodgkin's lymphoma. An NCI Canada Clinical Trials Group study. 182 34

Twenty previously treated patients with advanced bone sarcomas received thrice weekly im 50 X 10(6) IU/m2 doses of human alfa-interferon (interferon alfa-2a, recombinant; Roche). Seventeen patients had metastatic osteosarcomas and one each had fibrosarcoma, mesenchymal chondrosarcoma, and malignant fibrous histiocytoma. Two patients with osteosarcoma and the one with malignant fibrous histiocytoma experienced objective partial tumor regression for 1, 3, and 2 months, respectively. Fever, anorexia, myalgia, fatigue, lethargy, and moderate myelosuppression were observed commonly, and some patients developed mild nausea, vomiting, and diarrhea. No patient withdrew because of toxicity and no dose reductions were necessary except adjustments for changes in body surface area secondary to weight loss.
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PMID:Phase II study of recombinant alfa-2a interferon in patients with advanced bone sarcomas. 303 15

Tiazofurin is a novel C-nucleoside with significant antitumor activity in murine tumor models. In a phase I clinical trial, patients received tiazofurin by bolus iv infusion daily for 5 days. Six doses ranging from 550 to 4100 mg/m2/day were evaluated. Thirty-one treatment courses were initiated in 21 patients. Tiazofurin induced multiple, transient toxic effects at all but the lowest dose level, and treatment interruption was a common result. Nine of 28 treatment courses initiated at doses greater than or equal to 1100 mg/m2/day were interrupted at less than 5 days; only five of eight courses initiated at 1100 mg/m2/day were completed. Symptoms leading to treatment interruption included headache, nausea and emesis, and lethargy and malaise. Other significant, transient toxic effects included skeletal muscle injury manifest as pain, weakness, or serum biochemical abnormalities; mucocutaneous effects; and mental or mood changes. One case each of transient pericarditis and fatal cardiomyopathy occurred at the highest dose. Myelosuppression was observed but was transient and not dose limiting. In addition to leukopenia and thrombocytopenia, unexpected declines in serum hemoglobin were observed, although these were of uncertain significance. Tiazofurin induced significant increases in uric acid production which could be reversed with coadministration of allopurinol. Pharmacokinetic analysis revealed tiazofurin plasma elimination to be at least biphasic, with a beta-half-time of 4.2 hours; most of an injected dose could be recovered from the urine as unaltered compound within 24 hours. From this study we conclude that an appropriate dose for phase II trials with this schedule is less than or equal to 1000 mg/m2/day. The schedule may be a difficult one for clinical evaluation of antitumor activity, however, because of the possibility of frequent treatment interruption due to multiple systemic toxic effects.
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PMID:Phase I trial of tiazofurin administered by i.v. bolus daily for 5 days, with pharmacokinetic evaluation. 380 11

A Phase II study of interferon alfa-2a was conducted in 64 patients with multiple myeloma (42 IgG, 16 IgA, 5 Bence-Jones type, and 1 IgD) in a multi-institutional cooperative trial. Partial remission was obtained in 10 (21.3%) of 47 evaluable patients, and minor responses in 5 (10.6%) of 47. Remission was reached at 22 to 89 days (median, 29 days) after the initiation of interferon alfa-2a and lasted 4 to 55 weeks (median, 8 weeks). Side effects were noted in more than two-thirds of patients, and included fever (58%), malaise (20%), anorexia (52%), nausea-vomiting (26%), lethargy (2%), and myelosuppression (56%). They were all reversible on discontinuation of interferon alfa-2a. Antibody to interferon alfa-2a was detected in 1 of 20 patients tested during the course of treatment. Thus, interferon alfa-2a was effective in multiple myeloma, producing unequivocal response in 21.3% of patients without unacceptable side effects.
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PMID:Treatment of multiple myeloma with recombinant interferon alfa-2a. 394 39

A Phase I trial of 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC 286193, tiazofurin) was conducted using a 5-day continuous infusion schedule. Twenty-four patients with advanced cancer were entered on this trial. Dose levels ranged from 360 to 2350 mg/sq m/day for 5 days. Neurotoxicity was dose limiting and occurred in six patients. Neurotoxicity was expressed as confusion, lethargy, or obtundation and was associated with focal neurological deficits in four of six patients: hemiparesis, three; cortical blindness and bilateral upper extremity weakness, one. Neurotoxicity was not clearly dose related, occurring at 900 mg/sq m/day for 5 days (two patients), 1100 mg/sq m/day for 5 days (two patients), 1850 mg/sq m/day for 5 days, and 2350 mg/sq m/day for 5 days (one patient each). Other toxicities seen were myelosuppression, desquamation of palms and soles, malar erythema, and hyperpigmentation, stomatitis, chest pain, drug fever, and increased serum creatine phosphokinase. Administered drug [71.5 +/- 11.2% (SE)] was recovered intact in the urine within 24 h of administration. Terminal-phase mean harmonic half-life was 8.0 h. The unpredictable neurotoxicity seen following continuous infusion therapy with tiazofurin suggests that Phase II trials of this schedule are not indicated until better understanding of the biochemical effects of tiazofurin is achieved.
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PMID:Phase I clinical study with pharmacokinetic analysis of 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC 286193) administered as a five-day infusion. 398 12

A phase II study of recombinant human leukocyte A interferon was conducted in 64 patients with multiple myeloma in a multi-institutional cooperative trial. Partial remission was achieved in ten (21.3%) of 47 evaluable patients and minor response was observed in five (10.6%). Side effects were noted in more than two-thirds of the patients. They included fever (58%), malaise (20%), anorexia (52%), nausea and vomiting (26%), lethargy (2%), and myelosuppression (56%). An antibody to recombinant human leukocyte A interferon was detected in one of 20 patients.
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PMID:Treatment of multiple myeloma with recombinant human leukocyte A interferon. 407 17


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