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

Acivicin, an L-glutamine antagonist, was administered to 37 evaluable patients with refractory advanced solid tumors in a phase I trial. A total of 67 evaluable 72-hr iv infusions were given at 3- to 4-week intervals. Doses ranged from 3.0 to 90 mg/m2/course. Reversible CNS toxicity was dose-limiting and included lethargy, somnolence, anxiety, hallucinations, and paranoid psychoses. Four of five patients experienced unacceptable CNS toxicity at 90 mg/m2. Three of eight patients experienced reversible diaphoresis and chills without fever at 75 mg/m2, and two had dizziness and ataxia. Hematopoietic toxicity, nausea, emesis, and diarrhea were mild and dose-related. One patient developed a blue-green discoloration of the infusion arm. Serial plasma and urine specimens from 13 patients were assayed for acivicin using a microbiologic method. Peak plasma levels at the end of the 72-hr infusions correlated with dose and ranged from 0.09 to 1.10 microgram/ml. When data from six patients were fitted to a two-compartment open model, alpha-half-life ranged from 1.1 to 63 mins, while beta-half-life ranged fro 338 to 629 mins. Renal clearance ranged from 6 to 24 mL/min, and nonrenal clearance accounted for 58%-83% of the total drug clearance. CNS toxicity correlated with plasma acivicin levels which exceeded 0.9 microgram/ml for greater than 16 hrs, but not with peak plasma levels or with the integrals of the concentration x time curves. Minor responses were seen in one patient with melanoma, in one with epidermoid pulmonary carcinoma, and in two with colon carcinoma. A starting dose of 60 mg/m2/course was recommended for phase II trials, with possible escalation to 75 mg/m2 in the second course if the drug was well-tolerated.
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PMID:Phase I trial and pharmacokinetics of acivicin administered by 72-hour infusion. 687 83

Although site-specific direction of drugs within an organism would benefit patients with many diseases, active drug targeting is clinically not yet possible. To overcome some of the problems associated with active drug targeting, we have developed a magnetic fluid to which drugs, cytokines, and other molecules can be chemically bound to enable those agents to be directed within an organism by high-energy magnetic fields. In the first part of this study, various concentrations of the magnetic fluid were tested in rats and immunosuppressed nude mice with regard to subjective and objective tolerance. In the second part, the same parameters were evaluated after administration of the ferrofluid to which epirubicin (4'-epidoxorubicin) was chemically bound. Finally, two forms of therapy with the magnetic fluid were tested: tumor treatment by mechanical occlusion with the ferrofluid in high concentrations; and magnetic drug targeting, using small amounts of the ferrofluid as a vehicle to concentrate epirubicin locally in tumors. As a result, the ferrofluid did not cause major laboratory abnormalities; there was no LD50. With very high concentrations of the ferrofluid, animals showed lethargy for 1-2 days. There were no intolerances with the epirubicin-bound ferrofluid as well. Both forms of treatment led to complete tumor responses in an experimental human kidney as well as in a xenotransplanted colon carcinoma model. Thus, the magnetic fluid is a safe agent, which can be used in different ways for local forms of cancer treatment in conjunction with high-energy magnetic fields.
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PMID:Preclinical experiences with magnetic drug targeting: tolerance and efficacy. 923 Feb 23