ABSTRACT
PURPOSE: A novel nanomedicine, CYT-6091, constructed by simultaneously binding recombinant human tumor necrosis factor alpha (rhTNF) and thiolyated polyethylene glycol to the surface of 27-nm colloidal gold particles, was tested in a phase I dose escalation clinical trial in advanced stage cancer patients. EXPERIMENTAL DESIGN: CYT-6091, whose dosing was based on the amount of rhTNF in the nanomedicine, was injected intravenously, and 1 cycle of treatment consisted of 2 treatments administered 14 days apart. RESULTS: Doses from 50 µg/m(2) to 600 µg/m(2) were well tolerated, and no maximum tolerated dose (MTD) was reached, as the highest dose exceeded the target dosage of 1-mg rhTNF per treatment, exceeding the previous MTD for native rhTNF by 3-fold. The first 2 patients on the study, each receiving 50 µg/m(2), did not receive any prophylactic antipyretics or H2 blockade. A predicted, yet controllable fever occurred in these patients, so all subsequently treated patients received prophylactic antipyretics and H2 blockers. However, even at the highest dose rhTNF's dose-limiting toxic effect of hypotension was not seen. Using electron microscopy to visualize nanoparticles of gold in patient biopsies of tumor and healthy tissue showed that patient biopsies taken 24 hours after treatment had nanoparticles of gold in tumor tissue. CONCLUSIONS: These data indicate that rhTNF formulated as CYT-6091 may be administered systemically at doses of rhTNF that were previously shown to be toxic and that CYT-6091 may target to tumors. Future clinical studies will focus on combining CYT-6091 with approved chemotherapies for the systemic treatment of nonresectable cancers.
Subject(s)
Gold Colloid/administration & dosage , Neoplasms/drug therapy , Polyethylene Glycols/administration & dosage , Tumor Necrosis Factor-alpha/administration & dosage , Tumor Necrosis Factor-alpha/pharmacokinetics , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Dose-Response Relationship, Drug , Female , Gold Colloid/adverse effects , Gold Colloid/chemistry , Gold Colloid/pharmacokinetics , Humans , Injections, Intravenous , Male , Maximum Tolerated Dose , Middle Aged , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Neoplasms/metabolism , Neoplasms/pathology , Polyethylene Glycols/adverse effects , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacokinetics , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/chemistry , Recombinant Proteins/pharmacokinetics , Tumor Necrosis Factor-alpha/adverse effects , Tumor Necrosis Factor-alpha/chemistry , Young AdultSubject(s)
Gold Colloid/adverse effects , Spleen/diagnostic imaging , Splenic Diseases/chemically induced , Arthritis, Rheumatoid/drug therapy , Diagnosis, Differential , Female , Gold Colloid/therapeutic use , Humans , Middle Aged , Radiography , Spleen/drug effects , Splenic Diseases/diagnostic imagingABSTRACT
A case of left bundle branch block and a dilated, nonhypertrophic cardiomyopathy associated with ingestion of colloidal gold and silver as an 'energy tonic' is described. The cardiac disease was reversed within two months by a course of dimercaprol (Akorn Inc, USA) (British antiLewisite) and vitamin E. This is the first case of gold and silver cardiomyopathy in humans, and highlights the risks of these colloidal metal 'health supplements'.
Subject(s)
Bundle-Branch Block/chemically induced , Cardiomyopathy, Dilated/chemically induced , Chelating Agents/therapeutic use , Dimercaprol/therapeutic use , Gold Colloid/adverse effects , Silver/adverse effects , Tocopherols/therapeutic use , Adult , Bundle-Branch Block/diagnosis , Bundle-Branch Block/drug therapy , Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Dilated/drug therapy , Dietary Supplements/adverse effects , Echocardiography , Electrocardiography , Female , HumansABSTRACT
OBJECTIVE: Therapy with intrathecal colloidal gold has been used in the past as an adjunct in the treatment of childhood neoplasms, including medulloblastoma and leukemia. We describe the long-term follow-up period of a series of patients treated with intrathecal colloidal gold and emphasize the high incidence of delayed cerebrovascular complications and their management. METHODS: Between 1967 and 1970, 14 children with posterior fossa medulloblastoma underwent treatment at the University of Minnesota. Treatment consisted of surgical resection, external beam radiotherapy, and intrathecal colloidal gold. All patients underwent long-term follow-up periods. RESULTS: Of the 14 original patients, 6 died within 2 years of treatment; all experienced persistent or recurrent disease. The eight surviving patients developed significant neurovascular complications 5 to 20 years after treatment. Three patients died as a result of aneurysmal subarachnoid hemorrhage, and five developed ischemic symptoms from severe vasculopathy that resembled moyamoya disease. CONCLUSION: Although therapy with colloidal gold resulted in long-term survival in a number of cases of childhood medulloblastoma, our experience suggests that the severe cerebrovascular side effects fail to justify its use. The unique complications associated with colloidal gold therapy, as well as the management of these complications, are presented. We recommend routine screening of any long-term survivors to exclude the presence of an intracranial aneurysm and to document the possibility of moyamoya syndrome.
