Showing papers on "Toxicity published in 1986"

Clinical toxicity of interferons in cancer patients: a review.

Abstract: All major types of human interferons (IFNs) have been purified and clinically administered as antitumor agents. We summarize here experience to date with toxicity of IFNs in cancer patients. The acute syndrome consists of fever, chills, myalgias, arthralgias, and headache, with some variation according to type of IFN, route of administration, schedule, and dose. Fatigue, perhaps reflecting CNS toxicity, is the most prevalent nonacute symptom. At high doses, IFNs are neurotoxic; the abnormalities seen by EEG resemble those in diffuse encephalitis. Hematologic toxicity consists mainly of leukopenia, but anemia and thrombocytopenia occur in some patients. Nausea, vomiting, and diarrhea are the main gastrointestinal symptoms. Elevation of serum transaminases seems to reflect liver toxicity. Renal function is well preserved, except for rare instances of acute renal failure. Cardiac toxicity remains questionable, although heart failure and arrhythmias have been associated with the administration of IFNs. Most, if not all, of these effects are reversible or can be ameliorated. With IFN alpha, the type most widely used in clinical studies, doses of 1 million to 9 million units (MU) are generally well tolerated, but doses greater than or equal to 18 MU yield moderate to severe toxicity. Doses greater than or equal to 36 MU can induce severe toxicity and significantly alter the performance status of the patient.

Toxicity of Nitrite to Fish: A Review

Abstract: Nitrite, an intermediate in the oxidation of ammonium to nitrate, changes hemoglobin to methemoglobin, which does not carry oxygen; nitrite may thus cause anoxia in fish and other aquatic organisms. The published literature on nitrite toxicity to fish, which consists of about 40 papers, shows that the ratio of the 24-h LC50 (concentration lethal to half of the test organisms in 24 h) to the 96-h LC50 has a median value of 2.0 and is fairly uniform across species; toxicity tests of differing duration can therefore be standardized to a common duration. In general, chronic effects are difficult to detect at concentrations below one-fifth of the 96-h LC50. Most fish concentrate nitrite in fresh water; chloride in the external environment offsets the toxicity of nitrite by competing with nitrite for uptake through the chloride cells of the gills. The strength of the chloride effect is greatest for the least-sensitive species and smallest for the most-sensitive species. The addition of 1 mg/L chloride ...

Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity.

Abstract: Individual differences in metabolism of the sulfonamides may predispose patients to idiosyncratic reactions. Sulfonamides are metabolized by N-acetylation (mediated by a genetically polymorphic enzyme) and oxidation to potentially toxic metabolites. We examined 6 patients who had severe reactions to sulfonamides and compared them with 20 controls. Acetylator phenotype was determined with caffeine, a safe in-vivo probe of enzyme activity. All 6 patients were slow acetylators (expected, 55%; p less than 0.05). Detoxification of oxidative metabolites was studied in vitro with a lymphocyte assay evaluating cell death from metabolites generated by a murine hepatic microsomal system. Cells from each patient showed increased toxicity from sulfonamide metabolites but not from the drugs themselves. Cells from parents of 3 patients had intermediate toxicity from sulfonamide metabolites, whereas cells from a sibling of 1 patient had a normal response. Susceptibility to sulfonamide reactions may be due to interaction of metabolic pathways, possibly under genetic control, regulating N-acetylation and specific detoxification of toxic metabolites of the drugs.

Clinical effects and toxicity of interleukin-2 in patients with cancer

Abstract: Interleukin-2 (IL-2) is a 15,000 dalton glycoprotein produced naturally by human T-cells during an immune response. IL-2 has been demonstrated to have substantial activity alone or in combination with the adoptive transfer of lymphokine-activated killer cells in murine tumor models. IL-2 derived from both natural (Jurkat human T-cell tumor) and recombinant (Escherichia coli) sources has been studied in Phase I protocols designed to evaluate toxicity in patients with a variety of solid tumors and to ascertain improvement in clinical parameters and immunologic status. A total of 16 patients (7 with acquired immune deficiency syndrome [AIDS] and 9 with non-AIDS malignancies) were treated with Jurkat derived IL-2. The total maximum dose (1.3 X 10(5) U/kg) was limited only by supply of this reagent. A total of 25 patients have been treated with recombinant IL-2 (RIL-2) alone. Dose-limiting toxicity manifested by marked malaise and weight gain was achieved with doses of RIL-2 of 10(6) U/kg as a single bolus or 3000 U/kg/hr. IL-2 could be administered intraperitoneally with similar toxicity. Minimal renal or hepatic toxicity was demonstrated. Hematologic toxicity was limited to mild anemia (25/25), thrombocytopenia (10/25), and marked reversible eosinophilia (15/25). Pronounced weight gain greater than 2 kg (16/25) occurred in most patients, primarily those who received cumulative doses of greater than 1-3 X 10(5) U/kg of IL-2. The weight gain amounted to as much as 10% to 20% of the pretreatment weight over 3 weeks of treatment and limited our ability to give higher doses. Two partial responses (greater than 50% decrease in cross sectional diameters) were seen in two patients with melanoma metastatic to the lung.

Lipid peroxidation and cellular damage in extrahepatic tissues of bromobenzene-intoxicated mice

Abstract: The mechanisms of bromobenzene toxicity in extrahepatic tissues of mice were studied. Kidney, lung, heart and brain were examined. As observed in this as well as in a previous report for the liver, bromobenzene intoxication caused a progressive decrease in the glutathione content of all the tissues examined. Cellular damage (as assessed by both biochemical determinations and histologic observations) appeared after 6 hours in the case of the kidney and the heart and after 15 hours in the case of the lung. Lipid peroxidation (as assessed by the tissue content of malonic dialdehyde, a parameter correlating with both the diene conjugation absorption and the amount of carbonyl functions in cellular phospholipids) was found to occur at the same times at which cellular damage was observed or even before. As in the case of bromobenzene-induced liver injury, when the individual values for cell damage obtained at 15-20 hours were plotted against the corresponding glutathione contents, a severe cellular damage was generally observed when the glutathione levels reached a threshold value (3.0-0.5 nmol/mg protein). Such a glutathione threshold was also observed for the onset of lipid peroxidation. Glutathione depletion and lipid peroxidation are therefore general phenomena occurring not only in the liver but in all the tissues as a consequence of bromobenzene poisoning. The possibility that lipid peroxidation is the cause of bromobenzene-induced damage to liver and extrahepatic tissues is discussed.

Vascular toxicity associated with antineoplastic agents

Abstract: Vascular complications associated with antineoplastic agents are being reported with increasing frequency. Such vascular toxicity is clinically heterogeneous, ranging from asymptomatic arterial lesions to a fatal thrombotic microangiopathic syndrome. Mitomycin is most commonly implicated in the thrombotic microangiopathic syndrome, while bleomycin, either alone or in combination with a vinca alkaloid or cisplatin, appears to be an important cause of Raynaud's phenomenon. Acute arterial ischemic events, ie, myocardial infarction and cerebrovascular accidents, occur most frequently after cisplatin-based combination chemotherapy. Putative mechanisms for such toxicity include drug-induced endovascular damage, perturbation of the clotting system, platelet activation, an abnormality of thromboxane-prostacyclin homeostasis, autonomic dysfunction, vasculitis, and stimulation of fibroblasts. More than one mechanism may be operative in an individual patient. Better documentation of the incidence and types of vascular toxicity and studies to help elucidate the pathogenesis and management of such toxicity are needed.

Tumor necrosis factor enhances eosinophil toxicity to Schistosoma mansoni larvae.

Abstract: Tumor necrosis factor (TNF) is a monocyte product that kills or inhibits the growth of certain tumor cells. Its cell source and physical characteristics suggest that it is similar to a monokine, eosinophil-cytotoxicity-enhancing factor (M-ECEF), that activates human eosinophil toxicity to Schistosoma mansoni larvae. The availability of recombinant human TNF allowed us to test this possibility. The data show that TNF has no direct effect on the parasites but enhances eosinophil toxicity to the parasites in a dose-dependent fashion. This effect is specific for eosinophils and not neutrophils. TNF and the eosinophil-specific activity of TNF are coeluted with M-ECEF in reversed-phase HPLC. Further, M-ECEF activity in HPLC fractions is reduced by treatment with rabbit anti-TNF antibody and protein A-Sepharose. This demonstrates physical similarity and at least partial immunological identity of TNF and a fraction of M-ECEF. Thus, TNF can enhance eosinophil function and may constitute an important immunological regulatory mechanism. This effect should be considered when TNF is applied clinically.

The relationship between aquatic toxicity QSARs and bioconcentration for some organic chemicals

Abstract: Aquatic toxicity testing is conducted largely by means of a single experimental protocol-the concentration-response toxicity test. This procedure has a number of well-known limitations resulting from the fact that the relationship between the waterborne toxicant concentration and the actual body toxicant concentration which is producing the observed biological response is unknown. Hence quantifying the influence of chemical potency, physical, chemical and biological factors and elapsed time on the outcome of toxicity tests is difficult. Interpretation, and even more significantly, predictability may be severely restricted. Using, and further quantifying, the links between octanol-water partition coefficients, bioconcentration and acute and chronic toxicity quantitative structure-activity relationships (QSARs) for narcotic organic chemicals has allowed the following conclusions to be made: (1) Establishing internal toxicant concentrations related to acute and chronic effects, as estimated in this paper, will allow the toxicological significance of body burdens of certain organic chemicals, both singly and in certain mixtures, to be determined. (2) Chemical potency, as determined in the exposed organism, appears to be essentially constant for each of the biological responses and organic chemical groups examined. (3) The acute and chronic QSARs discussed herein are all parallel, each having a slope of unity. (4) It appears, as a first approximation, that a one-compartment, first-order kinetics model could provide a quantitative means of studying aquatic toxicity test results, both retrospectively and prospectively. (5) Bioconcentration and toxicity kinetics appear to be similar, but the internal toxicant concentration endpoint is different, fixed for toxicity and variable for bioconcentration.

Glucocorticoid toxicity in the hippocampus. Temporal aspects of synergy with kainic acid.

Abstract: Excessive exposure to glucocorticoids can damage neurons of the hippocampus, the principal neural target tissue for the steroid. Glucocorticoids, which are broadly catabolic throughout the body, appear to damage the hippocampus by inducing a metabolic vulnerability in its neurons, impairing their capacity to survive varied neuropathologic challenges which would normally be sublethal. As such, a number of interventions which damage the hippocampus--infusion of an excitotoxin or of an antimetabolite or induction of global ischemia--have their toxicity enhanced in rats with high circulating corticosterone concentrations and attenuated in adrenalectomized animals. The present report examines the temporal parameters with which corticosterone modulates the toxicity of the excitotoxin kainic acid (KA). Rats adrenalectomized and maintained corticosterone-free for 1 week prior to and following microinfusion of KA had minimal volumes of hippocampal damage. Administration of 10 mg/day of corticosterone (which produces circulating concentrations in the upper physiological range for the majority of a day) for as little as 1 day prior to and following KA infusion significantly potentiated damage; increasing periods of exposure to corticosterone bracketing the infusion of the toxin progressively increased damage. Both exposure to corticosterone only during the period prior to KA infusion or only in the aftermath of infusion potentiated damage. Thus, glucocorticoids appear to compromise the capacity of hippocampal neurons to survive KA via both rapid effects (manifest within as little as 24 h) as well as through more persistent actions.

Safety and tolerance of recombinant interferon alfa-2a (Roferon-A) in cancer patients.

Abstract: Recombinant interferon alfa-2a (Roferon-A, Hoffmann-La Roche Inc., Nutley, NJ) has been evaluated in clinical trials of more than 1300 patients with a broad spectrum of oncologic disease. Patients with either solid tumors or hematologic malignancies were treated with daily or three-times-weekly intramuscular injections for induction periods ranging from 8 to 16 weeks. Doses ranged from 1 X 10(6) units to 124 X 10(6) units per injection. When administered in low daily doses (approximately 3 X 10(6) units), Roferon-A was well tolerated, and dose attenuation was rarely required. Change to three-times-weekly treatment regimen at the same dose was usually sufficient to control toxicity when it occurred in this group of low-dose patients. Those patients receiving higher doses frequently required dose attenuation to 50% of the starting dose to improve clinical tolerance. Virtually all patients treated with Roferon-A experienced some degree of acute toxicity manifested as fever, chills, myalgia, and/or headache. These reactions usually occurred with initial dosing and frequently improved spontaneously with continued administration of the drug. Acetaminophen pretreatment was generally useful in ameliorating these symptoms. Common adverse experiences occurring after repeated dosing included fatigue, anorexia, and weight loss. Serious adverse reactions including cardiovascular and neurologic toxicity have occurred infrequently, primarily at higher doses. Hematologic toxicity and elevations in liver function parameters were also observed, but rarely required dose attenuation. Adverse effects were usually reversible after dose reduction or discontinuation of therapy. Approximately 27% of all patients developed antibodies to rHuIFN-alpha 2A during treatment. No adverse clinical sequelae have been associated with antibody development to date.

Toxicity Testing Using Microorganisms

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Toxicities and complications of implanted pump hepatic arterial and intravenous floxuridine infusion.

Abstract: Toxicities and complications were prospectively analyzed in patients with liver metastases receiving hepatic intra-arterial (IA) and systemic intravenous (IV) floxuridine (FUDR) with the Infusaid (Intermedics-Infusaid Corp., Norwood, MA) implantable pump. Among 55 patients treated with IA FUDR (0.3–0.1 mg/kg/day × 14, every 28 days), elevations in liver enzyme values, not attributable to disease progression, developed in 96% of patients. Serious biliary toxicity occurred in 31 patients (56%). In 16, biliary sclerosis was documented radiographically and was diagnosed clinically in 15 additional patients. Ten patients were hospitalized for biliary toxicity, including five who required cholecystectomy for acalculous cholecystitis. Because of the high reported incidence of serious gastroduodenal toxicity after IA FUDR infusion, our procedure for hepatic arterial cannulation was designed to eliminate misperfusion of the stomach and duodenum with drug; none of our patients experienced FUDR-associated gastroduodenal ulceration or bleeding. Cyclic IV FUDR (0.05–0.15 mg/kg/day × 14, every 28 days) was administered to 31 participants of the Northern California Oncology Group trial (3L-82-1) of IV versus IA FUDR. Dose-limiting toxicity was diarrhea. Serious toxicities were: protracted diarrhea (three), dermatitis (two), tear duct stenosis (two), and stomatitis (two). Three patients were hospitalized for toxicity. No hematologic or biliary toxicity occurred. The optimal route for treatment of hepatic metastases with continuous FUDR infusion has not yet been established. Systemic IV infusion has low morbidity, but preliminary response data need to be substantiated in controlled clinical trials before there can be widespread clinical application. High response rates for IA infusion have been previously documented. Morbidity due to acalculous cholecystitis and gastroduodenal ulceration can now be avoided. Despite significant progress in characterization of hepatobiliary toxicity, it remains dose-limiting. Continuous IA FUDR infusion should remain under the aegis of dedicated treatment centers until standardized protocols with diminished toxicity are established.

Toxic effects of cyclosporine on the endocrine pancreas of Wistar rats.

Abstract: The widely used immunosuppressive drug cyclosporine exerts toxic effects on various parenchymal organs including the liver and kidney. This study was performed with the aim of testing whether cyclosporine also affects the endocrine pancreas. Daily cyclosporine doses of 50 mg/kg body weight over 3 weeks in rats enhanced the serum bilirubin and creatinine concentrations, led to light-microscopic destruction in the liver and kidneys, and resulted in the development of an impaired glucose tolerance--and, later on, of hyperglycemia. The pancreatic insulin content decreased to 33% of values observed in vehicle-treated controls, which can be ascribed to a 50% decrease of beta-cell volume and a slightly smaller reduction of islet insulin content. The reduction of the cyclosporine dose to 15 mg/kg body weight daily, which also reduced the popliteal lymph node weight gain after allogeneic stimulation, was not accompanied by serochemical or morphological alterations of livers or kidneys in the rats when treated for 3 weeks. However, the animals had already developed an impaired glucose tolerance, accompanied by a decrease in pancreatic insulin content (to 50% that of controls), a decrease of islet insulin content (to 70%) and a reduced pancreatic beta cell volume (to 72%). The findings let us conclude that pancreatic beta cells are sensitive to toxic effects of cyclosporine in vivo. We suggest that the measurement of glucose tolerance, as a sensitive parameter of a toxic cyclosporine action, should be included in the monitoring of grafted patients under cyclosporine treatment.

High-dose combination alkylating agents with autologous bone marrow support: a Phase 1 trial.

Abstract: Twenty-nine patients were treated with 31 courses of high-dose combination cyclophosphamide, cisplatin, and carmustine (BCNU) with and without melphalan with autologous bone marrow support. Toxicity was dose related. The maximum tolerated dose for cyclophosphamide, cisplatin, and BCNU in this combination in mg/m2 was 5,625, 165, and 600, respectively. Further dose escalation was precluded by the development of multiple organ toxicity, including venoocclusive disease, refractory thrombocytopenia, and hypertension. Melphalan added to the three-drug combination produced excessive renal and gastrointestinal toxicity. Objective tumor regression occurred in 21 of 25 evaluable cases. The results suggest that selected alkylating agents can be combined in full or nearly full doses before nonmyelosuppressive dose-limiting toxicity precludes further escalation.

Comparative Long-Term Study of the Toxicities of Free and Liposome-Associated Doxorubicin in Mice After Intravenous Administration

Abstract: The toxicities of free doxorubicin (F-DOX) and liposome-associated doxorubicin (L-DOX) were investigated in inbred BALB/c and outbred Sabra mice treated iv with 5, 7.5, and 10 mg doxorubicin (DOX)/kg body weight every 2 weeks up to 8 injections and observed for 6 months. Sonicated liposomes containing phosphatidylcholine, phosphatidylglycerol, and cholesterol were used. The lethal effect was reduced in mice treated with L-DOX as compared to mice treated with F-DOX. At a dose of 7.5 mg DOX/kg, 100% of mice receiving the L-DOX survived a cumulative dose of 60 mg/kg administered over 98 days, while 92% of mice receiving the F-DOX died. Two distinct patterns of death were observed: an acute phase type occurring early after injection of high doses of DOX and apparently related to gastrointestinal toxicity and a delayed phase type requiring a long latency after initial drug exposure and characterized by a complex pattern of abnormalities. Delivery of DOX by liposomes effectively protected against both types of lethal effects. Reduced toxicity of L-DOX resulted in reduced body and organ weight losses, reduced severity of pathologic changes, and fewer blood biochemical alterations. The pathological damage to the heart muscle found in mice treated with L-DOX was less severe than with F-DOX, and in some cases it was reversible. Nephrotoxicity was extremely frequent and severe among F-DOX-treated mice, while it was totally insignificant among L-DOX-treated mice. Hyperlipidemia, hypoglycemia, and glycogen-depleted hepatocytes were characteristic findings in mice treated with F-DOX. Altogether, the data obtained in this study indicate that liposomes significantly diminish the toxicity of DOX with the use of an intermittent schedule of chemotherapy. In addition to changes in tissue distribution as a mechanism of reduced toxicity, it is proposed that DOX associated with liposomal lipids interacts less efficiently than the free drug with target intracellular phospholipids.

Mechanisms of nitrosourea-induced beta-cell damage. Alterations in DNA.

Abstract: The initial step in streptozocin (STZ)-induced beta-cell toxicity has been hypothesized to be the alkylation of specific sites on DNA bases. The enzymatic removal of these lesions results in single-strand breaks that over-activate the nuclear enzyme poly(ADP-ribose) synthetase and critically deplete the cell of NAD. Our studies were performed to quantitatively evaluate the extent of DNA damage in beta-cells and correlate this damage with toxicity. Monolayer cultures of neonatal rat beta-cells were used to determine cytotoxicity and DNA damage after exposure to STZ or the aglycone N-methyl-N-nitrosourea (MNU). Toxicity in beta-cells was determined by correlating morphological alterations observed by phase-contrast microscopy with decrements in immunoreactive insulin release. The extent of DNA damage was determined by alterations in nucleoid density and quantitation of N7-methylguanine formation. Toxicity tests revealed that STZ and MNU were not toxic at equimolar concentrations. Streptozocin was toxic at 10(-3) M, whereas only mild toxicity was observed with MNU at 10(-2) M. Surprisingly, however, at equimolar concentrations the two drugs caused comparable DNA-strand breaks as evidenced by their ability to shift the nucleoid migration ratio in neutral sucrose gradients. Additionally, quantitation of N7-methylguanine formation after exposure to equimolar concentrations of the drugs demonstrated that the two alkylated DNA to the same extent. These findings suggest that factors in addition to the activation of poly(ADP-ribose) synthetase must be responsible for the toxicity seen with STZ, because MNU at a nonlethal concentration is capable of causing comparable DNA damage.

Heavy metal toxicity to fish and the influence of water hardness

Abstract: Toxicity tests with rainbow trout confirm that cadmium is less toxic in hard water (96 hr LC50=2.6 mg Cd/L) than in soft water (96 hr LC50=1.3 mg Cd/L). Water quality studies indicate that this is not due to a chemical reduction of available cadmium in hard water and no significant differences in cadmium uptake were detected between fish from the two levels of hardness. Possible explanations for the effect of hardness on heavy metal toxicity to fish are discussed.

Reproductive toxicity of acrylamide and related compounds in mice ― effects on fertility and sperm morphology

Abstract: Acrylamide and its three neurotoxic analogues, which are known to induce testicular damage in animals, were tested for reproductive toxicity in male and female mice and for the effect on germ cells in males, after subchronic treatment. After mating the treated males with untreated females, a decrease in fertility rate for all analogues except for N-hydroxymethylacrylamide, and an increase in the number of resorptions/dam for all test compounds were found. When untreated males were mated with treated females, an increase in the number of resorptions/dam was seen only after acrylamide dosing without any effect on the fertility rate. The reproductive toxicity appeared with only slight or no testicular atrophy, and without any apparent neurotoxicity after treatment with all test compounds. High doses of all test compounds produced both a decreased sperm count and an increase in abnormal sperm morphology.

Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora.

Abstract: The mechanism of toxicity from 5-fluorocytosine chemotherapy is unclear. However, recent evidence suggests that the generation of 5-fluorouracil by a host may play an important role in the development of this toxicity. Using an in vitro semicontinuous culture system to mimic the intestinal microflora, we examined the capacity of this complex microbial community to convert 5-fluorocytosine to 5-fluorouracil. The system was dosed initially and after 2 weeks of chronic exposure to 5-fluorocytosine with radiolabeled 5-fluorocytosine. No detectable production of 5-fluorouracil was observed up to 8 h after the acute dose; however, at 24 h and at all time points thereafter, increasing levels of 5-fluorouracil were detected for 4 days. The chronic dose resulted in an increased rate of 5-fluorouracil production without the 8-h lag time. These findings suggest that the enzyme or enzymes responsible for the deamination of 5-fluorocytosine to 5-fluorouracil by the intestinal microflora can be induced by chronic exposure to 5-fluorocytosine and that this conversion may provide a mechanism through which 5-fluorocytosine toxicity is manifested.

Short- and long-term effects of heavy metals on urease activity in soils

Abstract: The inhibitory effects of cadmium, chromium, copper, lead, nickel and zinc on urease activity of five different soils during two different periods were investigated, in order to obtain information on the change in heavy metal toxicity with time. The results are presented graphically as logistic dose-response curves. When the ecological dose range was used as a measure of toxicity this value decreased significantly only for copper in the sandy soil. Considering toxicity as the ecological dose-50% (ED50) value, toxicity tended to increase over 1 1/2 years for cadmium, copper and zinc. For nickel and lead, however, the toxicity stabilized in all soils, except in sand and clay. The average ED 50 value of zinc varied between 100 and 300 mg kg−1 and its toxicity was highest. It is emphasized that these data may help to set limits for the heavy-metal pollution of soils.

Central nervous system toxicity of fludarabine phosphate.

Abstract: Fourteen patients developed severe central nervous system (CNS) toxicity after receiving an investigational antitumor agent, fludarabine phosphate (FAMP). The CNS toxicity has the distinctive features of delayed onset and progressive clinical course. Visual deficits were the most common presenting symptom and developed eventually in most cases. Deterioration of mental status and progressive encephalopathy were also observed. The development of clinical CNS toxicity appears dose-related; thirteen of 36 patients (36.1%) who received FAMP at high doses (greater than or equal to 96 mg/m2/day for 5-7 days per course) developed neurotoxicity, while only one of 443 patients (0.2%) who received the drug at low doses (less than or equal to 125 mg/m2 per course) developed similar toxicity. Although the precise mechanism responsible for this toxicity is yet unknown, progressive demyelination appears to be the responsible process. Extensive review of the clinical data failed to identify factors which might contribute to the development of CNS toxicity. Patients on trials of FAMP should be meticulously monitored for the possible development of neurotoxicity.

Gallium nitrate: the second metal with clinical activity

Abstract: Gallium nitrate is the anhydrate salt of the naturally occurring heavy metal. It has demonstrated antitumor activity in a variety of murine tumor models, including Walker carcinosarcoma 256, fibrosarcoma M-89, leukemia K-1964, adenocarcinoma 755, mammary carcinoma YMC, reticulum cell sarcoma A-RCS, lymphoma P1798, and osteosarcoma 124F. Preclinical studies performed in rats, rabbits, dogs, and monkeys showed the dose-limiting toxicity to be renal. The hepatic, pulmonary, gastrointestinal, hematologic, and integumentary systems were also involved. The major route of elimination is the kidneys, with 35%-71% of the infused dose excreted within 24 hours. Three phase I studies suggested the following phase II doses: 700-750 mg/m2 by short infusion, once every 2-3 weeks; 300 mg/m2/day by short infusion for 3 consecutive days, to be repeated every 2 weeks; and 300 mg/m2/day by continuous infusion for 7 consecutive days, to be repeated every 3-5 weeks. The major organ toxicity reported was renal; however, this can be adequately controlled either by hydration and osmotic diuresis or by use of continuous schedule. (Either maneuver appears to allow delivery of the recommended phase II dose with a less than 30% risk of change in serum creatinine.) In limited phase II evaluation, the drug has shown antitumor activity in patients with either refractory lymphomas or small cell lung carcinoma, with total objective response rates of 28% and 11%, respectively. In addition, it has been effective in the treatment of patients with cancer-related hypercalcemia by having an inhibitory effect on calcium reabsorption from bone. Single-agent phase II studies are planned in all major tumor types. Some are already ongoing in patients with genitourinary malignancies (renal, bladder, prostate, testicular), small cell lung carcinoma, and multiple myeloma. Metabolic studies are in progress at Memorial Sloan-Kettering Cancer Center to further elucidate the mechanism or mechanisms of the hypocalcemic effects.

Azathioprine toxicity in neuromuscular disease.

Abstract: Azathioprine toxicity was examined in 64 consecutively treated patients with various neuromuscular diseases. Reversible leukopenia was seen in 14 patients (22%). Hepatotoxicity developed in six patients (9%), and a systemic reaction characterized by fever, abdominal pain, nausea, vomiting, and anorexia occurred in eight patients (12%). Toxic effects limited the dose of azathioprine in 27 patients (42%) and led to discontinuation of therapy in 13 (20%). Macrocytosis developed in 20% of patients, but did not require an adjustment in the dose. Two patients received allopurinol and azathioprine; both developed reversible leukopenia and macrocytosis. Patients with hematologic and hepatic toxicity, but not those with systemic toxicity, successfully tolerated retreatment with azathioprine. Toxicity was delayed as long as 56 weeks after starting azathioprine in some patients.

Pharmacology and toxicity of high-dose cytarabine by 72-hour continuous infusion

Abstract: Most studies using high-dose cytarabine (ara-c) for the therapy of acute leukemia have employed intermittent short infusions. In this study, we have evaluated the pharmacology and toxicity of high-dose ara-c by 72-hour continuous infusion. Plasma ara-c concentrations varied from 3.6 microM at the starting dose of 4 g/m2/72 hours to 22.6 microM at 18 g. Plasma clearance appeared to decrease progressively at doses greater than 10 g, suggesting that the route of elimination was saturable. CSF ara-c concentrations ranged from 1.2 microM at 4 g to 4.1 microM at 18 g; the ratio of CSF to plasma ara-c decreased progressively from 0.33 at 4 g to 0.18 at 18 g. The toxic effects were significant and included myelosuppression, nausea, and vomiting in all patients. No single dose-limiting toxicity was identified. Further dose escalation was precluded by combined organ system effects, which included hepatic, pulmonary, renal, and gastrointestinal toxic effects. Attempts to incorporate a 72-hour infusion of ara-c into a combination chemotherapy regimen should proceed cautiously with a starting dose of 6 g/m2/72 hours.

Bilirubin and Brain Toxicity

Abstract: More than a century has passed since Hervieux first described yellow staining of the basal ganglia in association with neonatal jaundice (1). The term kernicterus was, however, first used by Schmorl in 1904 to describe the post-mortem finding of yellow staining of the basal ganglia in term infants whose cause of death was probably feto-maternal iso-immunization (2). This term has since been used to describe both the acute, often fatal condition in the newborn with substantial elevation of serum bilirubin levels, seizures, opisthotonus, and bleeding tendency, as well as the neurologic sequelae in survivors, consisting of choreoathetosis, asymmetric spasticity, paresis of upward gaze, and neurogenic hearing loss (3-7). Yellow staining of the brain has, in recent years, also been observed in infants dying without the clinical symptoms of kernicterus, and in whom only moderately elevated serum bilirubin values had been noted (8-10). Bilirubin has, in addition, been implicated in damage to cognitive functions (11, 12), but consensus is lacking regarding permanent damage to such functions (13, 14). The terms kernicterus and bilirubin encephalopathy have often been used interchangably, and without any clear definition of the terms. We suggest that bilirubin encephalopathy should be used in a broader sense so as to include all conditions in which bilirubin is known, or thought to be, the cause of brain toxicity. The term kernicterus would be reserved for cases exhibiting the classical acute symptoms described above, or surviving with the typical neurologic sequelae. During the past thirty years, considerable research has been carried out regarding the causes of hyperbilirubinemia and the mechanisms underlying bilirubin toxicity. Despite these efforts the basic mechanisms remain elusive. This research has been concentrated on three main areas. Firstly, the binding of bilirubin to albumin has been investigated in detail. Secondly, a number of studies have addressed the toxicity of bilirubin both in nervous tissue, and in other cell and organ systems. Finally, the mode of entry of bilirubin into the central nervous system has been examined.