Showing papers on "Toxicity published in 1992"

Gene transfer in vivo with DNA-liposome complexes: safety and acute toxicity in mice.

Abstract: DNA can be introduced into a variety of cell types after formation of liposomal complexes with cationic lipids. In this report, conditions have been established to optimize the production of DNA-liposome complexes that efficiently transfect cells. The safety and toxicity of this method of gene delivery have been assessed after in vivo administration, either by intravenous or direct intratumor injection. Nine to eleven days after intravenous injection, DNA was found primarily in heart and lung tissue by PCR analysis. No abnormalities were evident from histologic examination of tissue, examination of tissue-specific serum enzymes, routine biochemical parameters, or electrocardiographic monitoring. DNA-liposome complexes can therefore be used for the delivery of recombinant genes in vivo with minimal toxicity.

Phase I trial of intraperitoneal taxol: a Gynecoloic Oncology Group study.

Abstract: PURPOSETo evaluate the safety and pharmacology of the intraperitoneal (IP) administration of the antineoplastic agent taxol.PATIENTS AND METHODSTwenty-five pretreated patients who were entered onto a phase I clinical trial; 24 had advanced ovarian cancer. Patients were treated with taxol administered IP in 2 L of normal saline every 3 to 4 weeks. The starting dose was 25 mg/m2. There were no intrapatient dose escalations.RESULTSThe dose-limiting toxicity was the development of severe abdominal pain at taxol doses more than 175 mg/m2. Moderate leukopenia (WBC count less than 2,000/mm3) was observed at IP doses of greater than or equal to 175 mg/m2. The exposure of the peritoneal cavity (peak levels and area under the time-versus-concentration curve [AUC]) to taxol after IP delivery exceeded that of the plasma by approximately 1,000-fold. However, concentrations of the agent previously shown to produce cytotoxicity in experimental systems were demonstrated in the systemic compartment after regional delivery...

Evaluation of the retinal toxicity and pharmacokinetics of dexamethasone after intravitreal injection.

Abstract: • The intravitreal injection of steroids may be potentially useful in the treatment of endophthalmitis and other ocular inflammatory diseases. The retinal toxicity and intraocular turnover of aqueous solutions of dexamethasone sodium phosphate in doses ranging from 440 to 4000 μg were evaluated in the rabbit; evaluation was also performed for a 0.1-mL injection of a commercially available preparation (dexamethasone phosphate [Decadron] injection, 4 mg/mL). After the 440-μg dose, a transient increase in staining of the Muller cells was observed, which normalized after 2 days. Progressively higher doses resulted in an increasing spectrum of disorganization in Muller and other retinal cells. The half-life of the intravitreally injected drug was 3.48 hours. These findings suggest a primary interference in Muller cell function, possibly through dexamethasoneinduced alterations in retinal glutamate or glucose metabolism.

Extracellular superoxide dismutase, nitric oxide, and central nervous system O2 toxicity.

Abstract: Although reactive O2 species appear to participate in central nervous system (CNS) O2 toxicity, the exact roles of different reactive O2 species are undetermined To study the contribution of extracellular superoxide anion (O2-) to CNS O2 toxicity we constructed transgenic mice overexpressing human extracellular superoxide dismutase (ECSOD; superoxide:superoxide oxidoreductase, EC 11511) in the brain Remarkably, when exposed to 6 atm (1 atm = 1013 kPA) of hyperbaric oxygen for 25 min, transgenic mice demonstrated higher mortality (83%) than nontransgenic litter-mates (33%; P < 0017) Pretreatment with diethyldithiocarbamate, which inhibits both ECSOD and Cu/Zn superoxide dismutase (Cu/Zn SOD) activity, increased resistance to CNS O2 toxicity, in terms of both survival (100% in transgenics and 93% in nontransgenics) and resistance to seizures (4-fold increase in seizure latency in both transgenic and nontransgenic mice; P < 005) Thus, O2- apparently protects against CNS O2 toxicity We hypothesized that O2- decreased toxicity by inactivating nitric oxide (NO) To test this, we inhibited NO synthase (EC 11423) with N omega-nitro-L-arginine to determine whether NO contributes to enhanced CNS O2 toxicity in transgenic mice N omega-nitro-L-arginine protected both transgenic and nontransgenic mice against CNS O2 toxicity (100% survival and a 4-fold delay in time to first seizure; P < 005), as well as abolishing the difference in sensitivity to CNS O2 toxicity between transgenic and nontransgenic mice These results implicate NO as an important mediator in CNS O2 toxicity and suggest that ECSOD increases CNS O2 toxicity by inhibiting O2(-)-mediated inactivation of NO

Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials.

Abstract: Objective Preferred drugs for rheumatoid arthritis (RA) should be those that have maximal efficacy with the least toxicity. We evaluated the efficacy and toxicity tradeoffs for drugs frequently used in the treatment of RA. Methods We updated 2 metaanalyses of published clinical trials, by adding trials published through 1990 and trials of azathioprine (AZA). We tested 3 different definitions of efficacy, each plotted against 3 different toxicity measures, for antimalarial drugs, methotrexate (MTX), auranofin, injectable gold, D-penicillamine, sulfasalazine (SSZ), AZA, and placebo. Efficacy measures included composite efficacy (a combination of joint count, grip strength, and erythrocyte sedimentation rate), tender joint count alone, and a measure based on how many patients dropped out due to inefficacy. Toxicity measures were the proportion dropping out due to toxicity, the same dropouts with side effects weighted for severity using a modification of a published toxicity index, and the proportion with severe toxicities (defined as a score of at least 7 of 10 on the toxicity index). The latter were usually organ toxicities (e.g., cytopenias and renal involvement). Results All 9 efficacy/toxicity tradeoff plots suggested that MTX and antimalarial drugs had the highest efficacy relative to toxicity. MTX scored among the most efficacious of the drugs and, of these, had the least toxicity. Antimalarial drugs, though showing only moderate efficacy, had the lowest toxicity rate of all the drugs. SSZ scored close to MTX but was, in general, slightly more toxic. Conclusion In the short-term context of clinical trials, antimalarial drugs and MTX have the best efficacy/toxicity tradeoffs and may, therefore, be the preferred drugs.

Hepatic veno-occlusive disease--liver toxicity syndrome after bone marrow transplantation.

Abstract: Hepatic veno-occlusive disease (VOD) is the most common life threatening complication of preparative-regimen-related toxicity for bone marrow transplantation (BMT). The frequency of VOD varies greatly, from 1-2% in centers performing pediatric BMT for thalassemia to over 50% in some centers doing BMT for hematologic malignancy. The term liver toxicity syndrome is a clinicopathologic definition which encompasses the range of histopathology within the hepatic venules and surrounding sinusoids and hepatocytes. These histologic abnormalities are statistically associated with a clinical syndrome of jaundice, ascites, and painful hepatomegaly developing early post-transplant. Newer modalities which may aid accuracy are transvenous liver biopsy along with determination of the gradient between the wedged and free hepatic venous pressures, and measurement of blood coagulatory components, particularly protein C levels. Analyses of clinical risk factors for VOD are confounded by lack of a clear hierarchy of risk when comparing heterogeneous patient populations, the methods of patient selection and choice of controls, and whether analysis is univariate or multivariate. Prospective multivariate analyses indicate that the risk of developing liver toxicity is independently correlated with intensity of conditioning therapy, pre-transplant viral hepatitis, use of antimicrobial therapy with acyclovir, amphotericin, or vancomycin (reflecting fever), and mismatched or unrelated allogeneic marrow grafts. These analyses plus morphologic and biochemical data support the hypothesis that VOD is caused by cytoreductive injury to hepatocytes and endothelium in zone three of the liver acinus, and in turn strongly influenced by factors which induce the release of tumor necrosis factor-alpha (TNF-alpha) leading to enhancement or activation of coagulation with obstruction of hepatic sinusoids and venules. Pharmacokinetic measurements of busulfan as a conditioning agent demonstrate a correlation between high steady-state busulfan levels and liver toxicity and suggest that safer and/or more efficacious plasma busulfan concentrations can be obtained by making individual dose adjustments and by changing the schedule of administration. Conservative therapy of severe VOD, including the use of peritoneal-pleural shunts for relief of ascites, is unsatisfactory. Results from prophylactic studies aimed at preventing VOD by heparin or prostaglandin E1 indicate considerable differences with toxicity and efficacy. Use of the TNF-alpha blocker, pentoxifylline, has also shown promise in lessening VOD. A statistical model which predicts patients likely to have an unfavorable outcome from VOD has been used to select premorbid patients for promising new therapeutic modalities, such as recombinant tissue plasminogen activator.

Radiotherapy versus radiotherapy enhanced by cisplatin in stage III non-small cell lung cancer

Abstract: Between January 1987 and June 1991, 173 patients with inoperable non-small cell lung cancer, Stage III, were entered into a randomized trial comparing radiotherapy only (RT) (45 Gy/15 fractions/3 weeks) (arm A) versus RT and a daily low dose of cDDP (6 mg/m2) (arm B). An overall response rate of 58.9% was observed in arm A and 50.6% in arm B, respectively. No differences in the pattern of relapse were noted between the two treatment groups. Median time to progression was 10.6 months for arm A and 14.2 months for arm B. Median survivals were 10.3 months and 9.97 months, respectively. Toxicity was acceptable and no treatment-related death occurred in either treatment schedule. In this study no significant advantage of the combined treatment over radiation therapy only was found. The encouraging results achieved in some trials together with the intractability of the disease suggest that further efforts should be made to optimize clinical trial protocols, perhaps by reviewing the radiobiological and pharmacological basis of the combined treatment.

Selenium in the treatment of heavy metal poisoning and chemical carcinogenesis.

Abstract: Selenium (Se) has been shown to counteract the toxicity of heavy metals such as cadmium, inorganic mercury, methylmercury, thallium and to a limited extent silver. Although not as effective as Se, vitamin E significantly alters methylmercury toxicity and is more effective than Se against silver toxicity. Vitamin E is very effective against lead toxicity but Se has little effect. The presumed protective effect of Se against cadmium and mercury toxicity is through the diversion in their binding from low molecular weight proteins to higher molecular weight ones. Se appears effective in counteracting the chemical carcinogens (3-methyl-4-dimethyl-aminoazobenzene, 2-acetylaminofluorene, diethylnitrosamine, aflatoxin, 7,12-dimethylben (a) anthracene, benzopyrene and 3-methylcholanthrene) used to induce skin, liver and mammary tumors, but much less effective against those (dimethylhydrazine, azoxymethane, methylazoxymethanol, bis (2-oxopropyl) nitrosamine, benzopyrene, 1 methyl-1-nitrosourea and n-methyl-n-nitro-nitrosoguanidine) used to produce tumors in the colon, lungs, trachea and pancreas in laboratory animals. In contrast, Se many even increase pancreatic carcinomas in animals treated with bis (2-oxopropyl) nitrosamine. The health implications in humans of Se and heavy metal toxicities and in cancer are discussed.

The basis of toxicity testing

Abstract: Introduction Preliminary Considerations Introduction The Agent Being Tested The Vehicle Routes of Administration Species Pharmacokinetics/Toxicokinetics Biotransformation Diet Endpoints of Toxicity Animal Numbers Acute Toxicity Studies Purpose and Objectives Study Design Interpretation of Data Utility of the LD50 Studies Dermal Toxicity Studies Ocular Toxicity Studies Utility of Alternative Studies Conclusions Subchronic and Chronic Studies Introduction Experimental Design Evaluation of Results Carcinogenicity Studies Reproductive Toxicology Introduction Male Reproductive Toxicity Female Reproductive Toxicity Preimplantation Studies Teratogenicity Embryo Culture Harmonization Screening Tests Mutagenesis Carcinogenesis Introduction Mutagenesis Mutagenicity Testing with Prokaryotic Cell Systems Mutagenicity Testing with Eukaryotic Cell Systems In Vitro Mutagenicity Testing with Eukaryotic Cells In Vivo The Impossibility A Test for All Mutagens Carcinogenicity Testing Strategies for Limited Bioassays

Growth factors and vitamin E modify neuronal glutamate toxicity

Abstract: The sympathetic nerve cell line PC-12 is killed by glutamate in a concentration-dependent manner. Although glycine and the deletion of magnesium weakly potentiate glutamate toxicity and PC-12 cells express N-methyl-D-aspartate-receptor mRNA, most toxicity is mediated by means of a mechanism independent of typical N-methyl-D-aspartate receptors. Glutamate toxicity is, however, greatly enhanced by prior exposure to nerve growth factor or basic fibroblast growth factor. Glutamate killing is blocked by epidermal growth factor and, to a lesser extent, by vitamin E. These observations show that synergistic interactions between growth factors and excitotoxic amino acids may play critical roles in the developing nervous system and that antioxidants attenuate this toxicity.

Effects of the aggregation state of amphotericin B on its toxicity to mice.

Abstract: Amphotericin B (AmB) is a very effective antifungal agent for most systemic fungal infections. However, the relatively high toxicity of this drug imposes limits on its clinical usefulness. Most of the current work in this field is devoted to the search for less-toxic formulations of the drug. Here we describe the effects of three surfactants, one anionic and the other two nonionic, on the aggregation state of AmB in solutions which were injected intravenously into mice. The degree of aggregation of AmB was monitored spectroscopically and by light scattering. The toxicity was expressed as percentage of survivors. These results were compared with those obtained with doses of AmB the same as those present in a commercial formulation of AmB, Fungizone. Two surfactants, lauryl sucrose and sodium deoxycholate, used at concentrations which induced monomerization of AmB, substantially decreased the acute toxicity of AmB to mice. Conversely, the third surfactant, Tween 80, showed a synergistic potentiation of the toxicity of the antibiotic. A good correlation was found between the in vivo toxicity and the aggregation state of AmB in injected solutions. Solutions in which AmB was almost entirely monomeric were half as toxic after 24 h and about six times less toxic after 1 week than the corresponding solutions of Fungizone.

The use of methylphenidate in patients with incident cancer pain receiving regular opiates. A preliminary report.

Abstract: In this open, uncontrolled trial, 15 patients with severe incident cancer pain receiving regular opiates were administered 10 mg oral methylphenidate (MP) at 08.00 h and 15 mg at 12.00 h in order to antagonize opiate-induced sedation. The daily dose of opiate was increased by 30% 24 h after starting MP, followed by a 10% increase twice a day until maximal tolerated dose. In 14 evaluable patients, pain (VAS 0-100 mm), sedation (VAS), and mean equivalent daily dose (MEDD) of morphine were 55 +/- 17, 65 +/- 18 and 248 +/- 150 48 h before MP, versus 38 +/- 12 (P less than 0.01), 42 +/- 12 (P less than 0.01), and 405 +/- 130 (P less than 0.01) 48 h after MP, respectively. After 48 h of treatment, 12 of 14 patients felt better on MP, 2 of 12 patients felt no difference, and no patients felt worse (P less than 0.05). We conclude that the addition of MP allowed for an increase in the MEDD of morphine and increased pain control. Controlled double-blind trials should be performed.

CPT-11 in combination with cisplatin for advanced non-small-cell lung cancer.

Abstract: PURPOSEThe purpose of this study was to determine the maximum-tolerated dose and the dose-limiting toxicities of CPT-11, a new derivative of camptothecin, in combination with a fixed dose of cisplatin in patients with non-small-cell lung cancer (NSCLC).PATIENTS AND METHODSTwenty-seven previously untreated patients with stage IIIB or IV NSCLC were assessable for toxicity, and 26 were assessable for response. The initial dose of CPT-11 was 30 mg/m2 given as a 90-minute intravenous (IV) infusion on days 1, 8, and 15 in combination with cisplatin (80 mg/m2 IV on day 1) given every 4 weeks. The dose of CPT-11 was escalated in increments of 10 mg/m2 until severe or life-threatening toxic effects were observed.RESULTSSignificant toxicity was infrequent up to 60 mg/m2 of CPT-11. The maximum-tolerated toxicity was reached at a dose of 70 mg/m2. Three of six patients either had leukocyte count nadirs of less than 2,000/microL or experienced grade 4 diarrhea during the first cycle of therapy at 70 mg/m2. The major t...

Recognition and management of digitalis toxicity

Abstract: The most important step in the management of toxicity due to any of the cardiac glycosides is its recognition. Despite the development of an accurate clinical assay for serum levels of digoxin greater than 20 years ago, digitalis toxicity remains common and difficult to confirm, even if suspected, due primarily to 2 factors. First, the signs and symptoms of digitalis toxicity, most commonly an abnormal electrocardiogram showing ventricular or atrial arrhythmias, with or without some degree of concurrent atrioventricular block, often also occur in patients with congestive heart failure (CHF) and underlying coronary atherosclerosis who are not receiving a cardiac glycoside. Second, due to digoxin's narrow therapeutic ratio, the marked degree of variability in the sensitivity of individual patients to its toxic effects, and the common problem of obtaining blood samples inappropriately during the early distribution phase following dosing, a serum digoxin concentration often does not serve as a reliable indicator of toxicity. Despite these difficulties in diagnosis, the management of digoxin toxicity has been made much more effective with the widespread availability of F(ab) fragments of anti-digoxin antibodies. This drug provides the clinician with a rapidly acting, safe antidote for all commonly used digitalis preparations. Conventional therapy for digoxin toxicity remains the maintenance of serum potassium levels greater than or equal to 4 mEq/liter, reversal of decompensated CHF or overt myocardial ischemia, attention to serum magnesium levels and the patient's acid-base status, appropriate antiarrhythmics in the event of ventricular arrhythmias, and a temporary pacemaker for high-grade atrioventricular block. Nevertheless, the high specificity and documented safety of the antibody preparation provides a needed safety net for the continuing use of cardiac glycosides as first-line inotropic agents in the modern therapy of chronic CHF.

Comparative study of doxorubicin, mitoxantrone, and epirubicin in combination with ICRF-187 (ADR-529) in a chronic cardiotoxicity animal model.

Abstract: In this study doxorubicin, epirubicin, and mitoxantrone were compared for their cardiotoxic potential in a chronic mouse model in an effort to identify and compare their mechanism(s) of toxicity. In addition, the cardioprotective ability of ICRF-187 [(±)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] with each anticancer drug was evaluated in this model. The antioxidant capacity (superoxide dismutase, reduced glutathione, catalase, and glutathione peroxidase) was assessed following drug treatment. Five-week-old BALB/c mice received weekly i.p. injections of each drug or the drug and ICRF-187 over a 3-month period. ICRF-187 was administered 30 min prior to the anticancer drug. The hearts were examined by electron and light microscopy to assess subcellular changes, and the cardiac and hepatic antioxidant levels were measured concurrently. Chronic treatment with these drugs or each combined with ICRF-187 did not change the antioxidant levels relative to the control values. However, all three drugs caused cardiac damage during chronic exposure. Both epirubicin and mitoxantrone caused less severe damage than doxorubicin, and epirubicin was the least cardiotoxic of the three. ICRF-187 was cardioprotective for epirubicin and doxorubicin but not for mitoxantrone. These results suggest epirubicin acts by a mechanism similar to that of doxorubicin that is probably mediated by oxygen-free radicals, while mitoxantrone acts by a different mechanism to cause cardiotoxicity.

Isolated limb perfusion for melanoma: effectiveness and toxicity of cisplatin compared with that of melphalan and other drugs.

Abstract: In patients with advanced or recurrent melanoma confined to a limb, hyperthermic isolated limb perfusion (ILP) with melphalan produces complete remission in 35–40% of cases and partial remission in a further 35–40%. Mild or moderate limb toxicity is usual, but severe toxic reactions in the limb sometimes occur. After preliminary reports suggested that cisplatin administered by ILP was even more effective than melphalan yet less toxic, a study was undertaken to further assess the value of hyperthermic ILP with cisplatin in the management of limb melanoma. Ten patients were treated. The procedure failed to eliminate melanoma in the limb in 5 of the 6 who received therapeutic ILPs for recurrent disease, and recurrence developed in 2 of the 4 patients who received prophylactic ILPs. Toxicity in the perfused limbs was unacceptably high, with 2 of the 10 patients having severe reactions, one necessitating amputation. We conclude from the results of this study and from a review of literature that neither cisplatin nor any other drug or drug combination so far used for ILP in melanoma patients achieves results which are clearly superior to those achieved with melphalan. Studies are currently in progress investigating double perfusion protocols, new strategies with regional hyperthermia, and the administration by ILP of biological response modifiers such as tumor necrosis factor and interferon. However, for the present, hyperthermic ILP with melphalan remains the treatment most likely to be successful in eliminating or controlling advanced or recurrent melanoma in a limb.

Role of the Gastrointestinal Mucosa and Microflora in the Bioactivation of Dietary and Environmental Mutagens or Carcinogens

Abstract: (1992). Role of the Gastrointestinal Mucosa and Microflora in the Bioactivation of Dietary and Environmental Mutagens or Carcinogens. Drug Metabolism Reviews: Vol. 24, No. 4, pp. 425-492.

Pediatric craniopharyngiomas: Long term results of combined treatment with surgery and radiation

Abstract: From 1961 to 1981, 19 pediatric patients with craniopharyngiomas were treated with external beam radiation post surgery. Twelve underwent primary treatment while seven were treated for recurrence. Median follow-up is 21 years (range 8-28 years) with an overall 20-year survival of 62%. Twenty-six percent (5/19) developed disease recurrence following radiation. Of the multiple patient and treatment parameters analyzed, only initial disease status (i.e., primary vs recurrence), surgical extent, radiation dose, and treatment prior to routine use of CT scans (1961-1974) appeared to have major influence on patient outcome. The 20-year survival for those treated for primary disease was 78% versus 25% for those treated for recurrence. Fifty percent (3/6) of patients receiving tumor doses of 5400 cGy. Four of the five recurrences occurred in patients treated during the pre-CT era. Long term effects of treatment were analyzed. Surgical morbidity correlated strongly with extent of surgery. All patients who underwent total resection developed surgical sequelae. Radiation morbidity correlated strongly with radiation dose. The incidence of vascular or neurologic complications attributable to radiation were minimal, occurring in only two patients. Both received doses higher than that given with modern therapy. Long-term results from this series are better than those reported with surgery alone. Use of modern surgical and radiation equipment/technique along with CT/MRI imaging should yield improved treatment results both in terms of lower recurrence and lower toxicity rates.