Does the order of second-line treatment in rheumatoid arthritis matter?

In a prospective study 88 patients, with rheumatoid arthritis who had stopped taking gold, penicillamine, or levamisole were randomly allocated to one of the alternative drugs and followed up for a minimum of one year. Concurrent studies of the effects of gold, penicillamine, and levamisole prescribed in 123 patients as the first second-line drug were used for comparison. No difference in toxicity or efficacy between primary and secondary use of gold or penicillamine was identified. Variation in the toxicity of levamisole could in part be accounted for by changes in the dose regimen over the four years of study. The length of the treatment-free interval between drugs did not influence subsequent development of toxicity. These results suggest that an adverse reaction to one of the three second-line drugs studied should not prejudice the selection of another.     

Adverse reactions to D-penicillamine after gold toxicity.

The incidence of adverse reactions to D-penicillamine in 155 patients with rheumatoid arthritis was analysed and compared with their history of adverse reactions to gold. Out of 125 patients who took only D-penicillamine, 45 developed side effects from the drug, whereas of 27 patients with a history of gold toxicity, 18 also reacted adversely to D-penicillamine. All patients who took D-penicillamine within six months after an adverse reaction to gold developed side effects from D-penicillamine. Fourteen patients developed similar adverse reactions to D-penicillamine and gold, and the interval between treatments in this group was significantly shorter (p less than 0.01) than in those who developed either differing adverse reactions to both drugs or no reaction to D-penicillamine after treatment with gold. An interval exceeding six months between treatment with gold and treatment with D-penicillamine in patients who have developed adverse reactions to gold apparently reduces the risk of adverse reactions to D-penicillamine.     

Chronic cardiac toxicity after inhalation of 1,1,1-trichloroethane.

Two patients showed evidence of chronic cardiac toxicity after repeated exposure to 1,1,1-trichloroethane. In both cases there was circumstantial evidence of a deterioration after routine anaesthetic use of the related compound halothane. An adolescent boy who sniffed trichloroethane presented with multiple ventricular arrhythmias during tonsillectomy. Follow up showed mild chronic left ventricular impairment. A 54 year old man had repeated industrial exposure to trichloroethane and deteriorated from mild stable cardiac failure to end stage cardiac failure after halothane anaesthesia for herniorrhaphy. Chronic cardiac toxicity is a previously unreported feature of this type of solvent exposure. Related compounds such as halothane may have a toxic interaction after exposure to trichloroethane.     

Myelotoxicity of gold.

Of 55 patients who developed blood dyscrasias attributable to gold treatment 15 with bone marrow hypoplasia died. A few of the dyscrasias, occurring in patients who had taken a low total dose of sodium aurothiomalate, may have resulted from immune hypersensitivity, but most, occurring in patients who had taken a higher total dose, were due to cumulative toxicity. All patients receiving gold treatment should undergo frequent blood counts. Any pronounced or continuing fall in the counts is a warning of toxicity, and gold treatment should be stopped. Treatment should be resumed only with caution, and in some patients already in remission lower doses may be just as effective in controlling the disease.     

Combination Chemotherapy in Generalized Hodgkin's Disease

Fifty-two patients with generalized Hodgkin''s disease were treated with a combination of mustine hydrochloride, vinblastine, procarbazine, and prednisolone. Complete remissions were obtained initially in six out of seven patients (86%) who had previously received no treatment, in 15 out of 19 (79%) who had had only radiotherapy in the past, and in 9 out of 26 (35%) who had previously been given chemotherapy with or without radiotherapy. Of these 30 patients in whom a complete remission was obtained 22 have been free of any symptoms or signs of disease for periods ranging from 4 to 22 months. The response to treatment was rapid, and toxicity was not a major problem, except in those who had previously been treated with cytotoxic drugs used continuously and not in courses. A comparative trial of radiotherapy and combination therapy in the treatment of Stage III Hodgkin''s disease is strongly recommended.     

Prospective Study of Ampicillin Rash

A multicentre prospective study of 933 patients being treated with ampicillin showed a rash incidence of 7·3%. The rash was commonest in women and patients suffering from viral infections. Most rashes were maculopapular and were not associated with features of true penicillin allergy. We conclude that the development of a maculopapular rash during or after treatment with ampicillin is not in itself a contraindication to future treatment with the penicillins.     

The effect of human immunodeficiency virus-1 protease inhibitors on the toxicity of a variety of cells

Protease inhibitors in combination with other antiretroviral drugs have been shown to be efficacious in treating human immunodeficiency virus-1 (HIV-1) infection. The side effects of such a treatment usually involve perturbations of fat metabolism and insulin responsiveness. This has led to a number of studies on the adverse effects of these drugs in vitro. The concentrations of various protease inhibitors used in many of these studies were >20 microM. Although some investigators did address the toxicity of protease inhibitors, no overall effort was made to examine this effect during differentiation of fat or muscle. In this study, we assessed the toxicity of HIV-1 protease inhibitors over a range of concentrations (i.e., 0 to 100 microM) in nondifferentiating (e.g., human fibroblasts, 3T3-L1 preadipocytes, and L6 myoblasts) and differentiated cells (e.g., L6 myotubes). The most toxic protease inhibitor in all cell types was Saquinavir (sqv), whereas the least toxic protease inhibitor was Indinavir (idv). Ritonavir (rtv) and Amprenavir (apv) were more toxic than idv but not quite as toxic as sqv. In 3T3-L1 preadipocytes, treatment with sqv, rtv, and apv resulted in toxicity, whereas idv was not toxic even at the highest concentration used. Indinavir was not toxic to L6 myoblasts or L6 myotubes; however, sqv, rtv, and apv caused toxicity in L6 myoblasts. Saquinavir decreased L6 myotube viability in a dose-dependent manner. Human immunodeficiency virus-1 protease inhibitors were shown to be toxic in a variety of cell types. These effects on human fibroblasts and muscle cells have not been reported previously.     

Iron toxicity and its possible association with treatment of Cancer: Lessons from hemoglobinopathies and rare,transfusion-dependent anemias

Exposure to elevated levels of iron causes tissue damage and organ failure, and increases the risk of cancer. The toxicity of iron is mediated through generation of oxidants. There is also solid evidence indicating that oxidant stress plays a significant role in a variety of human disease states, including malignant transformation. Iron toxicity is the main focus when managing thalassemia. However, the short- and long-term toxicities of iron have not been extensively considered in children and adults treated for malignancy, and only recently have begun to draw oncologists’ attention. The treatment of malignancy can markedly increase exposure of patients to elevated toxic iron species without the need for excess iron input from transfusion. This under-recognized exposure likely enhances organ toxicity and may contribute to long-term development of secondary malignancy and organ failure. This review discusses the current understanding of iron metabolism, the mechanisms of production of toxic free iron species in humans, and the relation of the clinical marker, transferrin saturation (TS), to the presence of toxic free iron. We will present epidemiological data showing that high TS is associated with poor outcomes and development of cancer, and that lowering free iron may improve outcomes. Finally, we will discuss the possible relation between some late complications seen in survivors of cancer and those due to iron toxicity.     

Cardiac toxicity of lung cancer radiotherapy

Radical radiotherapy of lung cancer with dose escalation has been associated with increased tumor control. However, these attempts to continually improve local control through dose escalation, have met mixed results culminating in the findings of the RTOG trial 0617, where the heart dose was associated with a worse overall survival, indicating a significant contribution to radiation-induced cardiac morbidity. It is, therefore, very likely that poorly understood cardiac toxicity may have offset any potential improvement in overall survival derived from dose escalation and may be an obstacle that limits disease control and survival of patients. The manifestations of cardiac toxicity are relatively common after high dose radiotherapy of advanced lung cancers and are independently associated with both heart dose and baseline cardiac risk. Toxicity following the treatment may occur earlier than previously thought and, therefore, heart doses should be minimized. In patients with lung cancer, who not only receive substantial heart dose, but are also older with more comorbidities, all cardiac events have the potential to be clinically significant and life-threatening.Sophisticated radiation treatment planning techniques, charged particle therapy, and modern imaging methods in radiotherapy planning, may lead to reduction of the heart dose, which could potentially improve the clinical outcomes in patients with lung cancer. Efforts should be made to minimize heart radiation exposure whenever possible even at doses lower than those generally recommended. Heart doses should be limited as much as possible.A heart dosimetry as a whole is important for patient outcomes, rather than emphasizing just one parameter.     

Metabolic, idiosyncratic toxicity of drugs: overview of the hepatic toxicity induced by the anxiolytic, panadiplon

Preclinical drug safety evaluation studies, typically conducted in two or more animal species, reveal and define dose-dependent toxicities and undesirable effects related to pharmacological mechanism of action. Idiosyncratic toxic responses are often not detected during this phase in development due to their relative rarity in incidence and differences in species sensitivity. This paper reviews and discusses the metabolic idiosyncratic toxicity and species differences observed for the experimental non-benzodiazepine anxiolytic, panadiplon. This compound produced evidence of hepatic toxicity in Phase 1 clinical trial volunteers that was not predicted by rat, dog or monkey preclinical studies. However, subsequent studies in Dutch-belted rabbits revealed a hepatic toxic syndrome consistent with a Reye's Syndrome-like idiosyncratic response. Investigations into the mechanism of toxicity using rabbits and cultured hepatocytes from several species, including human, provided a sketch of the complex pathway required to produce hepatic injury. This pathway includes drug metabolism to a carboxylic acid metabolite (cyclopropane carboxylic acid), inhibition of mitochondrial fatty acid beta-oxidation, and effects on intermediary metabolism including depletion of glycogen and disruption of glucose homeostasis. We also provide evidence suggesting that the carboxylic acid metabolite decreases the availability of liver CoA and carnitine secondary to the formation of unusual acyl derivatives. Hepatic toxicity could be ameliorated by administration of carnitine, and to a lesser extent by pantothenate. These hepatocellular pathway defects, though not directly resulting in cell death, rendered hepatocytes sensitive to secondary stress, which subsequently produced apoptosis and hepatocellular necrosis. Not all rabbits showed evidence of hepatic toxicity, suggesting that individual or species differences in any step along this pathway may account for idiosyncratic responses. These differences may be roughly applied to other metabolic idiosyncratic hepatotoxic responses and include variations in drug metabolism, effects on mitochondrial function, nutritional status, and health or underlying disease.     

Developmental toxicity of pentostatin (2'-deoxycoformycin) in rats and rabbits

The developmental toxicity of the potent adenosine deaminase (ADA) inhibitor, pentostatin (2'-deoxycoformycin), was investigated in pregnant rats and rabbits administered daily iv doses during organogenesis. Rats received 0, 0.01, 0.10, or 0.75 mg/kg on gestation days 6-15 and rabbits received 0, 0.005, 0.01, or 0.02 mg/kg on gestation days 6-18 and maternal and fetal parameters were evaluated on gestation day 21 (rats) or 30 (rabbits). Live fetuses were examined for external, visceral, and skeletal malformations and variations. In rats, maternal body weight gain and food consumption were significantly suppressed at doses of 0.10 and 0.75 mg/kg during the treatment period but returned to control levels during posttreatment. Increased postimplantation loss and decreased numbers of live fetuses, litter size, and fetal body weight were observed at 0.75 mg/kg. A statistically significant increase in the incidence of vertebral malformations occurred at 0.75 mg/kg. The incidence of certain skeletal variations (extra presacral vertebrae, extra ribs, hypoplastic vertebrae) was also increased at 0.75 mg/kg. Ossification of cervical centra was reduced at 0.75 mg/kg compared with controls. In rabbits, marked maternal toxicity (death, body weight loss, and decreased food consumption) and reproductive toxicity (abortion and premature delivery) occurred in all pentostatin-treated groups. However, there were no significant effects on number of live fetuses, pre- or postimplantation loss, litter size, or fetal body weights in the animals with live litters. There was also no apparent increase in the incidence of malformations or variations in the live fetuses of pentostatin-treated rabbits. Thus, these studies demonstrate developmental toxicity of pentostatin in rats and rabbits, and teratogenicity in rats, at maternally toxic doses.     

SALICYLAZOSULFAPYRIDINE (SALAZOPYRIN OR AZOPYRIN) IN RHEUMATOID ARTHRITIS AND EXPERIMENTAL POLYARTHRITIS

Thirty patients with rheumatoid arthritis were treated with Salazopyrin® for periods from two months to one year.Fourteen patients were symptomatically relieved in varying degrees. This group included seven patients not previously benefited by gold therapy and four who had had toxic reaction to gold. The sedimentation rates tended to remain elevated in spite of symptomatic improvement. Extension of disease to joints not formerly involved appeared in only one patient under treatment.Continuation of small dosage for long intervals seemed advantageous in the small number of patients treated in this study.Fourteen patients were not relieved symptomatically by Salazopyrin, but they did not become worse. This group included eight patients with severe, advanced disease, six of whom had not been benefited by chrysotherapy.In one patient there was a moderate reduction in erythrocyte count and in hemoglobin. One patient refused medication, claiming extreme nervousness.Salazopyrin is variably and comparatively poorly absorbed in man.In experimental polyarthritis of rats, administration of 0.5 per cent Salazopyrin in the diet produced a slight beneficial effect, while 1 per cent made the infection worse. Changes in body weight and in leukocyte content in the blood of rats and mice showed Salazopyrin to have minimal toxic effect in these rodents.     

Chlorate toxicity in Aspergillus nidulans. Studies of mutants altered in nitrate assimilation.

Summary It had previously been held that chlorate is not itself toxic, but is rendered toxic as a result of nitrate reductase-catalysed conversion to chlorite. This however cannot be the explanation of chlorate toxicity in Aspergillus nidulans, even though nitrate reductase is known to have chlorate reductase activity. Among other evidence against the classical theory for the mechanism of chlorate toxicity, is the finding that not all mutants lacking nitrate reductase are clorate resistant. Both chlorate-sensitive and resistant mutants lacking nitrate reductase, also lack chlorate reductase. Data is presented which implicates not only nitrate reductase but also the product of the nirA gene, a positive regulator gene for nitrate assimilation, in the mediation of chlorate toxicity. Alternative mechanisms for chlorate toxicity are considered. It is unlikely that chlorate toxicity results from the involvement of nitrate reductase and the nirA gene product in the regulation either of nitrite reductase, or of the pentose phosphate pathway. Although low pH has an effect similar to chlorate, chlorate is not likely to be toxic because it lowers the pH; low pH and chlorate may instead have similar effects. A possible explanation for chlorate toxicity is that it mimics nitrate in mediating, via nitrate reductase and the nirA gene product, a shut-down of nitrogen catabolism. As chlorate cannot act as a nitrogen source, nitrogen starvation ensures.     

Expression of the mediators of dioxin toxicity,aryl hydrocarbon receptor (AHR) and the AHR nuclear translocator (ARNT), is developmentally regulated in mouse teeth

Dioxins are persistent and ubiquitous environmental poisons that become enriched in the food chain. Besides being acutely lethal, the most toxic dioxin congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is developmentally toxic to many animal species. We have previously found that developing teeth of children may be sensitive to environmental dioxins via their mother's milk and that rat and mouse teeth are dioxin-sensitive throughout their development. The aryl hydrocarbon receptor (AHR) together with the AHR nuclear translocator (ARNT) protein is believed to mediate the toxic effects of dioxins. To study the potential involvement of the AHR-ARNT pathway in the dental toxicity of TCDD, we analysed the expression of AHR and ARNT by in situ hybridization and immunohistochemistry in developing mouse teeth. AHR mRNA first appeared in the epithelium of E12 first molar tooth buds and both proteins were weakly expressed in the bud. After cytodifferentiation the expression was up regulated and became intense in secretory odontoblasts and ameloblasts. The coexpression of AHR and ARNT during early tooth development as well as during the information and mineralization of the dental matrices is suggestive of the AHR-ARNT pathway as a mediator of dental toxicity of TCDD.     

Analysis of treatment in childhood leukaemia. I. Predisposition to methotrexate-induced neutropenia after craniospinal irradiation. Report to the Medical Research Council of the Working Party on Leukaemia in Childhood.

The degree of drug-induced neutropenia resulting from a controlled trial (UKALL I) of treatment in acute lymphoblastic leukaemia was analysed. The main agent associated with severe neutropenia was methotrexate, and methotrexate-induced neutropenia was significantly greater in patients who had received craniospinal irradiation. The synergistic toxic effect of irradiation followed by methotrexate treatment seems to have contributed to three of the five deaths which occurred in complete remission in this trial; all deaths in remission occurred in patients who had received central nervous system prophylaxis. Analysis of patients who subsequently relapsed compared with those still in remission after 18 months of treatment indicated that the former, on average, had slightly lower neutrophil counts. This suggests that the children who relapsed did not receive any less aggressive treatment than those who remained in remission.     

Ascorbate enhances the toxicity of the photodynamic action of Verteporfin in HL-60 cells

As a reducing agent, ascorbate serves as an antioxidant. However, its reducing function can in some settings initiate an oxidation cascade, i.e., seem to be a "pro-oxidant." This dichotomy also seems to hold when ascorbate is present during photosensitization. Ascorbate can react with singlet oxygen, producing hydrogen peroxide. Thus, if ascorbate is present during photosensitization the formation of highly diffusible hydrogen peroxide could enhance the toxicity of the photodynamic action. On the other hand, ascorbate could decrease toxicity by converting highly reactive singlet oxygen to less reactive hydrogen peroxide, which can be removed via peroxide-removing systems such as glutathione and catalase. To test the influence of ascorbate on photodynamic treatment we incubated leukemia cells (HL-60 and U937) with ascorbate and a photosensitizer (Verteporfin; VP) and examined ascorbic acid monoanion uptake, levels of glutathione, changes in membrane permeability, cell growth, and toxicity. Accumulation of VP was similar in each cell line. Under our experimental conditions, HL-60 cells were found to accumulate less ascorbate and have lower levels of intracellular GSH compared to U937 cells. Without added ascorbate, HL-60 cells were more sensitive to VP and light treatment than U937 cells. When cells were exposed to VP and light, ascorbate acted as an antioxidant in U937 cells, whereas it was a pro-oxidant for HL-60 cells. One possible mechanism to explain these observations is that HL-60 cells express myeloperoxidase activity, whereas in U937 cells it is below the detection limit. Inhibition of myeloperoxidase activity with 4-aminobenzoic acid hydrazide (4-ABAH) had minimal influence on the phototoxicity of VP in HL-60 cells in the absence of ascorbate. However, 4-ABAH decreased the toxicity of ascorbate on HL-60 cells during VP photosensitization, but had no affect on ascorbate toxicity in U937 cells. These data demonstrate that ascorbate increases hydrogen peroxide production by VP and light. This hydrogen peroxide activates myeloperoxidase, producing toxic oxidants. These observations suggest that in some settings, ascorbate may enhance the toxicity of photodynamic action.     

Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study.

OBJECTIVES: To determine the profile of risk of upper gastrointestinal toxicity during continuous treatment with, and after cessation of, non-steroidal anti-inflammatory drugs. DESIGN: Cohort study with a prospectively constructed, population based, record linkage database containing details of exposure to all community dispensed non-steroidal anti-inflammatory drugs and also all admissions to hospital for upper gastrointestinal diagnoses. SETTING: The population of Tayside, Scotland. SUBJECTS: 52,293 subjects aged 50 and over who received one or more non-steroidal anti-inflammatory between 1 January 1989 and 31 December 1991 and 73,792 subjects who did not receive one during the same period (controls). MAIN OUTCOME MEASURES: Admission to hospital for upper gastrointestinal bleeding and perforation, and admission for other upper gastrointestinal diagnoses. RESULTS: About 2% of the non-steroidal anti-inflammatory cohort were admitted with an upper gastrointestinal event during the study period compared with 1.4% of controls. The risk of admission for upper gastrointestinal haemorrhage and perforation was constant during continuous non-steroidal anti-inflammatory exposure and carried over after the end of exposure. The results were similar for admissions for all upper gastrointestinal events. CONCLUSION: This study provides evidence that non-steroidal anti-inflammatory toxicity persists with continuous exposure. There seems to be carryover toxicity after the end of prescribing. These findings have implications for the management of patients requiring non-steroidal anti-inflammatory drugs.     

Overview: Evaluation of metabolism-based drug toxicity in drug development

Drug metabolism can be a key determinant of drug toxicity. A nontoxic parent drug may be biotransformed by drug metabolizing enzymes to toxic metabolites (metabolic activation). Conversely, a toxic drug may be biotransformed to nontoxic metabolites (detoxification). The approaches to evaluate metabolism-based drug toxicity include the identification of toxic metabolites and the evaluation of toxicity in metabolically competent and metabolically compromised systems. A clear understanding of the role of drug metabolism in toxicity can aid the identification of risk factors that may potentiate drug toxicity, and may provide key information for the development of safe drugs.     

Remission-inducing drugs in rheumatoid arthritis.

The administration of certain drugs to patients with established rheumatoid arthritis frequently results in improvement that is slow to appear but persists for long periods, even after the drug is discontinued. The three main drugs with this effect, whose efficacy and toxicity are reviewed in this paper, are gold salts, D-penicillamine and chloroquine. The cytotoxic agents used to treat rheumatoid arthritis, which likely have nonspecific anti-inflammatory actions and have serious long-term side effects, are also briefly reviewed. A new drug, levamisole, is currently being tested in patients with rheumatoid arthritis. It is suggested that the time for considering the introduction of a remission-inducing drug in patients with progressive rheumatoid arthritis is after an adequate trial of therapy with salicylates or other nonsteroidal anti-inflammatory agents, or both, and before the oral administration of steroids. It is difficult, however, on the basis of rigorous clinical comparisons, to recommend which of the three main remission-inducing drugs should be tried first, although gold salts have been used the most. Patients who have improved with 6 months of chrysotherapy may continue treatment for at least 3 years, during which time the frequency of mucocutaneous and renal toxic effects will steadily decrease. Some aspects of the medical economics of therapy with remission-inducing drugs for rheumatoid arthritis are discussed.     

Molecular bases of cellular iron toxicity

Patients with hereditary or secondary hemochromatosis are liable to cardiac and hepatic failure, and type II diabetes. Despite the highly likely conjecture that iron-mediated tissue damage involves the conspiracy of cellular oxidizing and reducing equivalents, the pathophysiologic events have not been fully elucidated. These latter likely involve toxic effects of iron on intracellular organelles, in particular, mitochondria and lysosomes. The tissues at risk-heart, liver, and pancreatic beta cells-all have highly active mitochondria, which incidentally generate activated oxygen species capable of causing synergistic toxicity with intracellular iron. This suggests the general concept that iron may be preferentially toxic to cells with high mitochondrial activity. At least part of the long-term toxicity may involve iron-mediated oxidative damage to the mitochondrial genome with an accumulation of mutational events leading to progressive mitochondrial dysfunction. An alternative-and not mutually exclusive-mechanism for cellular iron toxicity involves iron-catalyzed oxidative destabilization of lysosomes, leading to leak of digestive enzymes into the cell cytoplasm and eventuating in apoptotic or necrotic cell death.