Topical efficacy of dimercapto-chelating agents against lewisite-induced skin lesions in SKH-1 hairless mice.

Lewisite is a potent chemical warfare arsenical vesicant that can cause severe skin lesions. Today, lewisite exposure remains possible during demilitarization of old ammunitions and as a result of deliberate use. Although its cutaneous toxicity is not fully elucidated, a specific antidote exists, the British anti-lewisite (BAL, dimercaprol) but it is not without untoward effects. Analogs of BAL, less toxic, have been developed such as meso-2,3-dimercaptosuccinic acid (DMSA) and have been employed for the treatment of heavy metal poisoning. However, efficacy of DMSA against lewisite-induced skin lesions remains to be determined in comparison with BAL. We have thus evaluated in this study the therapeutic efficacy of BAL and DMSA in two administration modes against skin lesions induced by lewisite vapor on SKH-1 hairless mice. Our data demonstrate a strong protective efficacy of topical application of dimercapto-chelating agents in contrast to a subcutaneous administration 1h after lewisite exposure, with attenuation of wound size, necrosis and impairment of skin barrier function. The histological evaluation also confirms the efficacy of topical application by showing that treatments were effective in reversing lewisite-induced neutrophil infiltration. This protective effect was associated with an epidermal hyperplasia. However, for all the parameters studied, BAL was more effective than DMSA in reducing lewisite-induced skin injury. Together, these findings support the use of a topical form of dimercaprol-chelating agent against lewisite-induced skin lesion within the first hour after exposure to increase the therapeutic management and that BAL, despite its side-effects, should not be abandoned.

2,3-Dimercapto-1-propanol does not alter the porphobilinogen synthase inhibition but decreases the mercury content in liver and kidney of suckling rats exposed to HgCl2.

Heavy metals have received great attention as environmental pollutants mainly because once introduced in the biological cycle they are incorporated in the food chain. Especially the mercury toxicity due to a diversity of effects caused by different chemical species should be emphasized. Heavy metal intoxication has been treated with chelating agents such as 2,3-dimercapto-1-propanol (BAL). However, the efficacy of this treatment is questionable due to the lack of specific effect on the toxic metal. The present study examined the effects of HgCl2 exposure (five doses of 5.0 mg/kg between ages 8 to 12 days) on physiological parameters, on porphobilinogen synthase activity, and on mercury content in liver, kidneys and brain from suckling rats. The effect of BAL (one dose of 12.5-75 mg/kg) applied 24 hr after mercury intoxication on these parameters was also investigated. The results demonstrate that HgCl2 intoxication induced a decrease of corporal weight gain as well as brain weight and an increase in renal weight. The inhibition of porphobilinogen synthase from liver and kidney, is still significant and was not modified by subsequent BAL treatment. However, BAL altered two effects induced by mercury: increase in death percentage and decrease in mercury contents in liver and kidney. The increase of mortality induced by mercury was not promoted by metal redistribution to brain nor by the increase of porphobilinogen synthase inhibition induced by metal. More investigations are necessary to determine if the different effects of BAL on intoxication by metals are possibly related to other tissues and/or if the probable metal-chelating complex formed is more toxic than the metal itself.

Studies of congenic lines in the Brown Norway rat model of Th2-mediated immunopathological disorders show that the aurothiopropanol sulfonate-induced immunological disorder (Aiid3) locus on chromosome 9 plays a major role compared to Aiid2 on chromosome 10.

Brown Norway (BN) rats treated with aurothiopropanol-sulfonate (Atps) constitute a model of Th2-mediated immunological disorders associated with elevated IgE responses and renal IgG deposits. Using F(2) offspring between Atps-susceptible BN and Atps-resistant Lewis rats, we had previously mapped three quantitative trait loci on chromosomes 9, 10, and 20 for which BN alleles increased susceptibility to Atps-induced immunological disorders (Aiid). In this study we have used congenic lines for the latter two quantitative trait loci, formerly called Atps2 and Atps3 and now named Aiid2 (chromosome 10) and Aiid3 (chromosome 9), for fine mapping and characterization of their impact on Atps-triggered reactions. In Aiid2 congenic lines, the gene(s) controlling part of the IgE response to Atps was mapped to an approximately 7-cM region, which includes the IL-4 cytokine gene cluster. Two congenic lines in which the introgressed segments shared only a portion of this 7-cM region, showed an intermediate IgE response, indicating the involvement of several genes within this region. Results from BN rats congenic for the Lewis Aiid3 locus, which we mapped to a 1.2-cM interval, showed a stronger effect of this region. In this congenic line, the Atps-triggered IgE response was 10-fold lower than in the BN parental strain, and glomerular IgG deposits were either absent or dramatically reduced. Further genetic and functional dissections of these loci should provide insights into pathways that lead to Th2-adverse reactions.

Prolonged cholestasis and ductopenia following gold salt therapy.

Hepatotoxicity, predominantly cholestatic, is a rare adverse effect of gold salt therapy, which usually completely resolves within a few months. We report the case of a female patient treated for rheumatoid arthritis, who had gold salt overdose, and in whom acute cholestatic hepatitis occurred three weeks after beginning of therapy. Evolution of gold concentration was followed in plasma and urine, as well as in cutaneous and liver dry tissue. Liver biopsy showed marked inflammatory changes of interlobular bile ducts that evolved towards ductopenia, which was responsible for prolonged cholestasis still present 15 months later. In addition, sialadenitis with sicca syndrome was noted six months after onset of the disease. The mechanism of hepatotoxicity was probably immunoallergic since liver lesions were associated with hypersensitivity syndrome including dermatitis and blood and tissue eosinophilia. This is the first report of gold salt hepatotoxicity with histological demonstration of cholangitis followed by ductopenia.

Fatal pneumococcal sepsis following flexible bronchoscopy in an immunocompromised infant.

A 5-month-old boy who suffered from a leukocyte chemotactic defect underwent flexible bronchoscopy for persistent right upper lobe atelectasis and tachypnea. Ten hours after the procedure he developed fulminant sepsis, and he died 16 hrs after bronchoscopy. Streptococcus pneumoniae (serotype 23) grew from the bronchoalveolar lavage fluid and from the blood culture taken during the sepsis work-up. We, therefore, suggest administering prophylactic antimicrobial therapy immediately following bronchoscopy to immunosuppressed children, even when an acute respiratory infection is not suspected, in order to prevent bacteremia and sepsis.

CaEDTA vs CaEDTA plus BAL to treat children with elevated blood lead levels.

The effectiveness of CaEDTA alone vs CaEDTA plus BAL was compared retrospectively in a group of 72 children with lead levels between 2.41 mumol/L (50 micrograms/dL) and 2.90 mumol/L (60 micrograms/dL). The children who received both drugs had higher median zinc protoporphyrin (ZnP) concentrations at the initiation of therapy than children who received CaEDTA alone (160 micrograms/dL vs 96 micrograms/dL, p less than .01). There was a significantly increased incidence of vomiting and abnormal liver-function test results in the children who received both drugs. The children who received CaEDTA alone had a greater percent mean fall in lead level at one to three weeks postchelation (30.5% vs 18.1%, p less than .05). Children who received both CaEDTA and BAL had a greater percent decrease in ZnP at four to eight months postchelation, but there was no difference in percent decrease in lead levels. Children who received both drugs also had a greater number of repeat courses of chelation by six months. The addition of BAL to CaEDTA for treatment of children with lead levels of 2.41 mumol/L (50 micrograms/dL) to 2.90 mumol/L (60 micrograms/dL) produced greater toxicity and does not seem to prevent repeat chelations within six months.

[A method for the permanent maintainance aurotherapy of rheumatoid arthritis patients under the control of gold excretion]. / O metodike postoiannoi podderzhivaiushchei auroterapii bol'nykh revmatoidnym artritom pod kontrolem ékskretsii zolota.

UNLABELLED: A study is presented of 34 patients with rheumatoid arthritis. The authors propose a method of persistently maintained aurotherapy of patients with rheumatoid arthritis directed to prevention of recurrences and toxic effect of gold due to chrysanol treatment, the active substance of which is metallic gold. After course treatment with chrysanol (850-1020 mg) persistent treatment by maintained doses is instituted. RESULTS: prevention of recurrences of the disease and prevention of side effects due to the toxicity of cumulated gold.

[The comparative efficacy of slow-acting (basic) preparations in psoriatic arthritis]. / Sravnitel'naia éffektivnost' medlenno deistvuiushchikh preparatov pri psoriaticheskom artrite.

Overall 126 patients with verified and clinically active psoriatic arthritis (PA) were subjected to a randomized study of the efficacy of chrisanolum (Chr), sulfasalicylic drugs (SSD) (sulfasalazine and salazopyridazine) and methotrexate (MT) as compared to nonsteroidal anti-inflammatory drugs (NSAID). The treatment that lasted for a year was completed by 77 patients: in the group on NSAID, by 31, on Chr by 15, on SSD by 15, and on MT by 16. In the remainder, the treatment was discontinued because of side effects. The best clinical effect was recorded in patients on Chr. The improvement was observed in 73% of the patients, with a significant effect being attained in 60%. In the groups on SSD and MT, the improvement was observed in 80 and 69%, respectively. However, noticeable improvement was only recorded in 20 and 19%. SSD turned out more effective than MT. in the group on NAID, the improvement was ascertained but in 35% of the patients, with noticeable one being attained in 6%. According to Pearson's criterion chi 2, the results of the treatment with NAID alone were less potent than in the group given Chr (p < 0.001) and SSD (p < 0.05). The differences between the effect of the treatment with NAID and MT appeared nonsignificant (p > 0.1). Therefore, according to the diminution of the clinical efficacy in PA, the basic drugs may be distributed in the following way: Chr, SSD, MT. The side-effects in the group on NAID were. recorded in 37% of cases, in the group on Chr in 53%, on SSD in 33%, and on MT in 55%. This means that SSD were tolerated best of all.

Effect of the thiol group on experimental gold-induced autoimmunity.

Brown Norway rats injected with aurothiopropanolsulfonate sodium salt develop systemic autoimmunity. The aim of this study was to assess the influence of the sulfur-containing group in this experimental model of gold-induced autoimmunity. It was shown that the sulfur-containing group does not induce autoimmunity of itself, but potentiates the immunotoxic effects of gold.

[Fatal hepatic necrosis due to a treatment course of rheumatoid arthritis with gold salts]. / Nécrose hépatique fatale au cours d'un traitement aux sels d'or d'une polyarthrite rhumatoïde.

Gold salts are still a first choice for treatment of rheumatoid arthritis. Although adverse reactions are relatively frequent, hepatic abnormalities are rare. They consist largely of reversible cholestasis, and, exceptionally, the evolution can prove rapidly fatal due to extensive hepatic necrosis. We present an additional case of this kind which occurred after a total dose of 450 mg intramuscular Aurothiopropanol over 6 weeks. The pathogenetic mechanism is complex, toxic and/or immuno-allergic. Nevertheless, regular hepatic enzyme testing is not recommended.

Cholestasis and pneumonitis induced by gold therapy.

The authors describe the association of gold salt-induced cholestasis and lymphocytic alveolitis proved by liver biopsy and broncho-alveolar lavage. To our knowledge this is the third case report on the combination of liver disease and pulmonary infiltration induced by gold compounds.

[The effect of parenteral gold preparations on heart function in rheumatoid arthritis patients (based on echocardiographic data)]. / Vliianie parenteral'nykh preparatov zolota na funktsional'noe sostoianie serdtsa u bol'nykh revmatoidnym artritom (po dannym ékhokardiografii).

A total of 30 patients were treated by chrisanolum and myocrisin. The course of treatment lasted more than 2 years. The authors observed clear positive effect of parenteral preparations of gold on the contractile and pumping function of the heart in RA patients; clinical and laboratory manifestations of the disease were decreased.

Intravenous self-administration of elemental mercury: efficacy of dimercaprol therapy.

Deliberate parenteral self-injection of mercury is extremely rare, and is associated with a high degree of mortality and morbidity. Because mercury depresses cellular enzymatic mechanisms by combining with sulfhydryl groups, soluble mercuric salts are toxic to all cells. Embolization of mercury in the lungs has been reported with varying degrees of changes in pulmonary function. Mercury causes urticaria progressing to weeping dermatitis, leukopenia, anemia, diarrhea, salivation, liver damage, and renal damage progressing to acute renal failure with anuria. Dimercaprol is an effective antidote in acute heavy metal intoxication because its two sulfhydryl groups successfully compete with tissue enzyme sulfhydryl groups for the offending metal. Experience with dimercaprol therapy months after the original exposure to mercury is not available. We describe the hospital course of a patient after intravenous elemental injection and the results of dimercaprol therapy months after the original exposure.

Gold-induced aplastic anemia.

Three patients receiving gold salt treatment for rheumatoid arthritis developed severe aplastic anemia. All three patients experienced remission of their disease at the time of the occurrence of marrow aplasia. Reviewing data on these patients and recent literature indicate that fatal marrow aplasia seems to occur more frequently in sero-negative women who respond well to therapy with gold salts. Frequent blood monitoring in search for any pronounced or sustained drop in red, white or platelet count, even within normal range could serve as a warning sign for myelotoxicity. Despite intensive supportive measures and specific therapeutic attempts, all three patients eventually died of septic shock.