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.

Goldsalts, levamisole and D-penicillamine as first choice slow-acting antirheumatic drugs in rheumatoid arthritis--a long-term follow-up study.

In the present study, 345 rheumatoid arthritis patients were treated using goldsalts, D-Penicillamine or levamisole as the slow-acting antirheumatic drug of first choice. Goldsalts were given to 182 patients, levamisole to 139 and D-Penicillamine to 24. At the time of the present evaluation, 83 patients were still on goldsalts (44.6%), 63 on levamisole (45.2%) and 11 on D-Penicillamine (45.9%). Adverse reactions required interruption of treatment in 64 patients on goldsalts (35.2%), in 44 on levamisole (31.7%) and in 5 on D-Penicillamine (20.8%). Inefficacy was responsible for withdrawal of 33 patients receiving goldsalts (18.1%), 30 receiving levamisole (21.6%) and 8 receiving D-Penicillamine (33.3%). The duration of treatment was 4.6 years for goldsalts, 3.6 years for levamisole and 3.6 years for D-Penicillamine. In the present analysis none of the compounds was found to have a definite advantage over the others. The rather favourable treatment continuation rates in this study can be attributed to the fact that the slow-acting antirheumatic drugs were given at an early stage of the disease, preferably before the occurrence of radiological lesions.

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.

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.

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.

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.

[Hepatitis secondary to a gold salt overdose]. / Hépatite secondaire à un surdosage en un sel d'or.

The authors report the case of a 51-year-old woman who developed cholestatic and cytolytic hepatitis after an overdose of sodium aurothiopropanol sulfonate 1.1 g, namely 300 mg gold metal. Liver biopsy demonstrated cholestasis, centrolobular steatosis and portal fibrosis. Electron microscopy showed abundant lipo-pigments in the hepatic and cellular cells, as well as myelinic bodies. Gold analysis by atomic absorption spectroscopy showed a level of 22.76 micrograms per ml in the plasma and a level of 2.16 micrograms per g in the liver. Chelating agents increased the urinary gold excretion, but were without effect on the course of hepatitis. Dimercaptopropanol seemed to favor the occurrence of other gold salt side-effects and penicillamine increased the hepatic cytolysis. The patient recovered without sequelae.

[Herpes zoster--an unusual complication of gold therapy]. / Opoiasyvaiushchii lishai-neobychnoe oslozhnenie auroterapii.

The authors observed the development of herpes zoster in 2 rheumatoid arthritic patients against a background of chrysanol therapy. Such a complication should be regarded as an indication for aurum drug cancellation. The study provided an opportunity for specifying some aspects in the mechanism of action and indicated a possible immunodepressive effect.

[Treatment of psoriatic arthritis with gold salts (chrysotherapy)]. / Lechenie psoriaticheskogo artrita soliami zolota (khrizoterapiia).

The paper is concerned with the results of a 6- and 12-month comparative randomized study of the efficacy of chrysanol (calcium-aurothiopropanol-sulfonate) in 21 patients with verified psoriatic arthritis. Patients of the study group (11 patients) received in addition to chrysanol nonsteroid antiinflammatory drugs (NAD), patients of the control group (10) received NAD only. The efficacy of annual treatment was assessed in 10 patients (5 in each group). Therapeutic efficacy was assessed on the basis of an analysis of 19 clinical and laboratory findings. Six months later improvement was noted in 80% of the patients of the study group, of them considerable improvement in 30%. A significant positive time course was observed for 9 parameters including those characterizing vertebral mobility. Improvement in the control group was noted in 50% of the patients, 2 parameters changed significantly. One year later improvement was recorded in all the patients of the study group and in 40% of the patients of the control group. A significant positive time course was noted for 10 parameters in the study group and not a single one in the control group. In the latter group 7 values got worse, the deterioration of one value was statistically significant. Side effects of chrysanol were noted in 2 patients (agranulocytosis and nephropathy). The aggravation of skin psoriasis was not noted in any patients.

[Comparative analysis of the effectiveness and tolerance of chrysanol and myochrysine in patients with rheumatoid arthritis (preliminary report)]. / Sravnitel'nyi analiz éffektivnosti i perenosimosti krizanola i miokrizina u bol'nykh revmatoidnym artritom (predvaritel'noe soobshchenie).

Fifty patients with a significant rheumatoid arthritis (RA) were treated with gold salts for 6 months to 4 years. Patients with highly active conditions (stages II-III) and with erosive arthritis (stages IIb-IV) prevailed. Extraarticular manifestations were recognized in 76% of the patients. The efficacy of chrisanol given in a dose of 1.5 ml of a 5% solution was compared to that of myocrisin in a dose of 50 mg, i. e. 25 mg metallic gold once a week. The efficacy of the drugs was evaluated from their effects on the disease activity (clinical manifestations of the articular syndrome, ESR, morphological signs of rheumatoid synovitis) and progression (the rate of the development of erosive arthritis in hand and foot joints, the time course of serum RF content, and systemic disease manifestations). These characteristics were examined with the aid of modern ultrasonic and radionuclide research methods. The evaluations were made by the treatment onset and by months 3, 6, 12 and 18 of the treatment. Analysis of the data obtained attests to a high clinical efficacy of both the drugs exhibiting basic activity which is confirmed by a decrease in the degree of the morphological manifestations of synovitis and extraarticular signs of RA, particularly of myocarditis. A method for following up outpatients to prevent grave complications of chrysotherapy is offered.

[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.

[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.