The anthelmintic activity of a novel organic arsenical, R7/45, upon Brugia pahangi in Meriones unguiculatus.

The new organic arsenical R7/45 is a rapidly acting and very potent anthelmintic against adult Brugia pahangi in jirds. Against adult worms implanted into the peritoneal cavity 5 subcutaneous (SC) injections at 2.5 mg/kg of R7/45 killed 100% of adult worms. A single dose SC of 20 mg/kg was 100% effective and 10 mg/kg 76% effective against adult worms. When jirds were autopsied at different times after treatment at 20 mg/kg SC 89% of worms were dead within three days. R7/45 was not active when given by stomach intubation. Pretreatment of jirds with R7/45 had no effect on adult worms subsequently implanted into jirds. R7/45 was highly active against third and fourth stage larvae of B. pahangi in jirds.

The antifilarial activity of a novel group of organic arsenicals upon Brugia pahangi.

Mel W is a second generation anionic organic arsenical which is filaricidal but has sporadic and unacceptable lethal side effects. Eight new cationic derivatives have now been synthesized in an attempt to avoid the side effects and have been examined for their effects upon adult Brugia pahangi in Meriones unguiculatus. They were all shown to be potent filaricides and the two best compounds, Mel Ga and Mel Cy, were at least 95% effective in killing adult B. pahangi at 5 X 3.13 mg/kg when injected subcutaneously.

Study on the activity of antiparasitic agents against Onchocerca lienalis third stage larvae in vitro.

The in vitro drug response of third stage larvae of the cattle filarial worm Onchocerca lienalis has been studied. Larvae were maintained in Minimum Essential Eagles medium supplemented with 10% inactivated foetal calf serum and exposed to the following drugs: Mel W, caparsolate sodium, suramin, ivermectin, flubendazole, levamisole and amoscanate plus 3 novel melaminylthioarsenites. Antiparasitic activity of these compounds has been assessed on their killing effects and their ability to totally inhibit the moult from the third to the fourth stage. Unfortunately, moulting occurred at a low rate in the culture system used and was not suitable as a quantitative parameter for describing drug activity. However, the results indicated that if the rate of ecdysis could be increased by improving the culture conditions, moulting could be used in this manner since exsheathment has inhibited by certain compounds at concentrations where killing effects were less than 50%. Of the compounds evaluated ivermectin demonstrated good activity, totally preventing ecdysis at 0.001 microgram/ml. The drug assay system used in this study may offer a starting point for the eventual development of a meaningful and specific in vitro screen for new anti-Onchocerca agents.

Treatment of lead poisoning by 2,3-dimercaptosuccinic acid.

2,3-Dimercaptosuccinic acid (D.M.S.), a new orally effective agent for the treatment of heavy-metal intoxication, was administered to five lead-poisoned smelter workers for six days at dosages ranging from 8.4--12.7 mg/kg/day on the first day to 28.1--42.2 mg/kg/day on the last day. Mean blood-lead concentration decreased significantly from an initial value of 97 +/- 6 microgram/dl to 43 +/- 4 microgram/dl on the last day. Urinary lead excretion was significantly raised. D.M.S. was very well tolerated with no signs of toxicity and no effect on urinary zinc, calcium, magnesium, or iron excretion. Urinary copper excretion was significantly increased, but the magnitude of that effect was not clinically important. D.M.S. seems to be safe and effective for the treatment of lead poisoning.

The pharmacology of 2,3-dimercaptosuccinic acid and its potential use in arsenic poisoning.

Arsenic (As2O3)-poisoned rats were treated with either 2,3-dimercaptosuccinic acid (DMS) or dimercaptopropanol (BAL) at doses of 30 mg/kg/day. A control group received no treatment. The total quantity of arsenic excreted was not significantly different in response to 4 days of treatment with either DMS or BAL. In addition, there was no difference between the two drug treatment groups in the residual arsenic content of brain, liver, kidney and spleen after treatment. Both drugs reduced the arsenic content of each tissue to approximately 40% of that of untreated controls. Previous studies have shown that DMS is orally effective for the treatment of lead poisoning. The LD50 of DMS was determined to be in excess of 3 g/kg in rats and mice, approximately 30 times the LD50 of BAL. No gross, histopathological or biochemical evidence of toxicity was observed in mice, rats or dogs which received DMS 5 days per week for 6 months. DMS did not affect the excretion of zinc, iron, calcium or magnesium. Urinary copper excretion was significantly elevated in response to 30 mg/kg of DMS, suggesting that the drug might also be useful for the treatment of Wilson's disease.

2,3-Dimercaptosuccinic acid: a new agent for the treatment of lead poisoning.

Using minimally lead-poisoned rats, we have measured urinary and fecal lead excretion in response to 2,3-dimercaptosuccinic acid (DMS) administered i.p. or p.o. and compared it to that induced by dimercaptopropanol (BAL) (i.p.), EDTA (i.p.), D-penicillamine (p.o. and i.p.) and the combination of BAL and EDTA (i.p.). At doses of 30 mg/kg, parenterally administered DMS was as effective as i.p. BAL and these two drugs were more effective than the other treatment groups. However, p.o. DMS was only 20% less effective and was as effective as i.p. EDTA and the combination of EDTA + BAL i.p. and significantly more effective than D-penicillamine p.o. or i.p. Unlike BAL, most lead excretion in response to DMS was via the urine, undoubtedly reflecting the greater water solubility of DMS. When mice were fed a diet containing both lead and DMS, the drug prevented the accumulation of porphyrins in erythrocytes. Studies with 210Pb indicate that this prophylactic effect is not due to an inhibition of lead absorption but rather to enhanced excretion of lead. The residual tissue distribution of 210 Pb administered simultaneously with DMS was not different form that of 210Pb alone. Since DMS is orally effective and its LD50 is 30 times greater than that of BAL, we expect this compound to be clinically useful in the treatment of lead poisoning.

Therapeutic field trial of a macro- and microfilaricidal agent in canine filariasis.

The discovery in 1973 of a synergistic effect of the arsenical compound F 151, a macrofilaricide, and the benzimidazole compound HOE 33258, a microfilaricide, led to the preparation of the reaction product of F 151 and HOE 33258 (in the proportion 1 mol to 2 mol, respectively), which was designated by the letter E. This compound E proved to be an effective macro- and microfilaricidal agent when administered subcutaneously in a single well-tolerated dose to dogs that were naturally infected with Dirofilaria immitis.