Lucanthone Hydrochloride Research Articles

SPECTROPHOTOMETRIC DETERMINATION OF CERTAIN PHARMACEUTICAL SECONDARY AROMATIC AMINES USING 3-METHYLBENZOTHIAZOLIN-2-ONE HYDRAZONE

Out of 7 pharmaceutical secondary aromatic amines tested, the oxidative coupling reaction of 3-methyl-benzothiazolin-2-one hydrazone with aromatic amines in the presence of iron (III) ammonium sulphate was applied to the determination of folic acid, primaquine phosphate and lucanthone hydrochloride. The wavelengths of maximum absorption were 530 nm (for primaquine phosphate), 580 nm (for lucanthone hydrochloride) and 660 nm (for folic acid) with molar absorptivities of 4.6 x 104, 2.3 x104 and 5.0 x 104 respectively. Beer's law was obeyed in the concentration range of 2-10 mg ml-1 (for primaquine phosphate), 2-16mg ml-1 (for lucanthone hydrochloride) and 1-10mg ml-1 (for folic acid). The proposed method was applied for the quantitative of folic acid, primaquine phosphate and licanthone hydrochloride in pure form as well as in tablets. Results of analyses were compared with the B.P. and U.S.P. procedures.

Effect of lucanthone hydrochloride on the radiation response of intestine and bone marrow of the Chinese hamster.

A sublethal dose of 100 mg lucanthone hydrochioride/kg (Miracil D, Nilodin; NSC-14574) administered ip into Chinese hamsters [median lethal dose for 30-day survival (LD50/30) of 315 mg/kg] reduced the radiation tolerance of the small intestine and had little or no effect on the radiation tolerance of the bone marrow. Lucanthone hydrochloride was administered at various times before and after whole-body 60Co gamma-irradiation. The median lethal dose for 7-day survival (LD50/7), indicative of death from gastrointestinal epithelial denudation, was reduced from 1,235 rads to minimum values of 995 rads or 985 rads by lucanthone hydrochloride inoculation 10 hours before irradiation or 7.5 hours post irradiation, respectively. The LD50/30, indicative of death from bone marrow stem cell depletion, remained unaltered at approximately 990 rads over the entire treatment scheme, which indicated that the radioresponsiveness of bone marrow stem cells was unaffected by lucanthone hydrochloride. The lucanthone hydrochloride effect was reversible in that control values of LD50/7 were attained by 40 hours post inoculation. Serum concentration of lucanthone hydrochloride in the Chinese hamster, determined spectrophotometrically, reached a peak of 8 microgram/ml by 1.5 hours post inoculation and then decreased exponentially with a half-life of approximately 6 hours, so that by 30 hours post inoculation it was unmeasurable.

Clinically available antischistosomal drugs.

The indications, the contraindications, and the characteristics of the antimonial and nonantimonial drugs clinically available for the treatment of human schistosomiasis are outlined. Of the antimonial compounds, antimony potassium tartrate or antimony sodium tartrate, both given by the intravenous route, are effective against Schistosoma japonicum, S. mansoni, and S. hematobium, but the production of severe side effects limits their use outside the treatment of individuals. Sodium antimonyl gluconate is less effective against S. mansoni and S. hemotobium and is also given intravenously. Of those antimonial compounds given intramuscularly, antimony dimercaptosuccinate is the most effective against all three common human schistosomes. Four available nonmetallic schistosomicides are considered. Niridazole, orally administered, is effective against all three common species of schistosome infecting man, but activity is maximal against S. hematobium. Many minor side effects have been described, but the major and most important side effects, neuropsychiatric symptoms and signs, are fortunately rare. Lucanthone hydrochloride, of moderate efficiency when given orally for S. hematobium or S. mansoni infections, is probably best used as a suppressant in small doses. Troublesome gastrointestinal toxicity limits its therapeutic use. Metrifonate, a cholinesterase-inhibiting organophosphorus compound, is effective only against S. hematobium. Clinical tolerance is very good. Hycanthone mesylate is highly effective against S. mansoni and S. hematobium but ineffective against S. japonicum. It is given as a single intramuscular dose. Many contraindications to its use exist, and acute hepatotoxicity has occurred infrequently. Its association with mutagenicity in certain experimental test systems has stimulated numerous ongoing studies to clarify the implications of its use in humans.

Effect of lucanthone hydrochloride on the hepatic lesions induced by a Sudan strain of Schistosoma mansoni

The anthelmintic activity of lucanthone was investigated in experimental schistosomiasis in albino mice which were each infected with 100 cercariae. Groups were treated at the 8th week following infection with lucanthone at a dose level of 100 mg./kg. body weight. Treatment was continued for 6, 8 and 10 consecutive days. The histological and histochemical changes in the liver associated with successful therapy of Schistosoma mansoni were described. The number of worms in the portal and mesenteric vessels was considerably reduced after 6 and 8 doses. Most of the mice showed a complete absence of worms after 10 doses of treatment.

Non-intensive chemotherapy in bilharziasis with lucanthone hydrochloride: (Preliminary Report)

Two non-intensive regimes of lucanthone hydrochloride were given to 41 adults with bilharziasis (34 with S. mansoni, 4 with S. haematobium and 3 with mixed infection of both S. mansoni and S. haematobium). The dosage of the first regime was 500 mg. once weekly for 10 weeks and of the second, 500 mg. twice weekly for 5 weeks followed by 500 mg. once weekly for another 5 weeks. Persons receiving the highest total dosage (regime 2) had the greatest reduction in egg output. Some non-intensive regimes given to sick children are described, and the advantages and disadvantages of this form of therapy are discussed.

Suppressive treatment of schistosomiasis mansoni with spaced doses of lucanthone hydrochloride

From 60 children infected with S. mansoni who started treatment on 500 mg. lucanthone hydrochloride a week for 10 weeks, 49 were observed for 26 weeks and 20 for 10 weeks longer. At the end of treatment a mean reduction in egg output of 83·4% had been obtained, but this increased to 89·5% at the 14th week and remained at this level through the 26th and 36th weeks. An overall parasitological “cure” rate of 36·7% was recorded but all “cures” came from the group of 27 children who had initial egg loads of less than 10,000 per whole stool. The mean reduction in egg output was, however, essentially the same irrespective of initial egg load. Two smaller control groups given ferrous fumarate and observed over the same period, showed significant increases in egg output by the 26th week of the observation period; the mean egg load increased from 0 to 1,900 per stool in one group and from 6,300 to 9,500 per stool in the other. There were no side effects; the drug was given by a nurse.

Schistosomicidal Activity of Lucanthone Hydrochloride, Hycanthone and Their Metabolites in Mice and Hamsters

The schistosomicidal activities of hycanthone, the hydroxymethyl analog and the most active metabolite of lucanthone, and several human liver microsomal conversion metabolites of both compounds were tested against experimentally induced S. mansoni infection in mice and hamsters. The compounds were administered intragastrically (twice daily for 5 days) to groups of infected animals. Lucanthone, hycanthone, and two of the salts of hycanthone were also administered parenterally (single dose medica- tion). Hycanthone was the most active metabolite of lucanthone. On an equal weight basis the schis- tosomicidal activity of intragastrically administered hycanthone was 9 times greater in hamsters and 3 times greater in mice than that of lucanthone. Desethyl analogs and the sulfoxides of both compounds were less active than either parent compound. When administered parenterally lucanthone was inac- tive whereas hycanthone was highly schistosomicidal. The activity of a single dose of hycanthone ad- ministered parenterally was equal to that obtained by a 5-day regimen administered intragastrically, and the activity was maximal when given intravenously. It is generally conceded that the schisto- somicidal activity of thioxanthones depends upon the presence of the methyl group at the 4-position para to an amino side chain at the 1-position of Ring C. Alterations of the basic side chain cause changes in activity but re- placement of the 4-methyl group results in complete loss of activity (Mauss, Koelling, and

Studies on the treatment of molluscan schistosomiasis mansoni with antibiotics, non-antibiotic metabolic inhibitors, molluscicides and anti-schistosomal agents

50% of 16 antibiotics, non-antibiotic metabolic inhibitors, molluscicides and antischistosomal agents suppressed molluscan schistosomiasis mansoni. In addition to chloramphenicol which had previously been shown to do so, 3 other antibiotic inhibitors of protein synthesis also suppressed the disease (puromycin, erythromycin and streptomycin) as did both non-antibiotic metabolic inhibitors (6 mercaptopurine and methotrexate) and all 3 antischistosomal agents (antimony potassium tartrate, stibophen and lucanthone hydrochloride). Methotrexate was the first drug found to eradicate the infection rather than merely suppress it, and lucanthone hydrochloride is the most potent drug thus far discovered. In addition to suppression of the disease at 0·4 ppm, it completely prevents snail growth and egg laying at a concentration of 0·3 ppm.

TREATMENT OF URINARY SCHISTOSOMIASIS: Practice and Theory

In an earlier experiment in which established drugs were used in different regimens, monthly intramuscular injections of stibocaptate 10 mg. per kg. body-weight proved to be the best treatment for Zanzibari schoolboys infected with Schistosoma hœmatobium. This method has been matched quantitatively against three other regimens in which single doses of lucanthone hydrochloride 20 mg. per kg. of body-weight, niridazole 75 mg. per kg., or trichlorophone 10 mg. per kg. were given by mouth at 4-weekly intervals to schoolchildren with urinary schistosomiasis. No toxic side-effects were reported; and all four methods were successful in reducing the levels of urinary egg outputs of S. hœmatobium, but the best results were obtained using stibocaptate and trichlorophone.

Trial of an enteric-coated preparation of lucanthone hydrochloride in Schistosoma mansoni infection

Standard 250 mg. tablets of lucanthone hydrochloride were coated with cellulose acetate phthalate and given to 50 out-patients suffering from S. mansoni infections with pre-treatment egg loads of up to 75,000 per 24 hours. The purposes of the trial were to assess this oral preparation, which proved to have a low incidence of side effects, was widely accepted by the patients, and was efficient enough for use within a schistosomiasis control programme. At the end of the 12 weeks, 16 patients were classed as “cured,” but a mean overall reduction in egg output of 81·5% was obtained. 18 patients had completed 26 weeks of follow-up at the time of writing. The “cure” rates and mean percentage reduction in egg output obtaining at 12 weeks were maintained during this extended period. The recorded side effects were few compared with those encountered with the ordinary tablet (24% vs. 90%) and were minimal, nausea being the commonest. There were no cases of vomiting although this occurred in 41% with the uncoated, standard tablet in an earlier series.

Lucanthone hydrochloride in the treatment of Schistosoma mansoni infection

29 patients suffering from S. mansoni infection were treated from an out-patient clinic. They were aged 5–65 years and each patient was given lucanthone hydrochloride in a total dosage of 60 mg. per kg. body weight; the total dosage was administered in 6 unequal doses over a period of 3 days. The cure rate after 6 months was 82·7%, 4 of the 5 uncured either relapsing or being re-infected between the 12th and 26th week. Side effects were common (in 26 of the 29 patients) despite the routine administration of cyclizine hydrochloride before each dose of lucanthone. Dizziness, nausea and vomiting were the most frequent, but were in no case so intolerable that treatment had to be suspended. Children suffered less from side-effects than adults. It is concluded that lucanthone hydrochloride is valuable against S. mansoni infection and can be used on a large scale within a control or eradication programme.

Schistosomiasis in Tanzania long term results of TWSb and lucanthone hydrochloride combined in suppressive therapy in Schistosoma haematobium infection

Schistosomiasis in Tanzania long term results of TWSb and lucanthone hydrochloride combined in suppressive therapy in Schistosoma haematobium infection

Stosstherapy of Schistosoma haematobium infections using lucanthone hydrochloride

The treatment of S. haematobium infections with a single large dose of lucanthone hydrochloride is shown to be more toxic and less effective than standard courses of the drug, and therefore to be unsuitable for mass treatment of infected communities.

Schistosoma mansoni infection in children. Treatment with lucanthone hydrochloride (Nilodin).

Schistosomiasis is a problem of increasing importance when viewed on a world-wide scale. It is a serious problem in Africa and South America, especially in Brazil where the expanding population carries the disease with it into previously unsettled territory. In certain cities of the continental United States, such as New York, schistosomiasis has become important even though transmission does not occur. This is so because of the large number of inhabitants who come from the Caribbean Islands, especially Puerto Rico. Since approximately 10% of the people of Puerto Rico are infected with Schistosoma mansoni1,2and since more than 500,000 persons born in Puerto Rico reside in New York, it is estimated that there are more than 50,000 individuals with S. mansoni infection in that city alone. There were 8 deaths in New York from advanced schistosomiasis in the 3-year period from 1956-1958. Schistosoma mansoni is a blood fluke, the definitive

Comparison of lucanthone hydrochloride and TWSb in the treatment of Schistosoma haematobium infection in Tanganyika

Lucanthone hydrochloride and TWSb, with and without dimercaptosuccinic acid, were given to school children harbouring S. haematobium during a period when transmission was not taking place. When followed up after 4 months, two of 15 children who had been given lucanthone hydrochloride in a dose of 10 mg./kg. body weight twice daily for 3 days were excreting viable ova, and one of 9, who had been given three injections of 0.5 gramme of TWSb, was passing viable ova. Dimercaptosuccinic acid reduced the incidence of headache, nausea and abdominal pain accompanying TWSb therapy, but it resulted in a much reduced cure rate. Side-effects with lucanthone hydrochloride were moderately severe, though all patients completed treatment. Neither drug is considered satisfactory for schistosomiasis control in East Africa in the regions described above.

Laboratory studies on the effects of tris(p-aminophenyl)-carbonium salts, tris(p-aminophenyl)methanol, and lucanthone hydrochloride against Schistosoma mansoni.

Summary An approach to the evaluation of drugs for activity against Schistosoma mansoni in rhesus monkeys and several modifications regarding drug evaluations against this parasite in mice are presented. Seven tris(p-aminophenyl)carbonium salts (TAC salts) and tris(p-aminophenyl)methanol (TAC hydroxide) killed mature and immature forms of a Puerto Rican strain of Schistosoma mansoni when given orally to mice. TAC pamoate, TAC hydroxide, TAC chloride, and lucanthone HCl were studied extensively in infected mice and monkeys, and the last two substances were tested against sexually mature worms in vitro. Lucanthone HCl (studied as a reference drug) had only feeble to moderate effect in mice or monkeys even though several rigorous oral regimens were tried. In mice, its action seemed to be restricted to mature worms. It was schistosomicidal in vitro only in high concentrations during a period of several days. The three TAC substances resembled each other sufficiently in various studies to justify the following tentative characterization of their anthelmintic actions as a group. They are capable of killing a high proportion of mature and immature worms in mice and monkeys at well tolerated dose levels, are not highly effective intraperitoneally and are irritating by this route, are directly schistosomicidal in vitro at lower concentrations than lucanthone HCl, exhibit a flat-dose response relationship, are more effective in moderate doses for prolonged periods than in high doses for shorter periods, act slowly and probably by interfering with nutrition, and are not antagonized by p-aminobenzoic acid. Therapeutic and prophylactic tests in mice and monkeys support the conclusion that certain TAC salts are worthy of trial in man for purpose of cure, protection against infection, and prevention of egg excretion. Preliminary observations in dogs indicated TAC pamoate to be distinctly less emetic than TAC chloride or TAC hydroxide. Reference is made to work by others demonstrating oral action by TAC pamoate against the three most important schistosomes in man—S. mansoni, S. Haematobium, and S. japonicum.

Preliminary observations on metabolites of lucanthone

1. 1) Lucanthone hydrochloride (10 μg./ml.) did not kill Schistosoma mansoni kept in serum media within 20 days. The flukes were, however, damaged by the 5–6 μg./ml. of lucanthone and derivatives present in the serum from patients taking the drug. 2. 2) Ether extracts of serum from patients taking lucanthone contain an acid-soluble fraction, the drug itself, and an acid-insoluble fraction which had no effect on flukes kept in vitro for 10 days. 3. 3) Eleven chromatographic fractions were obtained from the urine of patients treated with lucanthone but none was active in vitro. 4. 4) Lucanthone is believed to act through metabolites, but activity has not been found in faecal extracts, urine extracts or in acid-insoluble serum extracts. The acid-soluble material extractable from serum remains to be tested.

Schistosomiasis in Saudi Arabia

SummaryIn Schistosoma mansoni infections in Saudi Arabia a cure was obtained in 6 out of 12 cases with lucanthone hydrochloride (Nilodin) in dosages of 55 to 75 mg./kg. body weight, and in 12 out of 18 cases with sodium antimonyl gluconate (Triostam) in dosages of 13 to 21.6 mg./kg. body weight. In S. haematobium infections, one case was cured with 110 mg./kg. of lucanthone hydrochloride and 4 out of 4 cases were cured with 20 to 24 mg./kg. of sodium antimonyl gluconate.