In vitro activity of the anthelmintic drug niclosamide against Sporothrix spp. strains with distinct genetic and antifungal susceptibility backgrounds.

The drugs available to treat sporotrichosis, an important yet neglected fungal infection, are limited. Some Sporothrix spp. strains present reduced susceptibility to these antifungals. Furthermore, some patients may not be indicated to use these drugs, while others may not respond to the therapy. The anthelmintic drug niclosamide is fungicidal against the Sporothrix brasiliensis type strain. This study aimed to evaluate whether niclosamide also has antifungal activity against Sporothrix globosa, Sporothrix schenckii and other S. brasiliensis strains with distinct genotypes and antifungal susceptibility status. Minimal inhibitory and fungicidal concentrations (MIC and MFC, respectively) were determined using the microdilution method according to the CLSI protocol. The checkerboard method was employed to evaluate niclosamide synergism with drugs used in sporotrichosis treatment. Metabolic activity of the strains under niclosamide treatment was evaluated using the resazurin dye. Niclosamide was active against all S. brasiliensis strains (n = 17), but it was ineffective (MIC > 20 µM) for some strains (n = 4) of other pathogenic Sporothrix species. Niclosamide MIC values for Sporothrix spp. were similar for mycelial and yeast-like forms of the strains (P = 0.6604). Niclosamide was fungicidal (MFC/MIC ratio ≤ 2) for most strains studied (89%). Niclosamide activity against S. brasiliensis is independent of the fungal genotype or non-wild-type phenotypes for amphotericin B, itraconazole, or terbinafine. These antifungal drugs presented indifferent interactions with niclosamide. Niclosamide has demonstrated potential for repurposing as a treatment for sporotrichosis, particularly in S. brasiliensis cases, instigating in vivo studies to validate the in vitro findings.

Niclosamide attenuates lung vascular remodeling in experimental pulmonary arterial hypertension.

Despite advances in medical therapy, pulmonary arterial hypertension (PAH) remains an inexorably progressive and highly lethal disease. Signal transducer and activator of transcription (STAT)-3 is one of the main intracellular transcription factors implicated in PAH vascular remodeling. We hypothesized that niclosamide, a STAT3 inhibitor, would reduce vascular remodeling in an established pulmonary arterial hypertension model, thus enhancing cardiac function. Male Wistar rats were treated either with monocrotaline (60 mg/kg), to induce PAH, or saline (C group) by intraperitoneal injection. On day 14, PAH animals were randomly assigned to receive oral (1) saline (PAH-SAL); (2) niclosamide (75 mg/kg/day) (PAH-NICLO); (3) sildenafil (20 mg/kg/day) (PAH-SIL); or (4) niclosamide + sildenafil (PAH-NICLO + SIL), once daily for 14 days. On day 28, right ventricular systolic pressure was lower in all treated groups compared to PAH-SAL. Pulmonary vascular collagen content was lower in PAH-NICLO (37 ± 3%) and PAH-NICLO + SIL (37 ± 6%) compared to PAH-SAL (68 ± 4%), but not in PAH-SIL (52 ± 1%). CD-34, an endothelial cell marker, was higher, while vimentin, a mesenchymal cell marker, was lower in PAH-NICLO and PAH-NICLO + SIL compared to PAH-SAL, suggesting attenuation of endothelial-mesenchymal transition. Expression of STAT3 downstream targets such as transforming growth factor (TGF)-ß, hypoxia-inducible factor (HIF)-1, and provirus integration site for Moloney murine leukemia virus (PIM-1) in lung tissue was reduced in PAH-NICLO and PAH-NICLO + SIL compared to PAH-SAL. In conclusion, niclosamide, with or without sildenafil, mitigated vascular remodeling and improved right ventricle systolic pressure. This new role for a well-established drug may represent a promising therapy for PAH.

Critical analysis of molluscicide application in schistosomiasis control programs in Brazil.

In Brazil, Biomphalaria glabrata, B. tenagophila, and B. straminea are naturally infected by the trematode Schistosoma mansoni, the causative agent of schistosomiasis. Despite decades of governmental efforts through official control programs, schistosomiasis remains an important public health problem in the country: thousands of people are infected with the trematode each year and millions live in endemic areas. The World Health Organization recommends using a combination of molluscicide (niclosamide) and mass chemotherapy to control the transmission of schistosomiasis, with this treatment successfully reducing the morbidity of the disease. In the past, niclosamide has been used in official schistosomiasis control programs in Brazil. However, as B. glabrata recolonizes even after molluscicide application, the use of molluscicides has gradually decreased in the country until they were discontinued in 2002, mainly due to the rising global pressure to preserve the environment and the difficulties of obtaining licenses from the Brazilian Ministry of Environment to use toxic substances in aquatic ecosystems. Therefore, the discovery of new molluscicides, which could be more selective to Biomphalaria species and less harmful to the aquatic ecosystem, is necessary. In addition, political efforts to sensitize funders to provide grants for this field of research are required. In this context, this article aims to make a critical analysis of molluscicide application in schistosomiasis control programs in Brazil.

Field trials of low dose Bayluscide on snail hosts of schistosome and selected non-target organisms in sahelian Cameroon.

More than 85% of all cases of schistosomiasis in Cameroon occur in the northern sahelian half of the country representing 20% of the population. Several workers have advocated the integrated approach to schistosomiasis control, including snail control, but the death and decay of aquatic organisms, and fish kill that often follows Bayluscide application at the dose of 1 g/m3 decrease its acceptability. The present study was designed to assess the effect of lower Bayluscide doses on snail host and non-target fish, frog, the tadpole kill. Bayluscide was applied to study ponds at concentrations of 0, 0.25, 0.5, and 1 g/m3 (ppm). Pre and post application assessment of snails hosts of schistosomes, fish, frog, and tadpole kill were carried out. All 0.25, 0.5, and 1 g/m3 Bayluscide concentrations reduced snail population significantly. Bayluscide concentration of 0.50 g/m3 applied in two rounds of 0.25 g/m3 resulted in high snail mortality and low lethality to fish, frogs, and tadpoles. Further studies are needed to assess the cost-effectiveness of Bayluscide in the control of schistosomiasis following the simplified approach.

Field trials of low dose Bayluscide on snail hosts of schistosome and selected non-target organisms in sahelian Cameroon

More than 85 percent of all cases of schistosomiasis in Cameroon occur in the northern sahelian half of the country representing 20 percent of the population. Several workers have advocated the integrated approach to schistosomiasis control, including snail control, but the death and decay of aquatic organisms, and fish kill that often follows Bayluscide application at the dose of 1g/m³ decrease its acceptability. The present study was designed to assess the effect of lower Bayluscide doses on snail host and non-target fish, frog, the tadpole kill. Bayluscide was applied to study ponds at concentrations of 0, 0.25, 0.5, and 1 g/m³ (ppm). Pre and post application assessment of snails hosts of schistosomes, fish, frog, and tadpole kill were carried out. All 0.25, 0.5, and 1 g/m³ Bayluscide concentrations reduced snail population significantly. Bayluscide concentration of 0.50 g/m³ applied in two rounds of 0.25 g/m³ resulted in high snail mortality and low lethality to fish, frogs, and tadpoles. Further studies are needed to assess the cost-effectiveness of Bayluscide in the control of schistosomiasis following the simplified approach.

Measures for the prevention and control of Taenia solium taeniosis and cysticercosis.

Taeniosis and cysticercosis due to Taenia solium are public health problems in many developing countries. Many studies of this parasitic zoonosis have focused on clinical features, diagnosis, treatment, surveillance, epidemiology and risk factors analysis. More recently projects on community and mass intervention strategies had been conducted in several rural areas worldwide focused on pig vaccination, pig cysticercosis treatment, human mass treatment, infrastructure development, as well as health education campaigns. Their advantages, disadvantages and public health impact have been published. This document discusses the feasibility and limitations of these interventions in order to assist countries in selection the best strategy for the prevention and control of this disease; we emphasized the specific strategies that might be recommended in different demographical situations.

Effects of Bayluscide WP 70 on the survival and water-leaving behaviour of Biomphalaria straminea, snail host of schistosomiasis in northeast Brazil.

The toxic and behavioural effects of niclosamide (Bayluscide WP 70) on Biomphalaria straminea from a highly endemic area of schistosomiasis in northeastern Brazil were investigated through laboratory bioassays. The LD50 and LD90 were 0.114 mg/l and 0.212 mg/l, respectively. Water-leaving behaviour occurred among 14% to 30% of the snails in the presence of sublethal doses of niclosamide and among 16% of the controls. It was concluded that both the relatively low susceptibility to niclosamide and water-leaving behaviour of local B. straminea may be responsible for the recolonization of transmission foci after mollusciciding. It was suggested that recently improved measures of snail control, such as controlled-release formulations of niclosamide and plant molluscicides should be considered in areas where snail control is recommended.

Efficacy of Niclosamide as a potential topical antipenetrant (TAP) against cercariae of Schistosoma mansoni in monkeys.

A 1% (W/V) formulation of Niclosamide (2', 5-Dichloro-4-nitrosalicylanilide) (TAP) was tested on Cebus apella monkeys as a topical prophylactic against schistosomiasis mansoni. Two experiments were conducted using the same formulation. In the first experiment, the TAP provided complete protection against schistosomiasis for 3 days. Of the 4 monkeys treated with TAP 7 days before exposure to Schistosoma mansoni cercariae, 2 were completely protected. The remaining 2 monkeys of the 7 day treatment group had a 78% or greater reduction in adult worm burdens when compared to the placebo treated monkeys. The second experiment was designed to determine the time between day 3 and 7 when the TAP no longer provided complete protection. However, all of the TAP treated monkeys in this experiment were completely protected, even the monkeys treated 7 days earlier. In both experiments, all monkeys used as infection controls and those receiving only the placebo became infected and showed typical experimental schistosomiasis. These results demonstrate that the TAP could provide fast acting, short-term protection to people who must enter cercariae infested water.

Repovoamento de criadouros de Biomphalaria glabrata apos tratamento com niclosamida / Repopulation of breeding habitats of Biomphalaria glabrata after treatment with niclosamide

Experimentos foram feitos no laboratorio e no campo nos anos de 1980 a 1984, objetivando detectar as causas do repovoamento de criadouros de Biomphalaria glabrata apos tratamento com niclosamida. Os bioensaios no laboratorio mostraram que a suscetibilidade a niclosamida emulsionavel de B. glabrata coletada mensalmente em um sistema de valas de irrigacao, variou durante o ano. As concentracoes letais 'CL IND. 90' foram 0,15 'mgl POT. -1' a 0,60 'mgl POT. -1', apresentando diferencas significantes estatisticamente (p<0,01) nos meses de maio/82 e janeiro/83 e dezembro/82 e janeiro/83, relacionadas a nutricao. No campo, foram tratados dois tipos de focos com solucao aquosa a 10 ppm de niclosamida. O primeiro era formado por reservatorio com cerca de 12.000 litros de agua e continha 14,5 por cento de moluscos infectados pelo Schistosoma mansoni. Uma unica aplicacao do produto, seguida de esvaziamento e limpeza do reservatorio, eliminou os moluscos. O segundo, era constituido por sistema de valas e poco com 5,6 por cento de moluscos infectados pos S. mansoni. Uma unica aplicacao do produto, sem limpeza das valas, reduziu a densidade planorbidica 98 por cento. As causas da sobrevivencia de 2 por cento dos moluscos do sistema de valas, sao discutidas, sendo relacionadas ao substrato do criadouro e a tecnica utilizada no tratamento.

[Repopulation of breeding habitats of Biomphalaria glabrata after treatment with niclosamide]. / Repovoamento de criadouros de biomphalaria glabrata após tratamento com niclosamida.

Experiments were undertaken both in the laboratory and in the field between 1980-1984 to evaluate the causes of repopulation of breeding places of Biomphalaria glabrata following treatment with Niclosamide. Laboratory bioassays showed that the susceptibility to emulsifiable Niclosamide of B. glabrata collected monthly from an irrigation ditch system varied during the year. Lethal concentrations (LC90) ranged between 0.15 mg/l-1 and 0.60 mg/l-1. Statistically significant differences (alpha = 0.01) were evident between the months of May/82 and January/83 and December/82 and January/83, and were related to snail nutrition. In the field two types of foci of B. glabrata were treated with 10 ppm of Niclosamide. The first one consisted of a reservoir of 12000 1 of water in which 14.5% of snails were infected with Schistosoma mansoni. One application of molluscicide followed by cleaning of the reservoir eliminated all the snails. The second one consisted of an irrigation system in which 5.6% of the snails were infected with S. mansoni. One application of molluscicide without cleaning the ditches reduced the density of snails by 98%. The causes of the survival of 2.0% of the snails in the ditches are discussed in relation to the substratum of the breeding places and the treatment technique.