The efficacy of topical, oral and surgical interventions for the treatment of tungiasis: A systematic review of the literature.

BACKGROUND: Tungiasis is a neglected disease caused by Tunga penetrans that can be complicated by secondary infections and local tissue destruction. Adequate treatment is important, especially in vulnerable populations; potential treatment options proposed range from surgical extraction to the use of oral and topical medications. We aimed to perform a systematic review to assess the efficacy of topical, oral and surgical interventions for the treatment of tungiasis. METHODOLOGY/PRINCIPAL FINDINGS: The present review is registered in PROSPERO (CRD42021234741). On September 1, 2020, we searched PubMed, EMBASE, Scopus, Web of Science, Science Direct, Scielo and LILACS BVS. We included clinical trials and longitudinal observational studies that evaluated any topical, systemic or mechanical treatment for tungiasis. We used the Revised Cochrane Risk of Bias (RoB) Tool for Randomized Trials for clinical trial analysis. Qualitative and quantitative descriptive syntheses were performed. Our search strategy resulted in 3376 references. Subsequently, 2568 titles/abstracts and 114 full texts were screened. We finally included 19 articles; 9 were classified as clinical trials. Two and 3 articles presented low and some RoB, respectively, according to the tool. Only two articles tested the efficacy of oral medications (niridazole, ivermectin), with discouraging results. Six clinical trials evaluated topical products for the treatment of tungiasis; 2 evaluated dimeticone-based compounds and reported positive results in lesion reduction and cure. None reported significant adverse reactions. Surgical extraction was evaluated only in observational studies. CONCLUSIONS/SIGNIFICANCE: We conclude that, although surgical extraction is the most commonly used treatment, there is sufficient evidence supporting the use of occlusive agents, especially manufactured dimeticone-based products.

Clinical interventions for tungiasis (sand flea disease): a systematic review.

Tungiasis (sand flea disease) is an epidermal parasitic skin disease occurring in resource-limited communities. There is no standard treatment for tungiasis, and available treatment options are scarce. To our knowledge, this is the first systematic review aimed to assess randomised controlled trials (RCTs) investigating interventions for tungiasis. We systematically searched databases including MEDLINE (EBSCOhost), CENTRAL, CINAHL, PubMed, Web of Science, SciELO, LILACS and Embase (Scopus) for RCTs in any language, from inception of the databases until June 12, 2021. RCTs exploring preventive and therapeutic interventions for tungiasis were eligible. We used the revised Cochrane Collaboration's risk of bias tool to assess the risk of bias and Jadad scale to quantify the methodological quality of the RCTs. Of the 1839 identified records, only eight RCTs involving 808 participants were included, and several methodological deficiencies were identified in most of the trials. Trial interventions included: oral drugs niridazole and ivermectin and topical interventions of ivermectin lotion, metrifonate lotion, thiabendazole lotion, thiabendazole ointment, dimeticones (NYDA), and a neem seed and coconut oils-based mixture for treatment and coconut oil-based lotion (Zanzarin) for prevention. The coconut oil-based lotion for prevention and dimeticones for treatment of tungiasis have displayed the most promise. Most of the RCTs included in this study had low methodological quality. There is a clear unmet need for high-quality RCTs examining safe and effective prevention and treatment alternatives of tungiasis in endemic settings.

Ethylcellulose inserts of an orphan drug for periodontitis: preparation, in vitro, and clinical studies.

Ethylcellulose inserts of niridazole fabricated by casting were studied for in vitro release and in vivo clinical effectiveness. The in vitro drug release was steady and sustained for over 7 days and followed diffusion kinetics. Selected batch, EN3, was evaluated clinically in patients with periodontitis for 6 months. A significant improvement (alpha < or = 0.05) in clinical indices from baseline was observed. Intergroup study revealed a significant (alpha < or = 0.01) change in the bleeding index, gingival index, plaque index, calculus criteria, and pocket depth. Significant reduction in total bacterial count in gingival crevicular fluid was observed before and postdevice insertion, as well as between control and treatment groups.

Niridazole biodegradable inserts for local long-term treatment of periodontitis: possible new life for an orphan drug.

Periodontal pocket inserts of niridazole (NZ) made with Resomer(R) (grades RG 503H and RG858, designated as RH and RG, respectively) were studied. Various formulation variables were evaluated to obtain a biodegradable delivery systems showing device degradation and drug depletion parallel to each other in vitro. Drug release from the prepared inserts was evaluated using a static dissolution setup (for 1 month). Incorporation of 3 parts of RG in 1 part of RH inserts caused a 50% decrease in the initial release rate. The RH-NZ inserts showed a spurt in release around the 10th day of the study, which coincided with the decrease in device weight, suggesting onset of device degradation. Pilot-scale clinical trials in 12 patients indicated improvements in clinical indices from the baseline values. The average pocket depth was reduced significantly (alpha = 0.05) from 6.34 +/- 1.86 mm at baseline to 5.94 +/- 0.28 mm after 28 days of treatment.

An in vivo evaluation of induction of abnormal sperm morphology by some anthelmintic drugs in mice.

Using the murine sperm-head abnormality test, the mutagenicity of pyrantel pamoate, levamisole, albendazole, mebendazole and niridazole was evaluated. Pyrantel pamoate and niridazole induced increases in sperm-head abnormalities statistically significant over the negative controls at all the dose levels that were considered; the induction was dose-dependent indicating that both drugs might be mutagenic. Levamisole, albendazole, mebendazole and thiabendazole, all were unable to induce statistically significant increases in sperm-head abnormalities over the negative controls at all the dose levels tested; there was no correlation between dose level of administered drugs and incidence of abnormal sperms, indicating that the drugs might not be mutagenic.

In pursuit of drugs for American trypanosomiasis: evaluation of some "standards" in a mouse model.

Forty-nine "standard" compounds known to be useful in the treatment of other diseases were tested for their suppressive activity against the trypomastigotes of Trypanosoma cruzi-infected mice. The most active was the antidepressant protriptyline, which was almost three times as effective as the reference drug, nifurtimox. A major value of the present data is to demonstrate the refractoriness of the T. cruzi parasite against many of the drug standards that have known biological activity.

Prevalence and intensity of Schistosoma haematobium urinary schistosomiasis in the Port St Johns district.

A urinary schistosomiasis survey undertaken in the Port St Johns district of the former Transkei showed the parasite to be endemic and noted an increase in overall infection rates in the region compared with previous studies. There was a general stability in infection over the sampling period 1987-1989. Prevalence rates were low to moderate with an overall prevalence of 42%. These ranged from approximately 10% in the low-prevalence settlement to 89.9% in the settlement with the highest prevalence. Infection rates were found to decrease nearer the coast, and settlements closest to the sea had the lowest prevalence rates. The intensity of infection was low, with the majority of patients having fewer than 200 eggs per 10 ml urine. Very few sufferers were treated with Ambilhar at clinics and hospitals.

Pregnancy following infertility due to pelvic schistosomiasis--a case report.

A case of infertility due to bilateral tubal blockage secondary to pelvic schistosomiasis in a Nigerian woman is presented. Intra uterine pregnancy followed treatment by peritubal adhesiolysis and the use of niridazole.

The role of oxygenation in embryotoxic mechanisms of three bioreducible agents.

Many xenobiotics used in the treatment of hypoxic pathogens and tumors require reductive bioactivation under anaerobic conditions for maximal effectiveness and/or toxicity. A number of agents of this type have been shown to be teratogenic in vitro and/or in vivo. Early conceptuses may be vulnerable to these agents because they exist in a relatively anaerobic environment and have the capacity to perform reductive metabolism. It has been hypothesized that the single electron redox potential of bioreducible agents plays a dominant role in the capacity to induce anomalies. We examined the in vitro embryotoxicity in rats of three bioreducible drugs of similar redox potential under normoxic and hypoxic conditions as well as the capacity of those drugs to redox cycle and to damage DNA in embryonic tissue. Adriamycin, mitomycin C, and niridazole were shown to have differential embryotoxic responses in vitro to altered oxygenation. Studies of the bases of drug action showed (1) Adriamycin induces DNA strand breaks at concentrations that correlate well with embryolethality; (2) Mitomycin C does not induce strand breaks, but its dysmorphogenicity is increased by hypoxia; and (3) Niridazole does not produce DNA damage but appears to induce asymmetric malformations by depleting embryonic oxygen through redox cycling. Together the studies show that dysmorphogenic and embryolethal effects may result from separate mechanisms and that oxygenation plays an important role in those mechanisms.

[Treatment of bilharziasis]. / Le traitement des bilharzioses.

Specific treatment of bilharziosis is obviously simplified by praziquantel which, unfortunately, is not easily available in endemic areas. Nevertheless, the major problem is an early treatment before the occurrence of severe sequellae. Mass chemoprophylaxis remains needed and, if possible, with praziquantel. For economic purposes, we have often to use either oxamniquine or niridazole-metrifonate combination.

Response of drug resistant isolates of Schistosoma mansoni to antischistosomal agents.

The susceptibility of four isolates of Schistosoma mansoni (BH, MAP, MPR-1 and K) to four multiple doses of anti-schistosomal agents (hycanthone, niridazole, oxamniquine, and praziquantel) were evaluated in infected female Swiss albino mice. These schistosomal isolates had been maintained in the laboratory without further drug pressure for 20 to 30 generations. Multiple dosage regimens were used for each drug against each isolate of S. mansoni to generate ED50 (effective dose 50%) values. Results demonstrated that the K isolate is resistant to niridazole, the MPR-1 isolate to oxamniquine, and the MAP isolate to both hycanthone and oxamniquine. The BH isolate was susceptible to all drugs and was used as the reference isolate. All isolates were susceptible to parziquantel. The significance of the difference in response of the MPR-1 and MAP isolates is discussed. These results confirm the resistance of these isolates of S. mansoni to three schistosomicides and demonstrate that the resistance of these isolates are stable over long periods of time without exposure to drugs.

Effect of addition of antimicrobial drugs to human collagen membrane.

Antimicrobial agents included in graft material for use in guided tissue regeneration of periodontally diseased tissue may be of value in combating infection, but may also alter the properties of the membrane material and exert an effect upon the host immune response. Metronidazole, niridazole and tinidazole were added to a cross-linked freeze-dried human type I collagen membrane in various doses and the following measured: (i) daily drug release into an aqueous solution, (ii) minimum inhibitory concentration (MIC) of the drugs against periodontopathogens, (iii) the effect of the drugs on mechanical properties of the membrane, and (iv) degradation by bacterial collagenase. In addition, the effects of the drugs on in-vitro cellular response was assessed by measuring blastogenesis of mononuclear cells obtained from patients suffering from periodontal disease and age/sex matched controls following incubation with the periodontopathogen Actinobacillus actinomycetemcomitans (AaY4). It was found that the collagen membranes released high levels of the drugs, at concentrations well above the MIC values. The mechanical properties of the membranes were not affected by the addition of the drugs, although resistance to the collagenases were. The cellular immune response was likewise suppressed in both patient and controls at drug doses comparable with the in-vitro drug release patterns. It is concluded that incorporation of antimicrobial drugs in a collagen barrier membrane may be of value when used in guided tissue regeneration.

Mutagenic effects of niridazole in animal-mediated and in liquid suspension assays using Escherichia coli K-12 as an indicator.

The mutagenic effects of the antischistosomal drug niridazole (1-(5-nitro-2-thiazolyl)-2-imidazolidinone) were investigated in liquid suspension and intrasanguineous animal-mediated assays with mice. As indicator strains Escherichia coli K-12 343/113 (Nir(S)) and a newly constructed niridazole nitroreductase-deficient derivative (Escherichia coli K-12 343/113 Nir(r) 200) were used. With the parental strain (Nir(S)) induction of nalidixic acid- and valine-resistant mutants was observed under in vivo conditions in the liver and, to a lesser extent, in the spleen. Positive results were also found when intestinal homogenates, blood sera, and urine samples of niridazole-treated animals were tested in vitro with the wild-type strain. With Escherichia coli K-12 343/113 Nir(r) 200 no clear-cut positive results were obtained in animal-mediated assays. In liquid suspension assays positive results were restricted to the urine samples. These findings indicate that the positive results obtained with the wild-type strain are due to nitroreduction and that the concentrations of mutagenic metabolites formed by activation processes in the living animal are too low to enable their detection in inner organs, intestines, and the blood with the reductase-deficient strain. In agreement with our present findings showing increased genotoxicity in urine, niridazole causes tumors in rodents preferentially in the kidneys and in the bladder.

Autoradiographic quantification of the efficacy of niridazole in mice infected with 75Se-labelled cercariae of Schistosoma mansoni.

The effects of the anti-schistosomal drug, niridazole, on the migration of Schistosoma mansoni larvae, biosynthetically radioisotope-labelled with 75[Se]-selenomethionine, was evaluated by autoradiography of compressed tissues of mice treated daily from Days 6 to 10 post-infection with 200 mg kg-1 niridazole. The results were compared with the migration of schistosomula in untreated controls. The distribution of schistosomula was altered in niridazole-treated mice, where there was a delayed migration from the lungs relative to the controls and significantly fewer schistosomula in total appeared to reach the liver. The total percentage of schistosomula detected as autoradiographic foci was significantly lower in treated mice than in the untreated controls. Niridazole-treated mice were free of any foci 10 days after the last treatment and no adult worms were recovered on perfusion of the hepatic portal system relative to control mice from which 5.8% of the infective cercariae were recovered as adult worms at Day 42 post-infection.

Schistosoma haematobium: histochemistry of glycogen, glycogen phosphorylase a and glycogen branching enzyme in niridazole-treated females.

The body posterior to the ovary of Schistosoma haematobium females was investigated. Glycogen, glycogen phosphorylase a (EC 2.4.1.1) and glycogen branching enzyme (EC 2.4.1.18) activities were detected in the subtegumental muscle system, parenchyma and mature vitelline cells, whereas no activities were detected in the tegument and immature vitelline cells of the parasite. Administration of a single niridazole dose of 250 mg kg-1 to the pouched mouse (Saccostomus camestris) produced the following changes in S. haematobium females: a relatively rapid depletion of glycogen stores due to disruption of the absorptive surface of the parasite, and to an increase in the activity of glycogen phosphorylase a; a reduction in the phosphorylase a to phosphorylase b-conversion capacity of glycogen phosphorylase phosphatase (EC 3.1.3.17); a decrease in glycogen branching enzyme activity; and a relatively rapid degeneration of parasite cells possibly due to their loss of endogenous energy reserves.

Asymmetric development of mitochondrial activity in rat embryos as a determinant of the defect patterns induced by exposure to hypoxia, hyperoxia, and redox cyclers in vitro.

Previous study has shown that midorganogenesis-stage rat embryos exposed to strong redox cyclers under moderate hypoxia in vitro develop severe necrotic defects on the right side. Similar effects can be produced by exposure to severe hypoxia alone. Studies presented here indicate that exposure to severe but survivable hyperoxia induces comparable necrotic degeneration on the left sides of all embryos. We hypothesize that the basis of these axially asymmetric defects is relatively precocious mitochondrial maturity on the left side of the embryo. In order to investigate this hypothesis, we compared mitochondrial oxygen utilization (NADH oxidase activities) on either side of rat embryos between days 11 and 14 of gestation. Activities were consistently higher on the left side during this period and significantly higher on day 11. We also found that the asymmetric embryotoxicity induced by niridazole, a strong redox cycler, could be attenuated by prior culture under hyperoxic conditions. We propose that mitochondrial immaturity on the right results in inadequate energy generation under hypoxic conditions, either directly or as a result of redox cycling. On the other hand, necrosis associated with hyperoxic conditions results from "leakage" of superoxide from functionally mature mitochondria on the left side.

Formation of N-(5-nitro-2-thiazolyl)-N'-carboxymethylurea from 5-hydroxyniridazole. Role of aldehyde dehydrogenase in the oxidative metabolism of niridazole.

N-(5-nitro-2-thiazolyl)-N'-carboxymethylurea (NTCU) has been identified as a urinary metabolite of the antischistosomal drug niridazole [1-(5-nitro-2-thiazolyl)-2-imidazolidinone]. When DBA/2J mice were treated with [14C]niridazole, a metabolite comprising 12-14% of the total radioactivity in 24-hr urine samples was resolved by HPLC. The compound was subsequently isolated from pooled urine of niridazole-treated patients. It was identified as NTCU by mass spectrometry, and the deduced structure was confirmed by chemical synthesis. NTCU is unique among known niridazole metabolites, because it lacks an intact imidazolidinone ring. Its structure allows for a ketoenol tautomerism in which the enolate is stabilized by conjugation with the nitrothiazole ring, as evidenced by a pH-dependent 80-nm red shift in the absorption spectrum. We hypothesized that NTCU arises via oxidation of an acyclic aldehyde tautomer of 5-hydroxyniridazole, one of two proximate oxidative niridazole metabolites. Indirect evidence for the aldehyde tautomer included the fact that 5-hydroxyniridazole displayed the same pH-dependent spectral shift as NTCU with a single isobestic point at 388 nm. The proposed precursor-product relationship was confirmed when we found that NTCU formation from 5-hydroxyniridazole was catalyzed by NAD(+)-dependent aldehyde dehydrogenase (EC 1.2.1.3). The activity copurified with benzaldehyde dehydrogenase activity from mouse liver cytosol. Furthermore, benzaldehyde was a competitive inhibitor of 5-hydroxyniridazole dehydrogenase activity. These results demonstrate that 5hydroxyniridazole is not an end product of niridazole metabolism. Because biotransformation of niridazole to its 4- and 5-hydroxy derivatives has been implicated in the drug's carcinogenicity and central nervous system toxicity, NTCU formation appears to represent a detoxication pathway in mammals.

Studies of embryotoxic mechanisms of niridazole: evidence that oxygen depletion plays a role in dysmorphogenicity.

Previous study has shown that niridazole (NDZ) is dysmorphogenic to rat embryos between days 10 and 11 under culture conditions including 5% oxygen. Other studies have found that reductive embryonic biotransformation is required but that covalent binding is not a major basis of this embryotoxicity. In research presented here, NDZ exposure of homogenates prepared from day 10 rat embryos resulted in stimulation of oxygen uptake from incubation media. Further studies showed that a large percentage of this increased oxygen uptake was associated with the generation of superoxide anion radical and hydrogen peroxide. These findings led us to hypothesize that redox cycling forms the basis of the in vitro dysmorphogenicity of NDZ. The basic premise of this hypothesis is that as a result of redox cycling, oxygen is depleted from the sensitive tissues of embryos. In order to investigate it, we devised a technique for carefully controlling and monitoring oxygen tensions in embryo cultures. We found that when oxygen concentrations of 4% were established, a highly significant incidence of asymmetric defects resulted. These defects appeared analogous to those induced by NDZ exposure, consisting of asymmetric necrosis of mesenchymal tissue near the cephalic end of the neural tube and thinning of the neuroepithelium on the right. We concluded that the hypoxia induced by redox cycling of NDZ and related nitroheterocycles represents a major embryotoxic principle of action.

[Synthesis of acylates of niridazole and its analogs as schistosomicides].

In order to decrease the toxicity and enhance the curative effect of niridazole against Schistosomiasis japonica, a series of acylates of niridazole has been prepared through acylation of niridazole, 2-substituted acetamido-5-nitrothiazoles and 1-(5-nitro-2-thiazolyl)-4-acylpiperazine were also prepared. The products has been tested against Schistosomiasis japonica in mice. Preliminary test results showed that the majority of aliphatic acylates of niridazole exhibited marked schistosomicidal effect against adult worms as well as larva (compounds 2, 4-8, 12, 13, 15, 18, 19), a few of aromatic and heterocyclic acylates (compounds 14, 22) and the analogs of niridazole (compounds 26, 39, 49) showed weak activity.