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.

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.

Comparative trials of regimes for the treatment of urinary schistosomiasis in The Gambia.

Alternative regimes for the treatment of Schistosoma haematobium infection were compared in two trials. Praziquantel at a dose of 40 mg kg-1 appeared to cure 63% of a random sample of heavily infected subjects; significantly more than the 18% cured by three fortnightly doses of metrifonate at 10 mg kg-1. However, praziquantel led to a greater incidence of mild, transient side-effects. A single dose of metrifonate was found to be an inadequate treatment in the same group of subjects as it left 53% with an egg count of at least 100 ova/10 ml. A combination of 10 mg kg-1 of metrifonate and 25 mg kg-1 of niridazole had a similar effect to that of a single dose of metrifonate alone and it had more side-effects. Reduced doses of praziquantel had less effect on egg counts than the standard regime, but the difference was not significant in the case of 20 mg kg-1. Although a combination of metrifonate and praziquantel, each at 10 mg kg-1, had a greater effect than either constituent alone, the difference was not significant. Factors affecting the choice of drug for use in mass treatment of urinary schistosomiasis in The Gambia are discussed. The present findings suggest that the standard regime of praziquantel should be used or, if this is not possible, a three-dose metrifonate regime.

Influence of dosing interval and in-patient versus out-patient status on incidence of side-effects of niridazole.

The side-effects of niridazole used for urinary schistosomiasis were studied prospectively over a 3-month period in male patients receiving the standard dose of 25 mg day-1 kg-1 for 7 days. Side-effects were detected in 80% of in-patients but only in 33% of out-patients. The range of side-effects was greater in in-patients taking their daily doses in two portions than in those taking theirs in three. Cure rates and degree of schistosoma egg suppression were significantly lower in out-patients suggesting that compliance with treatment was poorer.

Niridazole as an adjunct to "conventional" immunosuppression in kidney allograft transplantation. Long-term follow up.

To assess the value of niridazole as adjuvant immunosuppressant to conventional steroid and azathioprine therapy, a prospective randomized clinical study in 26 cadaver kidney recipients had been performed. No beneficial effect was observed on the kidney graft survival with the addition of niridazole. Neither was there any additional immunosuppressive action demonstrated in the serum of the patients in this group. On the basis of our limited clinical experience niridazole can not be recommended as an adjunct agent for kidney graft recipients.

Schistosoma mansoni: an in vivo study of drug-induced autophagy in the gastrodermis.

The effects of Astiban, Lucanthone, Hycanthone and Niridazole on autophagic activities in the gastrodermis of Schistosoma mansoni were determined in vivo, using different dosage levels and dosage times. With Astiban, high levels of autophagy were observed in the gastrodermis 2 hours after an injection of the drug into the mouse, and this response had declined by 20 hours, marking a recovery by the parasite from the drug. Hycanthone and Lucanthone produced an autophagic response several days after the onset of treatment, and no recovery was observed in the morphology of the gastrodermis after the drug was discontinued. The effects of Niridazole on the gastrodermis were to produce the most dramatic ultrastructural changes after high doses and over several days of treatment. With all the drugs examined, gastrodermal autophagy was characterized by the formation of vacuoles containing cell components, lipid droplets and sometimes hydrolytic enzyme reaction product. The autophagic vacuoles appeared to be formed by the sequestration of cytoplasmic material by the basal membrane infoldings, and the transfer of enzymes into the vacuole from within the limiting membrane. The residues from intracellular digestion appeared to be emptied into the caecal lumen.

Long-term efficacy of single-dose oral treatment in schistosomiasis haematobium.

A two-year follow-up was conducted in children who had been the subjects of a six-month double-blind trial in the single-dose treatment of Schistosoma haematobium infection. The trial had assessed therapeutic efficacy of three oral preparations-praziquantel 40 mg/kg, metrifonate 10 mg/kg, and the 'combination' (concurrent niridazole 25 mg/kg and metrifonate 10 mg/kg administration). Reduction in urinary egg excretion remained high up to follow-up at two years, based on a comparison of pre- and post-treatment geometric mean counts-praziquantel 96.9% (n = 96 at six months, 51 at two years); the 'combination' 93.9% (n = 97 at six months, 48 at two years); and metrifonate 90.3% (n = 92 at six months, 49 at two years). The differences in percentage reduction were not significant (p greater than 0.1). However, a significantly greater reduction in egg output was produced by praziquantel (81.7%) and the 'combination' (82.5%) than by metrifonate (54.2%), on comparing pre- and post-treatment arithmetic mean counts (p less than 0.01). A significantly smaller percentage of subjects were excreting greater than or equal to 125 ova/10 ml urine two years after treatment with praziquantel (10.3%), compared to treatment with the 'combination' (25.7%) and metrifonate (35.8%) (p less than 0.01). The cure rate was significantly higher in the praziquantel group (47.4%) compared to the 'combination' (24.7%) and metrifonate (17.4%) groups, for the six to 24-month follow-up period (p less than 0.001). The pattern and level of transmission had contributed to the long-term efficacy recorded in this study.

Single dose oral treatment in urinary schistosomiasis: a double blind trial.

A double blind trial of three oral preparations given in single doses for the treatment of Schistosoma haematobium infection was carried out in schoolchildren; selection was biased towards those who excreted large quantities of eggs. Praziquantel 40 mg/kg was the most effective drug giving a greater than 97% reduction in egg output six months after treatment; combined treatment with niridazole 25 mg/kg and metrifonate 10 mg/kg gave a reduction of greater than 92% and metrifonate 10 mg/kg alone a reduction of greater than 86%. Fewer children continued to have moderate to heavy infections (excretion greater than 124 ova/10 ml urine) six months after treatment with praziquantel (5%) and the combined regimen (7%) than with metrifonate (16%). Though our findings show that praziquantel appears to be the most effective and convenient drug available for individuals with S haematobium infection, the combined regimen is a cheaper alternative for treatment where cost is important and parasitological cure not an essential objective.

Urethritis due to Schistosoma haematobium with superimposed gonorrhea.

A case of urethritis due to Schistosoma haematobium with superimposed gonorrhea is described. The diagnosis was confirmed by the presence of gram-negative intracellular diplococci in the urethral discharge and of characteristic terminal spined Schistosoma haematobium ova in the urine, as well as by the favorable clinical response to treatment with the antischistosomal drug niridazole. A diagnosis of schistosomiasis should be considered for patients in whom treatment with drugs that are active against the common causes of urethritis fails, particularly when such patients live in an area where bilharzia is endemic or epidemic.

Sustained release of niridazole from silicone rubber implants for the treatment of Schistosoma mansoni infections.

Niridazole was incorporated into silicone rubber implants to investigate the potential of a sustained release of the drug in the therapy of murine schistosomiasis mansoni. The infected animals (200 cercariae for 6 weeks) were randomly divided into three groups: one group received silicone rubber implants containing 50% by weight niridazole; a second group received blank silicone rubber implants with no drug; and the third group received no implants. Mortality 4 weeks later was in excess of 80% for animals with no implants or with the blank silicone rubber implants. In contrast, 10% mortality was observed in the mice receiving the niridazole-silicone rubber implants over a 10-week period. The worm burden in the niridazole-silicone rubber implant group was reduced at 10 weeks post implantation by 77%.

Biochemical effects of niridazole. I. In vitro and in vivo effect of niridazole on the rate of gluconeogenesis and oxidation of pyruvate and some Krebs cycle intermediates in mice.

The effects of the antischistosomal drug, niridazole, on the rate of gluconeogenesis in kidney cortex slices and on the rate of oxidation of pyruvate and some Krebs cycle intermediates in liver homogenate of non infected mice were determined. In vitro, niridazole was found to inhibit the succinate and pyruvate oxidation at the high concentration tested (10(-3)M). The rate of gluconeogenesis from alpha-ketoglutarate was unaffected. In vivo, niridazole showed a stimulatory effect on the rate of gluconeogenesis from alpha-ketoglutarate and on the rate of oxidation of pyruvate at a dosage level of 100 mg/kg for 5 days. The observed changes were discussed and the differences observed between the in vivo and in vitro work were assumed to be due to exposure of the tissues to the unmetabolized drug in vitro and to the drug and its metabolites in vivo.