Emodepside for Trichuris trichiura and Hookworm Infection.

BACKGROUND: Current treatments for soil-transmitted helminth infections in humans have low efficacy against Trichuris trichiura. Emodepside - a drug in veterinary use and under development for the treatment of onchocerciasis in humans - is a leading therapeutic candidate for soil-transmitted helminth infection. METHODS: We conducted two phase 2a, dose-ranging, randomized, controlled trials to evaluate the efficacy and safety of emodepside against T. trichiura and hookworm infections. We randomly assigned, in equal numbers, adults 18 to 45 years of age in whom T. trichiura or hookworm eggs had been detected in stool samples to receive emodepside, at a single oral dose of 5, 10, 15, 20, 25, or 30 mg; albendazole, at a single oral dose of 400 mg; or placebo. The primary outcome was the percentage of participants who were cured of T. trichiura or hookworm infection (the cure rate) with emodepside 14 to 21 days after treatment, determined with the use of the Kato-Katz thick-smear technique. Safety was assessed 3, 24, and 48 hours after the receipt of treatment or placebo. RESULTS: A total of 266 persons were enrolled in the T. trichiura trial and 176 in the hookworm trial. The predicted cure rate against T. trichiura in the 5-mg emodepside group (85% [95% confidence interval {CI}, 69 to 93]; 25 of 30 participants) was higher than the predicted cure rate in the placebo group (10% [95% CI, 3 to 26]; 3 of 31 participants) and the observed cure rate in the albendazole group (17% [95% CI, 6 to 35]; 5 of 30 participants). A dose-dependent relationship was shown in participants with hookworm: the observed cure rate was 32% (95% CI, 13 to 57; 6 of 19 participants) in the 5-mg emodepside group and 95% (95% CI, 74 to 99.9; 18 of 19 participants) in the 30-mg emodepside group; the observed cure rates were 14% (95% CI, 3 to 36; 3 of 21 participants) in the placebo group and 70% (95% CI, 46 to 88; 14 of 20 participants) in the albendazole group. In the emodepside groups, headache, blurred vision, and dizziness were the most commonly reported adverse events 3 and 24 hours after treatment; the incidence of events generally increased in a dose-dependent fashion. Most adverse events were mild in severity and were self-limited; there were few moderate and no serious adverse events. CONCLUSIONS: Emodepside showed activity against T. trichiura and hookworm infections. (Funded by the European Research Council; ClinicalTrials.gov number, NCT05017194.).

Preclinical and Clinical Characteristics of the Trichuricidal Drug Oxantel Pamoate and Clinical Development Plans: A Review.

Soil-transmitted helminths (Ascaris lumbricoides, hookworm and Trichuris trichiura) infect about one-fifth of the world's population. The currently available drugs are all highly efficacious against A. lumbricoides. However, they are only moderately efficacious against hookworm and poorly efficacious against T. trichiura. Oxantel, a tetrahydropyrimidine derivative discovered in the 1970s, has recently been brought back to our attention given its high efficacy against T. trichiura infections (estimated 76% cure rate and 85% egg reduction rate at a 20 mg/kg dose). This review summarizes the current knowledge on oxantel pamoate and its use against T. trichiura infections in humans. Oxantel pamoate acts locally in the human gastrointestinal tract and binds to the parasite's nicotinic acetylcholine receptor (nAChR), leading to a spastic paralysis of the worm and subsequent expulsion. The drug is metabolically stable, shows low permeability and low systemic bioavailability after oral use. Oxantel pamoate was found to be safe in humans, with only a few mild adverse events reported. Several clinical trials have investigated the efficacy of this drug against T. trichiura and suggest that oxantel pamoate is more efficacious against T. trichiura than the currently recommended drugs, which makes it a strong asset to the depleted drug armamentarium and could help delay or even prevent the development of resistance to existing drugs. We highlight existing data to support the use of oxantel pamoate against T. trichiura infections.

Safety of an extended-release injectable moxidectin suspension formulation (ProHeart® 12) in dogs.

BACKGROUND: The safety of ProHeart® 12 (PH 12; extended-release injectable suspension; 10% moxidectin in glyceryl tristearate microspheres) was evaluated in four studies using Beagle dogs and one study using ivermectin-sensitive Collies. The recommended dose is 0.5 mg/kg subcutaneously once yearly. METHODS: Study 1: safety margin was evaluated as 3 treatments of PH 12 (0× (control); 1× (recommended dose); 3× (3 times recommended dose) and 5× (5 times recommended dose) in 12 months via clinical observations, body weights, food consumption, injection site observations, physical examinations, moxidectin tissue assay, pharmacokinetics, and clinical and anatomic pathology. Study 2: safety in breeding-age males was demonstrated by semen testing at 14-day intervals from Day 7 to Day 91 post-treatment (0× or 3×). Study 3: reproductive safety in females was demonstrated by monitoring dams and litters following treatments (0× or 3×) administered during breeding, gestation, or lactation. Study 4: safety in dogs surgically implanted with adult heartworms was evaluated by clinical and laboratory monitoring following treatment with 0× or 3× administered 61 days post-implantation. Study 5: safety in ivermectin-sensitive dogs (120 µg/kg SC) was by clinical monitoring for 1 week after administering 1×, 3× or 5×. RESULTS: Study 1: slight swelling clinically detectable at some 3× and 5× injection sites was characterized microscopically as granulomatous inflammation, like tissue responses to medical implants, interpreted as non-adverse. Pharmacokinetics were dose-proportional and there was little or no systemic accumulation. Residual moxidectin mean (range) at 1× injection sites after 1 year was 16.0% (0.045-37.6%) of the administered mass. Studies 2 and 3: no effects were identified in reproductive indices (females) or semen quality characteristics (males). Study 4: PH 12 produced marked reductions in circulating microfilariae and lower numbers of adult heartworms, but no adverse clinical signs were identified. Study 5: there were no abnormal clinical signs at 1×, 3× or 5× overdoses of PH 12 in ivermectin-sensitive dogs. CONCLUSIONS: PH 12 has a > 5× safety margin in both normal and ivermectin-sensitive dogs, has no effects on canine reproduction, and is well tolerated in heartworm-positive dogs. The only treatment-related finding was non-adverse, granulomatous inflammation at the injection site.

Hepatotoxicity caused by mebendazole in a patient with Gilbert's syndrome.

WHAT IS KNOWN AND OBJECTIVE: Mebendazole (MBZ) is a broad-spectrum antihelminthic agent of the benzimidazole type. Although MBZ has been reported to cause hepatic injury, case reports of severe hepatic injury are very rare. We report a case of severe hepatitis after administration of MBZ in a patient with Gilbert's syndrome affected by pinworms infestation. CASE SUMMARY: Differently from other cases of hepatitis due to MBZ reported in the scientific literature, our patient received standard doses of MBZ for a short period of time. After 18 days from the start of therapy, he developed hepatomegaly, and increases in hepatic enzymes and bilirubin. Hepatic enzymes returned to normal over the following 5 weeks. WHAT IS NEW AND CONCLUSION: This is the first case report of important liver injury after administration of MBZ in a patient with Gilbert's syndrome. We suspected that a diminished hepatic glucuronidation of MBZ due to the reduced activity of the glucuronosyltransferase enzyme in our patient could have caused an increase in unconjugated toxic metabolites of MBZ and the consequent liver damage.

An ocular myasthenia gravis attack after oral pyrantel pamoate: An unusual case report.

RATIONALE: Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction that can be triggered by anticholinergic agents. PATIENT CONCERNS: We present a 4-year-old female patient who was admitted to the outpatient clinic. She complained of drooped eyelids, which first appeared 2 days after taking a 200 mg dose of pyrantel pamoate. Past medical history is negative. DIAGNOSES AND TREATMENT: She was hospitalized with a diagnosis of ocular type MG, and pyridostigmine (40 mg/day) treatment was started. OUTCOMES: The patient recovered, and subsequently, the treatment dose was tapered. CONCLUSION: Pyrantel is an antihelminthic that acts as an agonist of nicotinic acetylcholine receptors (AChRs) of nematodes and exerts its therapeutic effects by depolarizing their muscle membranes. Consequently, there may be an association between pyrantel pamoate and MG.

Pharmacological and molecular dynamics analyses of differences in inhibitor binding to human and nematode PDE4: Implications for management of parasitic nematodes.

Novel chemical controls are needed that selectively target human, animal, and plant parasitic nematodes with reduced adverse effects on the host or the environment. We hypothesize that the phosphodiesterase (PDE) enzyme family represents a potential target for development of novel nematicides and anthelmintics. To test this, we identified six PDE families present in the nematode phylum that are orthologous to six of the eleven human PDE families. We characterized the binding interactions of family-selective PDE inhibitors with human and C. elegans PDE4 in conjunction with molecular dynamics (MD) simulations to evaluate differences in binding interactions of these inhibitors within the PDE4 catalytic domain. We observed that roflumilast (human PDE4-selective inhibitor) and zardaverine (selective for human PDE3 and PDE4) were 159- and 77-fold less potent, respectively, in inhibiting C. elegans PDE4. The pan-specific PDE inhibitor isobutyl methyl xanthine (IBMX) had similar affinity for nematode and human PDE4. Of 32 residues within 5 Å of the ligand binding site, five revealed significant differences in non-bonded interaction energies (van der Waals and electrostatic interaction energies) that could account for the differential binding affinities of roflumilast and zardaverine. One site (Phe506 in the human PDE4D3 amino acid sequence corresponding to Tyr253 in C. elegans PDE4) is predicted to alter the binding conformation of roflumilast and zardaverine (but not IBMX) into a less energetically favorable state for the nematode enzyme. The pharmacological differences in sensitivity to PDE4 inhibitors in conjunction with differences in the amino acids comprising the inhibitor binding sites of human and C. elegans PDE4 catalytic domains together support the feasibility of designing the next generation of anthelmintics/nematicides that could selectively bind to nematode PDEs.

Preclinical toxicity and pharmacokinetics of a new orally bioavailable flubendazole formulation and the impact for clinical trials and risk/benefit to patients.

BACKGROUND: Flubendazole, originally developed to treat infections with intestinal nematodes, has been shown to be efficacious in animal models of filarial infections. For treatment of filarial nematodes, systemic exposure is needed. For this purpose, an orally bioavailable amorphous solid dispersion (ASD) formulation of flubendazole was developed. As this formulation results in improved systemic absorption, the pharmacokinetic and toxicological profile of the flubendazole ASD formulation have been assessed to ensure human safety before clinical trials could be initiated. METHODS & FINDINGS: Safety pharmacology, toxicity and genotoxicity studies have been conducted with the flubendazole ASD formulation. In animals, flubendazole has good oral bioavailability from an ASD formulation ranging from 15% in dogs, 27% in rats to more than 100% in jirds. In in vivo toxicity studies with the ASD formulation, high systemic exposure to flubendazole and its main metabolites was reached. Flubendazole, up to high peak plasma concentrations, does not induce Cmax related effects in CNS or cardiovascular system. In repeated dose toxicity studies in rats and dogs, flubendazole-induced changes were observed in haematological, lymphoid and gastrointestinal systems and in testes. In dogs, the liver was an additional target organ. Upon treatment cessation, at least partial recovery was observed for these changes in dogs. In rats, the No Observed Adverse Effect Level (NOAEL) was 5 mg (as base)/kg body weight/day (mg eq./kg/day) in males and 2.5 mg eq./kg/day in females. In dogs, the NOAEL was lower than 20 mg eq./kg/day. Regarding genotoxicity, flubendazole was negative in the Ames test, but positive in the in vivo micronucleus test. CONCLUSIONS: Based on these results, in combination with previously described genotoxicity and reproductive toxicity data and the outcome of the preclinical efficacy studies, it was concluded that no flubendazole treatment regimen can be selected that would provide efficacy in humans at safe exposure.

Plasma and Urine Levamisole in Clinical Samples Containing Benzoylecgonine: Absence of Aminorex.

Aminorex has been reported as a metabolite of levamisole in man, but data on the aminorex concentrations in clinical samples are scant. We thus measured levamisole, aminorex and benzoylecgonine in urine, and levamisole and aminorex in plasma using achiral liquid chromatography-high resolution mass spectrometry. Centrifuged urine (50 µL) was diluted with LC eluent containing internal standard (benzoylecgonine-D3, 25 µg/L) (450 µL). For plasma, sample (200 µL) and Tris solution (2 mol/L, pH 10.6, 100 µL) were added to a 60.5 × 7.5 mm i.d. glass test tube. Internal standard solution (ketamine-D4, 200 µg/L) (10 µL) was added and the tube contents vortex-mixed (5 s). Butyl acetate:butanol (9 + 1, v/v; 200 µL) was added and after vortex-mixing (30 s) and centrifugation (13,680 × g, 4 min), the extract was evaporated to dryness and reconstituted in 10 mmol/L aqueous ammonium formate containing 0.1% (v/v) formic acid (150 µL). Prepared samples and extracts (100 µL) were analyzed using an AccucoreTM Phenyl-Hexyl column (2.6 mm a.p.s., 100 × 2.1 mm i.d.) maintained at 40°C. MS detection was in positive mode using heated electrospray ionization (ThermoFisher Q-ExactiveTM). Intra- and inter-assay accuracy and precision were ±20%, and ≤11%, respectively, for all analytes in both matrices. Lower limits of quantitation were 0.1 and 1 µg/L (all analytes) in plasma and urine, respectively. Of 100 consecutive urine samples submitted for drugs of abuse screening containing benzoylecgonine, levamisole was detected in 72 (median 565, range 4-72,970 µg/L). Levamisole was also measured in eight plasma samples (median 10.6, range 0.9-64.1 µg/L). A number of metabolites of levamisole (4-hydroxylevamisole, levamisole sulfoxide, levamisole glucuronide, and hydroxylevamisole glucuronide) were tentatively identified in urine. Neither aminorex, nor any of its reported metabolites were detected in any sample.

The public health benefit and burden of mass drug administration programs in Vietnamese schoolchildren: Impact of mebendazole.

BACKGROUND: Mass anthelmintic drug administration is recommended in developing countries to address infection by soil-transmitted helminthiases (STH). We quantified the public health benefit of treatment with mebendazole in eight million Vietnamese children aged 5-14 years from 2006 to 2011. This was compared to the environmental impact of the pharmaceutical supply chain of mebendazole, as the resource use and emissions associated with pharmaceutical production can be associated with a public health burden, e.g. through emissions of fine particulate matter. METHODOLOGY: Through Markov modelling the disability due to STH was quantified for hookworm, Ascaris lumbricoides and Trichuris trichiura. For each worm type, four levels of intensity of infection were included: none, light, medium and heavy. The treatment effect on patients was quantified in Disability-Adjusted Life Years (DALYs). The public health burden induced by the pharmaceutical supply chain of mebendazole was quantified in DALYs through Life Cycle Assessment. PRINCIPAL FINDINGS: Compared to 'no treatment', the modelled results of five-year treatment averted 116,587 DALYs (68% reduction) for the three worms combined and largely driven by A. lumbricoides. The main change in DALYs occurred in the first year of treatment, after which the results stabilized. The public health burden associated with the pharmaceutical supply chain was 6 DALYs. CONCLUSIONS: The public health benefit of the Mass Drug Administration (MDA) averted substantially more DALYs than those induced by the pharmaceutical supply chain. These results were verified in a sensitivity analysis. The starting prevalence for each worm was the most sensitive model parameter. This methodology is useful for policymakers interested in a holistic approach towards the public health performance of MDA programs, enveloping both the treatment benefit received by the patient and the public health burden associated with the resource consumption and environmental emissions of the pharmaceutical production and supply chain.

Cognitive and neuroanatomical impairments associated with chronic exposure to levamisole-contaminated cocaine.

Currently, levamisole is the most common cocaine adulterant worldwide and it is known to induce a variety of adverse side effects. Animal studies and human case reports suggest potential neurotoxicity of the compound but neither neuroanatomical nor cognitive effects of levamisole have been systematically investigated in cocaine users so far. We examined cognitive performance and cortical structural differences between chronic cocaine users with low and high recent exposure to levamisole objectively determined by quantitative toxicological hair analyses. In Study 1, we compared 26 chronic cocaine users with low levamisole exposure (lowLevCU), 49 matched cocaine users with high levamisole exposure (highLevCU), and 78 matched stimulant-naive controls regarding cognitive functioning employing a comprehensive neuropsychological test battery. In Study 2, we investigated cortical thickness by use of T1-weighted MRI in a subgroup of 12 lowLevCU, 17 highLevCU, and 38 stimulant-naive controls. In Study 1, both cocaine user groups showed significant impairments in the cognitive domains of attention and working memory as well as in the global cognitive index. However, highLevCU showed significantly worse executive functions compared to lowLevCU although both groups did not differ in severity of cocaine consumption and other clinical dimensions. Study 2 revealed that highLevCU, displayed reduced cortical thickness specifically in the middle frontal gyrus compared to both controls and lowLevCU. Our results suggest that levamisole exposure during the last months in cocaine users is associated with increased executive function impairments and pronounced thinning of the lateral prefrontal cortex. Consequently, prevention and drug policy-making should aim to reduce levamisole contamination of street cocaine.

Evaluation of the Cardiac Safety of Long-Acting Endectocide Moxidectin in a Randomized Concentration-QT Study.

Potential effects on cardiac repolarization of single doses of moxidectin, a potent long-acting macrocyclic lactone endectocide, were assessed in a concentration-QT (c-QT; exposure-response) study. This double-blind, placebo-controlled, parallel-group study in healthy male volunteers (n = 60) randomized subjects to a single oral dose of moxidectin (4 mg, 8 mg, 16 mg, 24 mg, or 36 mg) or matching placebo. Serial plasma samples for pharmacokinetic (PK) analysis and concurrent triplicate electrocardiogram measurements were taken at baseline and 14 prespecified time points over 72 hours, yielding 900 QT interval-plasma concentration time-matched pairs. Moxidectin had no statistically significant or clinically relevant impact on QT interval at any dose level. The primary mixed effects model analysis revealed no treatment-related impact on the Fridericia-corrected QT interval-plasma concentration gradient (-0.0077, 90% confidence interval (CI) -0.0255 to +0.0101).

Diagnosis and management of inflammatory bowel disease in a harpy eagle (Harpia harpyja) with suspected fenbendazole toxicosis.

CASE DESCRIPTION A 14-year-old 4.1-kg (9.02-lb) male harpy eagle (Harpia harpyja) was evaluated because of vomiting, anorexia, lethargy, and weight loss (decrease of 0.35 kg [0.77 lb]) of 4 weeks' duration. The bird had previously been treated orally with fenbendazole after the initial onset of clinical signs. CLINICAL FINDINGS An initial CBC revealed marked heteropenia and anemia, but whole-body contrast-enhanced CT images and other diagnostic test findings were unremarkable. Clinical signs persisted, and additional diagnostic testing failed to reveal the cause. During celiotomy, a biopsy specimen of the duodenum was obtained for histologic examination, which revealed lymphoplasmacytic inflammation, consistent with inflammatory bowel disease (IBD). TREATMENT AND OUTCOME Prior to histopathologic diagnosis of IBD, barium sulfate administered via gavage resulted in a temporary improvement of clinical signs. Following diagnosis of IBD, corticosteroid administration was initiated in conjunction with antifungal prophylaxis. Cessation of vomiting and a return to normal appetite occurred within 3 days. Fifteen months after cessation of corticosteroid treatment, the eagle continued to do well. CLINICAL RELEVANCE To our knowledge, this was the first report of diagnosis and management of IBD in an avian species. For the eagle of the present report, results of several diagnostic tests increased clinical suspicion of IBD, but histologic examination of an intestinal biopsy specimen was required for definitive diagnosis. Although successful in this case, steroid administration in avian species must be carefully considered. Conclusive evidence of fenbendazole toxicosis was not obtained, although it was highly suspected in this bird.

Efficacy of Moxidectin Versus Ivermectin Against Strongyloides stercoralis Infections: A Randomized, Controlled Noninferiority Trial.

BACKGROUND: Infections with Strongyloides stercoralis are of considerable public health relevance. Moxidectin, a well-established drug in veterinary medicine under consideration for regulatory submission for the treatment of onchocerciasis, might serve as an alternative to the widely used ivermectin. METHODS: We conducted an exploratory, randomized, single-blind trial to evaluate the efficacy and safety of moxidectin (8 mg) vs ivermectin (200 µg/kg) against S. stercoralis infections. Cure rate (CR) against S. stercoralis was the primary outcome. Safety and efficacy against coinfections with soil-transmitted helminths and Opisthorchis viverrini were secondary outcomes. Noninferiority required the lower limit of the 95% confidence interval (CI) of the differences in CRs not exceed 7 percentage points. RESULTS: A total of 127 participants were enrolled and randomly assigned to the 2 treatments whereby 1 participant per arm was lost to follow-up. We observed a CR of 93.7% (59/63) for moxidectin compared to 95.2% (59/62) for ivermectin. Differences between CRs were estimated as -1.5% percentage points (95% CI, -9.6 to 6.5), thus the lower limit of the CI exceeds the noninferiority margin of 7 percentage points. No side effects were observed. CRs against hookworm infection were 57% (moxidectin) and 56% (ivermectin). Low efficacy for both drugs against O. viverrini was observed. CONCLUSIONS: Moxidectin might be a safe and efficacious alternative to ivermectin for the treatment of S. stercoralis infection, given that only slight differences in CRs were observed. However, noninferiority could not be demonstrated. Larger clinical trials should be conducted once the drug is marketed. CLINICAL TRIALS REGISTRATION: Current Controlled Trials: ISRCTN11983645.

Syndrome of Inappropriate Anti-Diuretic Hormone Secretion Secondary to Strongyloides stercoralis Infection in an Allogeneic Stem Cell Transplant Patient: A Case Report and Literature Review.

Syndrome of inappropriate anti-diuretic hormone (SIADH) has been reported to be associated with systemic Strongyloides stercoralis. Here, we report a case of a stem cell transplant (SCT) recipient who developed severe SIADH secondary to systemic S Stercoralis. The SIADH resolved quickly after treating the systemic S Stercoralis with ivermectin. A systematic review of the literature was performed by PubMed, Scopus, and Cochrane database search. Only eight cases of S Stercoralis in allogeneic SCT recipients have been previously reported. To our knowledge, ours is the first reported case of SIADH secondary to S Stercoralis infection in an allogeneic SCT recipient. Prior to transplantation, even if asymptomatic, patients from endemic regions should be screened with strongyloides immunoglobulin (Ig)G serology. Pretransplantation eosinophilia should be evaluated by screening multiple stool samples for ova and parasites. Transplant candidates with positive serology or stool tests can be treated pretransplantation to eradicate infection. Patients at risk for S Stercoralis who develop nonspecific gastrointestinal complaints, rash, pulmonary infiltrates, or gram-negative bacteremia or meningitis may have S Stercoralis hyperinfection syndrome. Our case indicates that the development of SIADH may be an additional clue to this diagnosis. Appropriate diagnostic studies, including repeat stool and other body fluid sampling, should be expedited and ivermectin therapy initiated rapidly to prevent significant morbidity and mortality.

Eyelid Necrosis and Secondary Cicatrical Ectropion Secondary to Levamisole-Associated Vasculitis.

A 56-year-old female presented with eyelid necrosis secondary to systemic levamisole-induced vasculitis. Skin biopsy revealed necrotic epidermis with small-vessel thrombosis, fibrinoid reaction, and neutrophilic infiltration of vessel walls in the dermis with +pANCA. She was treated with plasmapheresis and steroids. Six months later, she developed severe, symptomatic cicatrical ectropion with marked anterior lamellar shortage and middle lamellar contracture. Scar release in the middle lamellar plane with lateral tarsal strip procedures was performed, with full-thickness skin grafts from the upper eyelids. She remained fully epithelialized postoperatively with improvement in symptoms, although she incomplete graft take due to her eyelid necrosis and compromised dermal blood supply.

Use of new targeted cancer therapies in children: effects on dental development and risk of jaw osteonecrosis: a review.

New targeted cancer therapies such as bisphosphonates, denosumab, and bevacizumab are routinely used in adult for the past decades. Their introduction into pediatric medicine is more recent that means there is a paucity of data on long-term effects on dental development and on the risk of osteonecrosis of jaw. This study aimed to outline adverse effects of new targeted cancer therapies on oral cavity including dental abnormalities observed in pediatric population treated with these molecules and the risk of osteonecrosis of the jaw (ONJ). The impact of bisphosphonates and denosumab on bone remodeling (inhibition of osteoclasts) could interfere with teeth exfoliation and eruption processes, causing a tooth eruption delay. This hypothesis was confirmed, bisphosphonate-treated rats presented tooth eruption delay, and bisphosphonate therapy was associated with a mean delay of 1.67 years in tooth eruption in children with osteogenesis imperfecta. Another study showed that the inhibition of RANK/RANKL by denosumab was associated with a lack of tooth eruption in animals. Several animal studies reported that bisphosphonate could also induce dental abnormalities including defective amelogenesis and dentinogenesis in rats, but there is no evidence of such effects in children; only one case of enamel hypoplasia in a child treated for idiopathic arterial calcification with bisphosphate was reported. To date, there has been no reported case of ONJ in children treated with bisphosphonates, denosumab, or bevacizumab.