Autotaxin inhibition attenuates the aortic valve calcification by suppressing inflammation-driven fibro-calcific remodeling of valvular interstitial cells.

BACKGROUND: Patients with fibro-calcific aortic valve disease (FCAVD) have lipid depositions in their aortic valve that engender a proinflammatory impetus toward fibrosis and calcification and ultimately valve leaflet stenosis. Although the lipoprotein(a)-autotaxin (ATX)-lysophosphatidic acid axis has been suggested as a potential therapeutic target to prevent the development of FCAVD, supportive evidence using ATX inhibitors is lacking. We here evaluated the therapeutic potency of an ATX inhibitor to attenuate valvular calcification in the FCAVD animal models. METHODS: ATX level and activity in healthy participants and patients with FCAVD were analyzed using a bioinformatics approach using the Gene Expression Omnibus datasets, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and western blotting. To evaluate the efficacy of ATX inhibitor, interleukin-1 receptor antagonist-deficient (Il1rn-/-) mice and cholesterol-enriched diet-induced rabbits were used as the FCAVD models, and primary human valvular interstitial cells (VICs) from patients with calcification were employed. RESULTS: The global gene expression profiles of the aortic valve tissue of patients with severe FCAVD demonstrated that ATX gene expression was significantly upregulated and correlated with lipid retention (r = 0.96) or fibro-calcific remodeling-related genes (r = 0.77) in comparison to age-matched non-FCAVD controls. Orally available ATX inhibitor, BBT-877, markedly ameliorated the osteogenic differentiation and further mineralization of primary human VICs in vitro. Additionally, ATX inhibition significantly attenuated fibrosis-related factors' production, with a detectable reduction of osteogenesis-related factors, in human VICs. Mechanistically, ATX inhibitor prohibited fibrotic changes in human VICs via both canonical and non-canonical TGF-ß signaling, and subsequent induction of CTGF, a key factor in tissue fibrosis. In the in vivo FCAVD model system, ATX inhibitor exposure markedly reduced calcific lesion formation in interleukin-1 receptor antagonist-deficient mice (Il1rn-/-, P = 0.0210). This inhibition ameliorated the rate of change in the aortic valve area (P = 0.0287) and mean pressure gradient (P = 0.0249) in the FCAVD rabbit model. Moreover, transaortic maximal velocity (Vmax) was diminished with ATX inhibitor administration (mean Vmax = 1.082) compared to vehicle control (mean Vmax = 1.508, P = 0.0221). Importantly, ATX inhibitor administration suppressed the effects of a high-cholesterol diet and vitamin D2-driven fibrosis, in association with a reduction in macrophage infiltration and calcific deposition, in the aortic valves of this rabbit model. CONCLUSIONS: ATX inhibition attenuates the development of FCAVD while protecting against fibrosis and calcification in VICs, suggesting the potential of using ATX inhibitors to treat FCAVD.

Impact of residual microcalcifcations on prognosis after neoadjuvant chemotherapy in breast cancer patients.

BACKGROUND: Residual microcalcifications after neoadjuvant chemotherapy (NAC) are challenging for deciding extent of surgery and questionable for impact on prognosis. We investigated changes in the extent and patterns of microcalcifications before and after NAC and correlated them with pathologic response. We also compared prognosis of patients depending on presence of residual microcalcifications after NAC. METHODS: A total of 323 patients with invasive breast carcinoma treated with neoadjuvant chemotherapy at Kangbuk Samsung Hospital and Samsung Medical center from March 2015 to September 2018 were included. Patients were divided into four groups according to pathologic response and residual microcalcifications. Non-pCRw/mic group was defined as breast non-pCR with residual microcalcifications. Non-pCRw/o mic group was breast non-pCR without residual microcalcifications. pCRw/mic group was breast pCR with residual microcalcifications. pCRw/o mic group was breast pCR without residual microcalcifications. The first aim of this study is to investigate changes in the extent and patterns of microcalcifications before and after NAC and to correlate them with pathologic response. The second aim is to evaluate oncologic outcomes of residual microcalcifications according to pathologic response after NAC. RESULTS: There were no statistical differences in the extent, morphology, and distribution of microcalcifications according to pathologic response and subtype after NAC (all p > 0.05). With a median follow-up time of 71 months, compared to pCRw/o mic group, the hazard ratios (95% confidence intervals) for regional recurrence were 5.190 (1.160-23.190) in non-pCRw/mic group and 5.970 (1.840-19.380) in non-pCRw/o mic group. Compared to pCRw/o mic group, the hazard ratios (95% CI) for distant metastasis were 8.520 (2.130-34.090) in non-pCRw/mic group, 9.120 (2.850-29.200) in non-pCRw/o mic group. Compared to pCRw/o mic, the hazard ratio (95% CI) for distant metastasis in pCRw/mic group was 2.240 (0.230-21.500) without statistical significance (p = 0.486). CONCLUSIONS: Regardless of residual microcalcifications, patients who achieved pCR showed favorable long term outcome compared to non-pCR group.

Andrographolide regulates H3 histone lactylation by interfering with p300 to alleviate aortic valve calcification.

BACKGROUND AND PURPOSE: Our previous studies have found that andrographolide (AGP) alleviates calcific aortic valve disease (CAVD), but the underlying mechanism is unclear. This study explores the molecular target and signal mechanisms of AGP in inhibiting CAVD. EXPERIMENTAL APPROACH: The anti-calcification effects of the aortic valve with AGP treatment were evaluated by alizarin red staining in vitro and ultrasound and histopathological assessment of a high-fat (HF)-fed ApoE-/- mouse valve calcification model. A correlation between the H3 histone lactylation (H3Kla) and calcification was detected. Molecular docking and surface plasmon resonance (SPR) experiments were further used to confirm p300 as a target for AGP. Overexpression (oe) and silencing (si) of p300 were used to verify the inhibitory effect of AGP targeting p300 on the H3Kla in vitro and ex vivo. KEY RESULTS: AGP significantly inhibited calcium deposition in valve interstitial cells (VICs) and ameliorated aortic valve calcification. The multi-omics analysis revealed the glycolysis pathway involved in CAVD, indicating that AGP interfered with lactate production by regulating lactate dehydrogenase A (LDHA). In addition, lactylation, a new post-translational modification, was shown to have a role in promoting aortic valve calcification. Furthermore, H3Kla and H3K9la site were shown to correlate with Runx2 expression inhibition by AGP treatment. Importantly, we found that p300 transferase was the molecular target of AGP in inhibiting H3Kla. CONCLUSIONS AND IMPLICATIONS: Our findings, for the first time, demonstrated that AGP alleviates calcification by interfering with H3Kla via p300, which might be a powerful drug to prevent CAVD.

Local injection of infliximab into calcinosis lesions in patients with juvenile dermatomyositis (JDM): a clinical trial.

BACKGROUND: Juvenile Dermatomyositis (JDM) is a rare autoimmune disorder that primarily affects muscles and skin. One of the severe complications associated with JDM is calcinosis, and treating this condition presents significant challenges. This study aimed to evaluate the efficacy and safety of local injection of infliximab into calcinosis lesions in patients with JDM. METHODS: In this clinical trial, five patients diagnosed with JDM and calcinosis lesions were enrolled. The primary treatment consisted of weekly infliximab injections for 16 weeks, targeting all four sides of each lesion. Lesion dimensions, including length and width, were documented and monitored weekly. Before the intervention, patients underwent radiographic imaging. After the final injection in week 16, a follow-up radiographic assessment was performed. Data were analyzed using the Generalized Estimating Equation (GEE) method. RESULTS: The lesions' size significantly decreased in both length and width during each visit. On average, the lesion length reduced by 2.66%, and the width shrank by 3.32% per visit. Based on radiographic findings, the average length and width of lesions at the initial visit were 12.09 ± 5.05 mm (range: 6.00-25.50 mm) and 6.35 ± 3.00 mm (range: 2.00-16.00 mm), respectively. The average length and width at the last visit were 5.59 ± 7.05 mm (range: 0-23.00 mm) and 3.41 ± 4.05 mm (range: 0-13.00 mm), respectively. No specific side effects related to the treatment were reported. CONCLUSIONS: The results suggest that the direct administration of infliximab into the calcinosis lesions of patients with JDM could be a safe and effective treatment approach. TRIAL REGISTRATION: Name of the registry: The effect of infliximab injection into calcinosis lesions on patients with juvenile dermatomyositis (JDM), Trial registration number: IRCT20210808052107N1, Registration date: 2022-07-22, URL of trial registry record: https://en.irct.ir/trial/58329 .

Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation.

Calcific aortic valve disease is a prevalent cardiovascular disease with no available drugs capable of effectively preventing its progression. Hence, an efficient drug delivery system could serve as a valuable tool in drug screening and potentially enhance therapeutic efficacy. However, due to the rapid blood flow rate associated with aortic valve stenosis and the lack of specific markers, achieving targeted drug delivery for calcific aortic valve disease has proved to be challenging. Here we find that protease-activated-receptor 2 (PAR2) expression is up-regulated on the plasma membrane of osteogenically differentiated valvular interstitial cells. Accordingly, we develop a magnetic nanocarrier functionalized with PAR2-targeting hexapeptide for dual-active targeting drug delivery. We show that the nanocarriers effectively deliver XCT790-an anti-calcification drug-to the calcified aortic valve under extra magnetic field navigation. We demonstrate that the nano-cargoes consequently inhibit the osteogenic differentiation of valvular interstitial cells, and alleviate aortic valve calcification and stenosis in a high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr-/-) mouse model. This work combining PAR2- and magnetic-targeting presents an effective targeted drug delivery system for treating calcific aortic valve disease in a murine model, promising future clinical translation.

Biologic drugs in the treatment of juvenile dermatomyositis: a literature review.

There is no clear consensus in the literature regarding the choice of biologic therapies and efficacy in juvenile dermatomyositis (JDM). In this review, we aimed to examine previous studies regarding biologic drug use in JDM patients. We screened MEDLINE and Scopus for articles involving JDM patients treated with biologic drugs. We identified 74 articles describing 495 JDM patients treated with biologic drugs (538 biologic treatments) during our literature search. The median (min-max) age of these patients was 9.8 (1-17) years (F/M:1.8). The most frequently used biologic drugs were rituximab (RTX, 50%) and tumor necrosis factor (TNF) inhibitors (34.8%). In a few cases, abatacept (4.3%), anti-interleukin-1 agents (0.9%), tocilizumab (0.9%), bortezomib (0.4%), ustekinumab (0.2%), eculizumab (0.2%), and golimumab (0.2%) were used. RTX was most frequently preferred in patients with severe skin involvement (46.3%). Improvement with RTX was obtained in 60.1% of RTX treatments. Infliximab was most frequently preferred in calcinosis (43.3%), while adalimumab in skin involvement (50%) and etanercept in resistant/recurrent diseases (80%). Improvement was achieved in 44.4% of anti-TNF treatments. Adverse events were observed in 46.8% (58/124) of all treatments. Our results suggest that biologic agents may be a promising alternative for the treatment of particularly resistant JDM cases. Controlled studies are required to provide higher level of evidence for the timing of biologic use in JDM treatment. Key Points • There is no consensus on the choice and efficacy of biologic therapies in JDM. • RTX and TNF inhibitors are the most commonly used biologic drugs. • Biologics were especially preferred in severe skin involvement, calcinosis, and resistant diseases.

Effectiveness of topical sodium thiosulfate for ectopic calcifications and ossifications. Results of the CATSS-O study.

INTRODUCTION: Ectopic calcifications (ECs) and heterotopic ossifications (HOs) form in non-mineralized tissues, most often in subcutaneous and muscular areas. Local and systemic complications can cause severe disability. Systemic administration of sodium thiosulfate (STS) gives promising results but is difficult to use in clinical practice. OBJECTIVE: Evaluation of the efficacy and safety of topical STS in ECs and HOs. METHODS: Retrospective analysis of the CATSS-O registry that included patients receiving topical STS 25 % prepared by the pharmacy of Limoges hospital during 2014-2020. The efficacy of STS was assessed by imaging (radiography or CT) after at least 6 months' treatment. RESULTS: Among 126 patients who received STS 25 %, 35 had complete clinical and radiographic data for analysis (28 with ECs and 7 with HOs; 18 children [mean age 8.9 years, range 1.5-16], 17 adults [mean age 52.4 years, range 24-90]). Calcifications or ossifications were due to dermatomyositis (8 children, 6 adults), systemic scleroderma (6 adults) or pseudo-hypoparathyroidism 1A (7 children). They were single (37.1 %) or multiple (62.9 %). Treated regions were in the lower limbs (31.4 %), upper limbs (37.1 %) or both (28.6 %) and the axial region (2.9 %). Topical STS was clinically effective in 9/28 (32.1 %) patients with ECs and 2/7 (28.6 %) children with HOs. Three patients experienced complete disappearance of their calcifications. Response for ECs was better in children than adults (54.5% vs 17.6 %, p = 0.035). Topical STS was well tolerated. CONCLUSION: Local STS seems effective for ossifications, particularly pediatric calcifications or ossifications. Randomized and experimental studies are needed to confirm this observation and to identify the underlying mechanisms.

Effects of vitamins K2 and D3 supplementation in patients with severe coronary artery calcification: a study protocol for a randomised controlled trial.

INTRODUCTION: Coronary artery calcification (CAC) and especially progression in CAC is a strong predictor of acute myocardial infarction and cardiovascular mortality. Supplementation with vitamin K2 and D3 has been suggested to have a protective role in the progression of CAC. In this study, we will examine the effect of vitamins K2 and D3 in men and women with severe CAC. We hypothesise that supplementation with vitamins K2 and D3 will slow down the calcification process. METHOD AND ANALYSIS: In this multicentre and double-blinded placebo-controlled study, 400 men and women with CAC score≥400 are randomised (1:1) to treatment with vitamin K2 (720 µg/day) and vitamin D3 (25 µg/day) or placebo treatment (no active treatment) for 2 years. Among exclusion criteria are treatment with vitamin K antagonist, coagulation disorders and prior coronary artery disease. To evaluate progression in coronary plaque, a cardiac CT-scan is performed at baseline and repeated after 12 and 24 months of follow-up. Primary outcome is progression in CAC score from baseline to follow-up at 2 years. Among secondary outcomes are coronary plaque composition and cardiac events. Intention-to-treat principle is used for all analyses. ETHICS AND DISSEMINATION: There are so far no reported adverse effects associated with the use of vitamin K2. The protocol was approved by the Regional Scientific Ethical Committee for Southern Denmark and the Data Protection Agency. It will be conducted in accordance with the Declaration of Helsinki. Positive as well as negative findings will be reported. TRIAL REGISTRATION NUMBER: NCT05500443.

Role of mitochondria in the myopathy of juvenile dermatomyositis and implications for skeletal muscle calcinosis.

OBJECTIVES: To elucidate mechanisms contributing to skeletal muscle calcinosis in patients with juvenile dermatomyositis. METHODS: A well-characterized cohorts of JDM (n = 68), disease controls (polymyositis, n = 7; juvenile SLE, n = 10, and RNP + overlap syndrome, n = 12), and age-matched health controls (n = 17) were analyzed for circulating levels of mitochondrial (mt) markers including mtDNA, mt-nd6, and anti-mitochondrial antibodies (AMAs) using standard qPCR, ELISA, and novel-in-house assays, respectively. Mitochondrial calcification of affected tissue biopsies was confirmed using electron microscopy and energy dispersive X-ray analysis. A human skeletal muscle cell line, RH30, was used to generate an in vitro calcification model. Intracellular calcification is measured by flow cytometry and microscopy. Mitochondria were assessed for mtROS production and membrane potential by flow cytometry and real-time oxygen consumption rate by Seahorse bioanalyzer. Inflammation (interferon-stimulated genes) was measured by qPCR. RESULTS: In the current study, patients with JDM exhibited elevated levels of mitochondrial markers associated with muscle damage and calcinosis. Of particular interest are AMAs predictive of calcinosis. Human skeletal muscle cells undergo time- and dose-dependent accumulation of calcium phosphate salts with preferential localization to mitochondria. Calcification renders skeletal muscle cells mitochondria stressed, dysfunctional, destabilized, and interferogenic. Further, we report that inflammation induced by interferon-alpha amplifies mitochondrial calcification of human skeletal muscle cells via the generation of mitochondrial reactive oxygen species (mtROS). CONCLUSIONS: Overall, our study demonstrates the mitochondrial involvement in the skeletal muscle pathology and calcinosis of JDM and mtROS as a central player in the calcification of human skeletal muscle cells. Therapeutic targeting of mtROS and/or upstream inducers, such as inflammation, may alleviate mitochondrial dysfunction, leading to calcinosis. AMAs can potentially identify patients with JDM at risk for developing calcinosis.

Prenatal asfotase alfa-mediated enzyme replacement therapy restores delayed calcification in a severe infantile form of hypophosphatasia model mice.

Hypophosphatasia (HPP) is a congenital disorder caused by mutations in the tissue-nonspecific alkaline phosphatase (TNALP) gene. The pathogenesis of HPP varies, ranging from severe cases in which there is total absence of fetal bone calcification, which leads to stillbirth, to relatively mild cases in which the effects are confined to the teeth, such as early loss of the primary teeth. In recent years, the establishment of enzyme supplementation as a treatment method has prolonged survival in patients; however, this approach does not provide sufficient improvement for failed calcification. Furthermore, the effects of enzyme replacement therapy on the jawbone and periodontal tissues have not yet been studied in detail. Therefore, in this study, we investigated the therapeutic effects of enzyme replacement therapy on jawbone hypocalcification in mice. Recombinant TNALP was administered to mothers before birth and newborns immediately after birth, and the effect of treatment was evaluated at 20 days of age. The treated HPP mice had improved mandible (mandibular length and bone quality) and tooth quality (root length of mandibular first molar, formation of cementum), as well as improved periodontal tissue structure (structure of periodontal ligament). Furthermore, prenatal treatment had an additional therapeutic effect on the degree of mandible and enamel calcification. These results suggest that enzyme replacement therapy is effective for the treatment of HPP, specifically in the maxillofacial region (including the teeth and mandible), and that early initiation of treatment may have additional beneficial therapeutic effects.

Asfotase alfa improved skeletal mineralization and fracture healing in a child with MCAHS.

Tissue non-specific alkaline phosphatase (TNSALP) is an enzyme that is tethered to the cell membrane by glycosylphosphatidylinositol (GPI) and converts inorganic pyrophosphate to inorganic phosphate. Inorganic phosphate combines with calcium to form hydroxyapatite, the main mineral in the skeleton. When TNSALP is defective, conversion of inorganic pyrophosphate to inorganic phosphate is impaired and the skeleton is at risk of under-mineralization. Phosphatidylinositol glycan anchor biosynthesis class N (PIGN) is one of more than 20 genes in the GPI-biosynthesis family. Pathogenic variants in PIGN have been identified in multiple congenital anomalies-hypotonia-seizures syndrome (OMIM 614080), although a metabolic bone disease or skeletal fragility phenotype has not been reported. We describe a female child with multiple congenital anomalies-hypotonia-seizures syndrome due to a compound heterozygous pathogenic variant in PIGN who sustained a low-trauma distal femur fracture at age 7.4 years. We hypothesized that the GPI synthesis defect may result in metabolic bone disease from inadequate anchoring of TNSALP in bone and initiated asfotase alfa, a human bone-targeted recombinant TNSALP-Fc-deca-aspartate peptide, as it could bypass the PIGN genetic defect that possibly caused her skeletal fragility. Asfotase alfa was begun at 8.5 years. Baseline X-rays revealed mild rachitic findings of wrists and knees, which resolved by 5 months of treatment. Bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA) showed mild improvement in spine, hip and total body less head after 16 months of treatment, while radius declined. She sustained additional low trauma fractures at right tibia and left humeral neck at 11 and 15 months into treatment, which healed quickly. Calcium, phosphorus, and parathyroid hormone levels have remained within the normal range over the 18 months of treatment. For adverse effect, she experienced a rash and discomfort in the first week of treatment which resolved with ibuprofen and diphenhydramine. She also developed subcutaneous fat atrophy. Overall, in this child with a compound pathogenic variant in PIGN, off-label use of asfotase alfa has been generally well tolerated with minimal side effects and resolution of rickets, but she continues to remain skeletally fragile.

[Degenerative aortic valve stenosis: looking for a pharmacological prevention]. / Stenosi valvolare aortica degenerativa: alla ricerca di una prevenzione farmacologica.

Degenerative calcific aortic valve stenosis (CAVS) is a chronic disease whose prevalence has increased over the last decade because of the aging of the general population. CAVS pathogenesis is characterized by complex molecular and cellular mechanisms that promote valve fibro-calcific remodeling. During the first phase, referred to as initiation, the valve undergoes collagen deposition and lipid and immune cell infiltration due to mechanical stress. Subsequently, during the progression phase, the aortic valve undergoes chronic remodeling through osteogenic and myofibroblastic differentiation of interstitial cells and matrix calcification. Knowledge of the mechanisms underlying CAVS development supports the resort to potential therapeutic strategies that interfere with fibro-calcific progression. Currently, no medical therapy has demonstrated the ability to significantly prevent CAVS development or slow its progression. The only treatment available in symptomatic severe stenosis is surgical or percutaneous aortic valve replacement. The aim of this review is to highlight the pathophysiological mechanisms involved in CAVS pathogenesis and progression and to discuss potential pharmacological treatments able to inhibit the main pathophysiological mechanisms of CAVS, including lipid-lowering treatment with lipoprotein(a) as emergent therapeutic target.

Perforating Calcinosis Cutis as a Complication of Intraosseous Fluid Infusion in the Setting of a Near-Drowning Event.

Iatrogenic calcinosis cutis represents a subset of calcinosis cutis resulting secondary to treatments or procedures. We present the first report of calcinosis cutis resulting from the intraosseous infusion and one of a few cases with associated transepidermal elimination. A previously healthy 2-year-old female presented with a new-onset unilateral shin rash 1 week following hospitalization for a near-drowning event. A dermatologic exam revealed multiple small, tender, firm, chalky-white papules with surrounding erythema, in addition to two erythematous macules superior and medial to the papular lesions, corresponding to prior intraosseous access sites. The rash persisted despite trials of topical mupirocin and acyclovir cream, prompting a referral to a dermatologist. An excisional biopsy was performed, revealing circumscribed dermal deposits of acellular basophilic material connected to the overlying epidermis through an invaginated keratin plug. A von Kossa silver stain highlighted the deposits, confirming the diagnosis of perforating calcinosis cutis. The lesions did not recur following the excisional biopsy. Iatrogenic calcinosis cutis may be seen as a complication of the infusion of calcium-containing fluids via intraosseous access, in addition to the more commonly observed peripheral intravenous access. Awareness of this disorder is important in order to distinguish it from an infectious mimic and guide the selection of therapy.

Anticalcification effects of DS-1211 in pseudoxanthoma elasticum mouse models and the role of tissue-nonspecific alkaline phosphatase in ABCC6-deficient ectopic calcification.

Pseudoxanthoma elasticum (PXE) is a multisystem, genetic, ectopic mineralization disorder with no effective treatment. Inhibition of tissue-nonspecific alkaline phosphatase (TNAP) may prevent ectopic soft tissue calcification by increasing endogenous pyrophosphate (PPi). This study evaluated the anticalcification effects of DS-1211, an orally administered, potent, and highly selective small molecule TNAP inhibitor, in mouse models of PXE. Calcium content in vibrissae was measured in KK/HlJ and ABCC6-/- mice after DS-1211 administration for 13-14 weeks. Pharmacokinetic and pharmacodynamic effects of DS-1211 were evaluated, including plasma alkaline phosphatase (ALP) activity and biomarker changes in PPi and pyridoxal-phosphate (PLP). Anticalcification effects of DS-1211 through TNAP inhibition were further evaluated in ABCC6-/- mice with genetically reduced TNAP activity, ABCC6-/-/TNAP+/+ and ABCC6-/-/TNAP+/-. In KK/HlJ and ABCC6-/- mouse models, DS-1211 inhibited plasma ALP activity in a dose-dependent manner and prevented progression of ectopic calcification compared with vehicle-treated mice. Plasma PPi and PLP increased dose-dependently with DS-1211 in ABCC6-/- mice. Mice with ABCC6-/-/TNAP+/- phenotype had significantly less calcification and higher plasma PPi and PLP than ABCC6-/-/TNAP+/+ mice. TNAP plays an active role in pathomechanistic pathways of dysregulated calcification, demonstrated by reduced ectopic calcification in mice with lower TNAP activity. DS-1211 may be a potential therapeutic drug for PXE.

Fourteen Days vs 28 Days of Albendazole Therapy for Neurocysticercosis in Children: An Open Label Randomized Controlled Trial.

BACKGROUND: There is a paucity of literature to support 14-days albendazole therapy for neurocysticercosis (NCC). OBJECTIVE: To compare the efficacy of 14-day and 28-day albendazole therapy in the management of children with newly diagnosed active NCC. STUDY DESIGN: Open-labelled randomized controlled trial. PARTICIPANTS: Children aged 1-14 years with newly diagnosed active neurocysticercosis. INTERVENTION: Albendazole (15 mg/kg/day) for either 14 days or 28 days. OUTCOME: The primary outcome measure was proportion of children with radiological resolution of active lesion at 6-month follow up. Secondary outcome measures were proportion of children with seizure recurrence, duration to seizure recurrence and calcification on follow up imaging. RESULTS: 65 children with newly diagnosed NCC were rando-mized to receive albendazole therapy for 14 days (n=32) or 28 days (n=33). The proportion of children with complete resolution was comparable between the two groups [6 (18.8%) vs. 9 (27.3%); OR (95%CI):0.61 (0.19 to 1.98); P=0.56]. Similarly, proportion of children with seizure recurrence [5(15.6%) vs 2(6.1%); OR (95%CI): 2.87(0.51-16.0); P=0.26] and proportion of children with calcification on follow-up imaging [26(81.2%) vs 23(69.7%); OR (95%CI): 1.88 (0.59-5.99); P=0.39] were also comparable. There were no major side-effects noted during the study. CONCLUSION: 14-day treatment with albendazole therapy is as effective as 28-day treatment in achieving radiological resolution at six-month follow up. However, high rate of calcification in both the groups indicates need for further evaluation with an adequately powered study and longer follow up.