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Cureus May 2024Wilson's disease (WD), or "hepato-lenticular degeneration," is a rare genetic disorder of autosomal recessive inheritance causing toxic tissue accumulation of copper,...
Wilson's disease (WD), or "hepato-lenticular degeneration," is a rare genetic disorder of autosomal recessive inheritance causing toxic tissue accumulation of copper, mainly in the liver, brain, and cornea. Its phenotypic and genotypic heterogeneity characterizes it. This study aimed to clarify the clinical features and spectrum of Wilson's disease in children from the eastern region of Morocco and to study the evolutionary profile and survival in this population while discussing and highlighting the various diagnostic and therapeutic difficulties encountered in the management of WD in our context. This retrospective study encompassed 24 children diagnosed with Wilson's disease, selected from the gastroenterology-hepatology and pediatric nutrition units at Mohamed VI University Hospital in Oujda, Morocco, over a span of nine years, from January 2015 to November 2023. Our series results show 14 boys and 10 girls; the median age of discovery was 11 years, with extremes ranging from 18 months to 15 years. The consanguinity was found in 13 patients. Clinically, the edemato-ascitic syndrome was noted in 14 patients with an alteration of the general state; icterus was found in 13 patients; signs of portal hypertension were present in six patients; and neurological signs in seven cases. Skin manifestations occurred in three cases, and arthralgia in three cases. Six children were diagnosed on the occasion of a family screening. Biologically, hepatic cytolysis was found in 20 patients, with signs of hepatocellular failure in 15 cases. Hemolytic anemia was present in nine patients. Ceruloplasminemia was decreased in 21 patients and cupremia in 19 patients. Cupruria was increased in 22 cases. The Kayser-Fleicher ring was found in 10 cases. Abdominal ultrasound showed ascites in 16 patients, hepatomegaly in 1, splenomegaly in two cases, hepatosplenomegaly in five cases, and cirrhosis in two. MRI showed signal abnormalities in 11 patients. Therapeutically, D-penicillamine was initially introduced in 18 patients and zinc acetate in 6 patients. The evolution was favorable for 15 patients still followed up in the department. Three patients died of hepatocellular failure, and two died of hepatic encephalopathy. Four patients were lost to follow-up.
PubMed: 38854322
DOI: 10.7759/cureus.60023 -
Arquivos de Neuro-psiquiatria May 2024Wilson disease (WD) is an autosomal recessive disorder that leads to organ toxicity due to copper overload. Early diagnosis is complicated by the rarity and diversity...
BACKGROUND
Wilson disease (WD) is an autosomal recessive disorder that leads to organ toxicity due to copper overload. Early diagnosis is complicated by the rarity and diversity of manifestations.
OBJECTIVE
To describe the diagnostic features and response to treatment in our cohort of WD patients.
METHODS
This was a retrospective analysis of 262 WD patients stratified by clinical presentation, complementary exams, genotyping, and response to treatment.
RESULTS
Symptoms occurred at an average age of 17.4 (7-49) years, and patients were followed up for an average of 9.6 (0-45) years. Patients presented mainly with hepatic (36.3%), neurologic (34.7%), and neuropsychiatric (8.3%) forms. Other presentations were hematologic, renal, or musculoskeletal, and 16.8% of the patients were asymptomatic. Kayser-Fleischer rings occurred in 78.3% of the patients, hypoceruloplasminemia in 98.3%, and elevated cupruria/24h in 73.0%, with an increase after D-penicillamine in 54.0%. Mutations of the gene were detected in 84.4% of alleles. Brain magnetic resonance imaging showed abnormalities in the basal ganglia in 77.7% of patients. D-penicillamine was the first choice in 93.6% of the 245 patients, and 21.1% of these patients were switched due to adverse effects. The second-line therapies were zinc and trientine. The therapeutic response did not differ significantly between the drugs ( = 0.2). Nine patients underwent liver transplantation and 82 died.
CONCLUSION
Wilson disease is diagnosed at a late stage, and therapeutic options are limited. In people under 40 years of age with compatible manifestations, WD could be considered earlier in the differential diagnosis. There is a need to include genotyping and therapeutic alternatives in clinical practice.
Topics: Humans; Hepatolenticular Degeneration; Retrospective Studies; Female; Male; Adolescent; Child; Adult; Copper-Transporting ATPases; Young Adult; Penicillamine; Treatment Outcome; Middle Aged; Adenosine Triphosphatases; Mutation; Genotype; Magnetic Resonance Imaging; Chelating Agents; Cation Transport Proteins; Copper
PubMed: 38811021
DOI: 10.1055/s-0044-1786855 -
Pharmaceutics Dec 2023(1) Background: In patients with Wilson's disease, the deficiency of the copper carrier ATP7B causes the accumulation of copper in the liver, brain and various other...
(1) Background: In patients with Wilson's disease, the deficiency of the copper carrier ATP7B causes the accumulation of copper in the liver, brain and various other organs. Lifelong treatment is therefore mandatory, using copper chelators to increase the excretion of copper and to avoid life-threatening damage. The clinically used reference drug, D-penicillamine, exhibit numerous adverse effects, especially a frequent severe and irreversible neurological worsening, mainly due to its lack of metal selectivity; (2) Methods: A new tetradentate ligand based on an 8-aminoquinoline entity, named TDMQ20, which is highly selective for copper compared with other metal ions, is evaluated in "toxic milk" TX mice as an oral treatment of this Wilson's disease murine model; (3) Results: The concentration of copper in the liver of "toxic milk" TX mice decreased and the fecal excretion of copper increased upon oral treatment with TDMQ20. Both effects are dose-dependent, and more pronounced than those of D-penicillamine; (4) Conclusions: The TDMQ20 copper chelator is more efficient than the reference drug D-penicillamine for the treatment of a Wilson's disease murine model. Pharmacological data obtained with TDMQ20 on the TX mouse model strongly support the selection of this ligand as a drug candidate for this genetic disease.
PubMed: 38140060
DOI: 10.3390/pharmaceutics15122719 -
Journal of Korean Medical Science Apr 2024Wilson's disease (WD) is an autosomal recessive disorder in which copper (Cu) accumulates in organs, particularly in the liver and central nervous system. This study...
BACKGROUND
Wilson's disease (WD) is an autosomal recessive disorder in which copper (Cu) accumulates in organs, particularly in the liver and central nervous system. This study aimed to investigate the prevalence, incidence, and treatment patterns of WD patients in Korea.
METHODS
National Health Insurance System (NHIS) claims data from 2010 to 2020 were analyzed. patients with WD as a primary or additional diagnosis at least once were identified using the International Classification of Diseases (ICD)-10 disease code E83.0 and a record for a registration program for rare intractable diseases in Korea.
RESULTS
The average age- and sex-adjusted prevalence and incidence of WD between 2010 and 2020 were 3.06/100,000 and 0.11/100,000, respectively. The mean age of the patients with newly diagnosed WD was 21.0 ± 15.9 years. Among the 622 WD incident cases during the study period, 19.3% of the patients had liver cirrhosis and 9.2% had received liver transplantation. Psychological and neurological diseases were present in 40.7% and 48.1% of the patients, respectively. Regarding the diagnosis of WD, liver biopsy was performed in only 51.6% of new cases. D-penicillamine, trientine, or zinc were prescribed in 81.5% of the incident cases, and the treatment uptake rates decreased with increasing age.
CONCLUSION
The prevalence of WD in Korea is 3.06/100,000 and approximately 1,800 patients use medical services annually. A significant proportion of patients are diagnosed at the cirrhotic stage and not treated with Cu-chelating therapeutics, suggesting the need for early diagnosis and adequate treatment to improve prognosis.
Topics: Humans; Child, Preschool; Child; Adolescent; Young Adult; Adult; Hepatolenticular Degeneration; Prevalence; Incidence; Chelating Agents; Republic of Korea
PubMed: 38565173
DOI: 10.3346/jkms.2024.39.e115 -
Children (Basel, Switzerland) Jul 2023One of the most prevalent illnesses in neonates that needs care and treatment is neonatal jaundice. Several drugs are used as pharmacological modalities for treating...
BACKGROUND
One of the most prevalent illnesses in neonates that needs care and treatment is neonatal jaundice. Several drugs are used as pharmacological modalities for treating hyperbilirubinemia, like intravenous immunoglobulin, D-penicillamine, metalloporphyrin, phenobarbital, zinc sulfate and clofibrate. Previous studies suggest the usefulness of fenofibrate in the treatment of hyperbilirubinemia.
OBJECTIVES
The study aims at assessing the effectiveness of oral fenofibrate in the treatment of indirect neonatal hyperbilirubinemia in full-term neonates.
METHOD
This is a quasi-experimental study that was conducted at Heevi Pediatrics Teaching Hospital in Duhok, which is located in the Kurdistan Region of Iraq. It involved term infants who had jaundice. The neonates who were eligible for the study were randomly assigned to one of two groups: the intervention group or the control group. Both groups were treated with conventional phototherapy. Fenofibrate was administered in a single oral dose of 10 mg/kg to the participants in the intervention group. Throughout the entirety of the treatment, levels of total serum bilirubin were compared and contrasted between the two groups.
RESULTS
After 12 h of treatment, a statistically significant difference (-value = 0.001) was seen in the serum bilirubin levels between the two groups. The difference in serum bilirubin levels became significantly progressively pronounced after 24, 48, and 72 h. The average time of discharge was 63.6 h for the intervention group and 90.9 h for the control group, and this difference was statistically significant (-value < 0.001).
CONCLUSIONS
The time it takes to lower high bilirubin levels in neonates may be shortened by combining conventional phototherapy with a single oral dosage of 10 mg/kg fenofibrate. Consequently, these neonates will experience a shorter hospitalization and an accelerated discharge from the hospital.
PubMed: 37508689
DOI: 10.3390/children10071192 -
Orphanet Journal of Rare Diseases Mar 2024This study aimed to assess medication adherence and demographic, clinical, and psychopathological parameters such as quality of life, depression, and anxiety levels that...
BACKGROUND
This study aimed to assess medication adherence and demographic, clinical, and psychopathological parameters such as quality of life, depression, and anxiety levels that can affect pediatrics with Wilson's Disease (WD).
METHODS
A prospective cohort study was conducted at an outpatient clinic in Turkey among pediatric patients (2 to 18 years) with WD between November 2022 and April 2023. The Medication Adherence Report Scale (MARS-5) as a subjective and Medication Possession Ratio (MPR) as an objective assessment were scored. Physical, genetic and biochemical parameters, the Pediatric Quality of Life Inventory (PedsQL) for both parents and patients, Childhood Depression Inventory, State Trait Anxiety Inventory were also administered.
RESULTS
A total of 30 pediatric outpatients who were prescribed D-penicillamine (n = 27) or trientine (n = 3) as chelators and zinc (n = 29) and pyridoxine (n = 19) as supplements were included. Proteinuria (n = 3), skin rash (n = 2), and gastrointestinal upset (n = 2) were observed. When the correlation between MARS-5 and duration of follow-up was examined, a significant negative correlation was found (p = 0.014). According to MPRs, non-adherence rates (missed doses ≥ 20%) were 29.6%, 17.2% and 5.3% for D-penicillamine, zinc and pyridoxine, respectively. PedsQL scores were higher than those of parents, with a positive correlation between them (p < 0.001). Also, there was a significant positive correlation between PedsQL and State Anxiety Inventory (p < 0.001). Comparing the change in urinary copper levels between different levels of treatment knowledge, significant differences were observed between high- and low levels (p = 0.043).
CONCLUSIONS
Overall, nonadherence rates were 23.3% based on MARS-5 and 5.3-29.6% based on MPR. It is essential to consider factors such as the duration of follow-up, biochemical parameters, treatment knowledge, quality of life and anxiety as potential influencers of medication adherence.
Topics: Adolescent; Child; Humans; Cohort Studies; Hepatolenticular Degeneration; Penicillamine; Prospective Studies; Pyridoxine; Quality of Life; Turkey; Zinc; Child, Preschool
PubMed: 38454433
DOI: 10.1186/s13023-024-03113-0 -
Food Chemistry Aug 2023With the food safety issues abounding, exploring reliable and efficient methods for evaluating food safety is crucial. Herein, a ratiometric test strip was proposed by...
With the food safety issues abounding, exploring reliable and efficient methods for evaluating food safety is crucial. Herein, a ratiometric test strip was proposed by using green-yellow fluorescent d-penicillamine capped silver nanocluster (DPA-AgNCs) as indicator and red-emitting bimetallic gold/silver nanoclusters (AuAgNCs) as an internal reference, providing a real-time and visual monitoring system for food freshness. Results showed that the as-prepared DPA-AgNCs displayed an excellent response and good sensitivity for volatile basic nitrogens (VBNs), with a limit of detection (LOD) of 0.51 μM and 0.08 ppm for spermidine and ammonia hydroxide, respectively. Subsequently, a ratiometric test strip was developed to visually monitor ammonia vapour, displaying an obvious fluorescence colour variation from mustard to deep-red. Moreover, the presented ratiometric test strip was successfully applied for non-contact and visual evaluating and monitoring VBNs in the shrimp sample, showing high potential for in-situ monitoring.
Topics: Silver; Nitrogen; Ammonia; Coloring Agents; Penicillamine; Seafood; Fluorescent Dyes; Metal Nanoparticles; Spectrometry, Fluorescence
PubMed: 36934615
DOI: 10.1016/j.foodchem.2023.135725 -
Journal of Biological Inorganic... Apr 2024In addition to its primary oxygen-atom-transfer function, cysteamine dioxygenase (ADO) exhibits a relatively understudied anaerobic disproportionation reaction...
In addition to its primary oxygen-atom-transfer function, cysteamine dioxygenase (ADO) exhibits a relatively understudied anaerobic disproportionation reaction (ADO-Fe(III)-SR → ADO-Fe(II) + ½ RSSR) with its native substrates. Inspired by ADO disproportionation reactivity, we employ [Fe(tacn)Cl] (tacn = 1,4,7-triazacyclononane) as a precursor for generating Fe(III)-thiolate model complexes in buffered aqueous media. A series of Fe(III)-thiolate model complexes are generated in situ using aqueous [Fe(tacn)Cl] and thiol-containing ligands cysteamine, penicillamine, mercaptopropionate, cysteine, cysteine methyl ester, N-acetylcysteine, and N-acetylcysteine methyl ester. We observe trends in UV-Vis and electron paramagnetic resonance (EPR) spectra, disproportionation rate constants, and cathodic peak potentials as a function of thiol ligand. These trends will be useful in rationalizing substrate-dependent Fe(III)-thiolate disproportionation reactions in metalloenzymes.
Topics: Kinetics; Sulfhydryl Compounds; Hydrogen-Ion Concentration; Ferric Compounds; Electron Spin Resonance Spectroscopy; Dioxygenases; Electrochemical Techniques
PubMed: 38722396
DOI: 10.1007/s00775-024-02051-3 -
The Journal of Pediatric Pharmacology... Jun 2024The study aims to describe drug shortages affecting lead chelators in the United States from 2001 through 2022.
OBJECTIVE
The study aims to describe drug shortages affecting lead chelators in the United States from 2001 through 2022.
METHODS
Drug shortage data were retrieved from the University of Utah Drug Information Service from January 1, 2001, through December 31, 2022. Shortages of first- and second-line lead chelators were analyzed. Drug class, formulation, administration route, shortage reason, shortage duration, generic status, single-source status, and presence of temporally overlapping shortages were examined. Total shortage months, percentages of study period on shortage, and median shortage durations were calculated.
RESULTS
Thirteen lead chelator shortages were reported during the study period. Median duration was 7.4 months and the longest shortage (24.8 months) involved calcium disodium edetate. Calcium disodium edetate and dimercaprol had the greatest number of shortages, 4 each, and 61.5% of shortages involved parenteral medications. Median shortage duration was 14.2 months for parenteral agents and 2.2 months for non-parenteral agents. All shortages involved generic, single-source products. Supply/demand and manufacturing problems were the most common shortage reasons provided. Overlapping shortages occurred for 3.7% of the study period. Median shortage duration increased from 3 to 11 months in the second half of the study period, and 61.5% of shortages occurred in the second half of the study period.
CONCLUSIONS
All chelators experienced multiple shortages, which became increasingly frequent and prolonged over time. Concurrent shortages occurred, potentially hampering substitution between different agents. Health care stakeholders must build supply chain resilience and develop guidelines regarding how to modify chelation therapy based on shortage conditions.
PubMed: 38863853
DOI: 10.5863/1551-6776-29.3.306 -
Frontiers in Pediatrics 2023Retinopathy of prematurity (ROP) is the leading cause of preventable childhood blindness worldwide. Although interventions such as anti-VEGF and laser have high success...
PURPOSE
Retinopathy of prematurity (ROP) is the leading cause of preventable childhood blindness worldwide. Although interventions such as anti-VEGF and laser have high success rates in treating severe ROP, current treatment and preventative strategies still have their limitations. Thus, we aim to identify drugs and chemicals for ROP with comprehensive safety profiles and tolerability using a computational bioinformatics approach.
METHODS
We generated a list of genes associated with ROP to date by querying PubMed Gene which draws from animal models, human studies, and genomic studies in the NCBI database. Gene enrichment analysis was performed on the ROP gene list with the ToppGene program which draws from multiple drug-gene interaction databases to predict compounds with significant associations to the ROP gene list. Compounds with significant toxicities or without known clinical indications were filtered out from the final drug list.
RESULTS
The NCBI query identified 47 ROP genes with pharmacologic annotations present in ToppGene. Enrichment analysis revealed multiple drugs and chemical compounds related to the ROP gene list. The top ten most significant compounds associated with ROP include ascorbic acid, simvastatin, acetylcysteine, niacin, castor oil, penicillamine, curcumin, losartan, capsaicin, and metformin. Antioxidants, NSAIDs, antihypertensives, and anti-diabetics are the most common top drug classes derived from this analysis, and many of these compounds have potential to be readily repurposed for ROP as new prevention and treatment strategies.
CONCLUSION
This bioinformatics analysis creates an unbiased approach for drug discovery by identifying compounds associated to the known genes and pathways of ROP. While predictions from bioinformatic studies require preclinical/clinical studies to validate their results, this technique could certainly guide future investigations for pathologies like ROP.
PubMed: 37492605
DOI: 10.3389/fped.2023.1151239