Transient D-Penicillamine-Induced Nephrogenic Diabetes Insipidus during Treatment of a Patient with Cystinuria —D-Penicillamine-Induced Nephrogenic Diabetes Insipidus

Background: Diabetes insipidus (DI) is a rare disorder characterized by inappropriate polyuria and hypo-osmolar urine. It is caused by inadequate production of antidiuretic hormone, in response to hypothalamic osmoreceptor-stimulation, from the pituitary gland (central DI) or resistance to its action at terminal distal convoluted tubules and collecting ducts (nephrogenic DI). Most cases of nephrogenic DI are caused by drugs, especially chronic lithium use. The Case: A 46-year-old man manifested such a disorder 8 months following d-Penicillamine (d-P) therapy for cystinuria. The drug was discontinued and the patient was managed conservatively with high fluid intake, diet low in protein and salt as well as alkalization of urine with Urolyte U to a pH > 7.5. Six weeks later, such side effect disappeared. Our patient had developed such phenomenon: a) without significant liver or renal disease to account for cumulative toxicity, and b) with a conventional dosage range of d-P. Such isolated toxicity indicates inherited a predisposition to this side effect. Conclusion: DI is a potential side effect of d-P therapy that is nephrogenic in site, transient in prognosis and an isolated phenomenon likely to reflect genetic predisposition.

Functional analysis and drug response to zinc and D-penicillamine in stable ATP7B mutant hepatic cell lines

AIM: To study the effect of anti-copper treatment for survival of hepatic cells expressing different ATP7 B mutations in cell culture. METHODS: The most common Wilson disease(WD) mutations p.H1069 Q, p.R778 L and p.C271*, found in the ATP7 B gene encoding a liver copper transporter, were studied. The mutations represent major genotypes of the United States and Europe, China, and India, respectively. A human hepatoma cell line previously established to carry a knockout of ATP7 B was used to stably express WD mutants. m RNA and protein expression of mutant ATP7 B, survival of cells, apoptosis, and protein trafficking were determined.RESULTS: Low temperature increased ATP7 B protein expression in several mutants. Intracellular ATP7 B localization was significantly impaired in the mutants. Mutants were classified as high, moderate, and no survival based on their viability on exposure to toxic copper. Survival of mutant p.H1069 Q and to a lesser extent p.C271* improved by D-penicillamine(DPA) treatment, while mutant p.R778 L showed a pronounced response to zinc(Zn) treatment. Overall, DPA treatment resulted in higher cell survival as compared to Zn treatment; however, only combined Zn + DPA treatment fully restored cell viability. CONCLUSION: The data indicate that the basic impact of a genotype might be characterized by analysis of mutant hepatic cell lines.

Challenges and dilemmas in pediatric hepatic Wilson’s disease

Wilson disease is an autosomal recessive disorder affecting the ATP7B gene located on chromosome 13q.This leads to copper deposition in various organs,most importantly in the liver and brain.The genetic mutations are vast,well reported in the West but poorly documented in developing countries.Hence the diagnosis is made with a constellation of clinico-laboratory parameters which have significant overlap with other liver diseases and often pose a significant dilemma for clinicians.Diagnostic scoring systems are not fool-proof.The availability and affordability of chelators in developing countries impact the drug compliance of patients.While D-penicillamine is a potent drug,its side effects lead to drug discontinuation.Trientine is cost-prohibitive in developing countries.There is no single test to assess the adequacy of chelation.Exchangeable urinary copper is an essential upcoming diagnostic and prognostic tool.In the presence of cirrhosis,hypersplenism clouds the assessment of myelosuppression of drugs.Similarly,it may be difficult to distinguish disease tubulopathy from druginduced glomerulonephritis.Neurological worsening due to chelators may appear similar to disease progression.Presentation as fulminant hepatic failure requires rapid workup.There is a limited window of opportunity to salvage these patients with the help of plasmapheresis and other liver-assisted devices.This review addresses the challenges and clinical dilemmas faced at beside in developing countries.

Pediatric Wilson disease presenting as acute liver failure:Prognostic indices

BACKGROUND Acute liver failure(ALF)can be a primary presentation of Wilson disease(WD).Mortality rates are high in WD with ALF(WDALF).Predictions of mortality in WDALF vary by model and are sometimes contradictory,perhaps because few patients are studied or WD diagnoses are questionable.AIM To determine the outcomes among well-documented WDALF patients and assess mortality model performance in this cohort.METHODS We reviewed the medical records of our pediatric WDALF patients(n=41 over 6-years-old,single-center retrospective study)and compared seven prognostic models(King’s College Hospital Criteria,model for end-stage liver disease/pediatric end-stage liver disease scoring systems,Liver Injury Unit[LIU]using prothrombin time[PT]or international normalized ratio[INR],admission LIU using PT or INR,and Devarbhavi model)with one another.RESULTS Among the 41 Han Chinese patients with ALF,WD was established by demonstrating ATP7B variants in 36.In 5 others,Kayser-Fleischer rings and Coombs-negative hemolytic anemia permitted diagnosis.Three died during hospitalization and three underwent liver transplantation(LT)within 1 mo of presentation and survived(7.3%each);35(85.4%)survived without LT when given enteral D-penicillamine and zinc-salt therapy with or without urgent plasmapheresis.Parameters significantly correlated with mortality included encephalopathy,coagulopathy,and gamma-glutamyl transpeptidase activity,bilirubin,ammonia,and serum sodium levels.Area under the receiver operating curves varied among seven prognostic models from 0.981 to 0.748 with positive predictive values from 0.214 to 0.429.CONCLUSION WDALF children can survive and recover without LT when given D-penicillamine and Zn with or without plasmapheresis,even after enlisting for LT.

Practical insights into chronic management of hepatic Wilson’s disease

Wilson’s disease(WD)is a rare inherited disorder of human copper metabolism,with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric manifestations.In healthy individuals,the bile is the main route of elimination of copper.In WD patients,copper accumulates in the liver,it is released into the bloodstream,and is excreted in urine.Copper can also be accumulated in the brain,kidneys,heart,and osseous matter and causes damage due to direct toxicity or oxidative stress.Hepatic WD is commonly but not exclusively diagnosed in childhood or young adulthood.Adherent,non-cirrhotic WD patients seem to have a normal life expectancy.Nevertheless,chronic management of patients with Wilson’s disease is challenging,as available biochemical tests have many limitations and do not allow a clear identification of non-compliance,overtreatment,or treatment goals.To provide optimal care,clinicians should have a complete understanding of these limitations and counterbalance them with a thorough clinical assessment.The aim of this review is to provide clinicians with practical tools and suggestions which may answer doubts that can arise during chronic management of patients with hepatic WD.In particular,it summarises current knowledge on Wilson’s disease clinical and biochemical monitoring and treatment.It also analyses available evidence on pregnancy and the role of low-copper diet in WD.Future research should focus on trying to provide new copper metabolism tests which could help to guide treatment adjustments.

Chelation therapy in liver diseases of childhood: Current status and response

Chelation is the mainstay of therapy in certain pediatric liver diseases.Copper and iron related disorders require chelation.Wilson’s disease(WD),one of the common causes of cirrhosis in children is treated primarily with copper chelating agents like D-penicillamine and trientine.D-Penicillamine though widely used due its high efficacy in hepatic WD is fraught with frequent adverse effects resulting discontinuation.Trientine,an alternative drug has comparable efficacy in hepatic WD but has lower frequency of adverse effects.The role of ammonium tetra-thiomolybdate is presently experimental in hepatic WD.Indian childhood cirrhosis is related to excessive copper ingestion,rarely seen in present era.DPenicillamine is effective in the early part of this disease with reversal of clinical status.Iron chelators are commonly used in secondary hemochromatosis of liver in hemolytic anemias.There are strict chelation protocols during bone marrow transplant.The role of iron chelation in neonatal hemochromatosis is presently not in vogue due to its poor efficacy and availability of other modalities of therapy.Hereditary hemochromatosis is rare in children and the use of iron chelators in this condition is limited.

Kinetically controlled synthesis of atomically precise Ag nanoclusters for the catalytic reduction of 4-nitrophenol

Synthesizing atomically precise Ag nanoclusters(NCs),which is essential for the general development of NCs,is quite challenging.In this study,we report the synthesis of high-purity atomically precise Ag NCs via a kinetically controlled strategy.The Ag NCs were prepared using a mild reducing agent via a one-pot method.The as-prepared Ag NCs were confirmed to be Ag_(49)(D-pen)_(24)(D-pen:D-penicillamine)on the basis of their matrix-assisted laser desorption ionization time-of-flight mass spectrometric and thermogravimetric characteristics.The interfacial structures of the Ag NCs were illustrated by proton nuclear magnetic resonance and Fourier-transform infrared spectroscopy.The Ag NCs were supported on activated carbon(AC)to form Ag NCs/AC,which displayed excellent activity for the catalytic reduction of 4-nitrophenol with a kinetic reaction rate constant k of 0.21 min^(-1).Such a high k value indicates that the composite could outperform several previously reported catalysts.Moreover,the catalytic activity of Ag NCs/AC remained nearly constant after six times of recycle,which suggests its excellent stability.

Uncommon Side Effects of D-Pencillamine— 2 Case Reports

D-Penicillamine is one of the diseases modifying medication used to treat Rheumatoid arthritis and Systemic sclerosis. In this article we have described two interesting cases of Dermatomyositis and Bullous pemphigoid secondary to D-Penicillamine. This article emphasizes the fact that D-Penicillamine remains as one of the effective and well-tolerated medications, however patients need close monitoring while on medication, so that uncommon side effects are recognized and treated promptly.

Quantum Chemical Studies of Host-guest Nanostructures of PAMAM Dendrimers in Drug Deliver

Using B3LYP and M06-2X functionals,eight noncovalent configurations for the adsorption of D-penicillamine drug(DPA)drug on poly(amidoamine)G0 generation dendrimer(PAMAMG0)carrier have been investigated.The quantum molecular descriptors and the binding and solvation energies were examined in aqueous solution and gas phase.The binding energies demonstrated the energetic stability of non-bonded species(PAMAMG0/DPA1-8).The solvation energies showed that solubility of DPA rises in the vicinity of PAMAMG0 carrier which is a fundamental factor for applicability of a carrier.Considering quantum molecular descriptors such as electrophilicity power and global hardness,the toxicity of DPA drug in the vicinity of PAMAMG0 carrier decreases and drug release is facilitated.The AIM analysis for all PAMAMG0/DPA1-8 structures indicated that the hydrogen and pseudo-hydrogen bonds play important roles in the functionalization of PAMAMG0 with DPA drug.The configuration in which DPA drug interacts simultaneously with two-NH2 functional groups of PAMAMG0 is the most stable configuration.

ClinicalandExperimentalStudyofRAMixtureinTreatmentofRhematoidArthritislxl

The RA mixture is composed of Tripterygium wilfordii (TW) and other Chinese medicinalherbs with effect of expelling Wind, activating blood circulation, invigorating the Kidney and Qi . The authorstreated rheumatoid arthritis ( RA) patients with RA mixture and compared it with D-Penicillamine as ocntrol .The two group's therapeutical effect is similar ( P >0. 05) , but side effect occuring ratio in treatment groupwas obviously lower than that of control group ( P<0 . 01 ) . After treatment with RA mixture, the patient's hu-man lymphocytic antigen-degenerative reaction ( HLA-DR+ ) cell, CD4/CD8 ratio were reduced and auto-mixed lymphocytic reaction ( AMLR) level enhanced ( P < 0. 05) . The results of animal experiment showedthat swelling of rheumatoid arthritis model mouse's joint could be reduced by both RA mixture and TW. Com-paring with TW. RA mixture had stronger effect in controlling the inflammation of synovial cell and fibroid de-generation of fibrocytes. At the same time, RA mixture had stronger effect in protecting immune organ fromatrophy and maintaining functions of cellular immunity. All these suggest that RA mixture can reduce the syn-droms of RA by improving distribution of T Iymphocyte subsets and functions of cellular immunity. The Chinesemedicinal herbs for reinforcing Kidney, supplementing Qi , activating blood circulation and expelling evil windin the RA mixture could enhance TW's therapeutical effect and reduce it's side effect.

Advance in the pathogenesis and treatment of Wilson disease

Wilson disease is an autosomal recessive disorder of copper metabolism.Diagnosis depends primarily on clinical features,biochemical parameters and the presence of the Kayser-Fleischer ring.Genetic analysis for mutations within ATP7B is a convincing diagnostic tool.The traditional treatment for WD includes chelation of excessive copper accumulation and reduction of copper intake.Medical therapy is effective but WD is not yet curable.Liver transplantation is especially helpful for patients who fail to respond to medical therapy or present with fulminant liver failure,although evaluation of its long-term effect are still in need.