Transferrin Coated d-penicillamine-Au-Cu Nanocluster PLGA Nanocomposite Reverses Hypoxia-Induced EMT and MDR of Triple-Negative Breast Cancers.

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, lacks effective targeted therapies due to negative expression of the targetable bioreceptors. Additionally, hypoxic condition in solid tumors contributes to the epithelial to mesenchymal transition (EMT), which aggravates cancer progression, multidrug resistance (MDR), migration, and stemness of the TNBC. A therapeutic module has been established in this regard by coating PLGA nanoparticle with d-penicillamine templated Au-Cu bimetallic nanoclusters. Further, the resultant nanomaterials were coated with recombinant transferrin protein to specifically target transferrin receptor overexpressing TNBC. The synthesized nanocomposites showed strong orange emission band at 630 nm with fluorescence quantum yield of 2%, rendering it suitable for theranostic applications. Experimental results demonstrated efficient cellular internalization and significant innate anti-cell proliferative potential of the nanocomposites. The fabricated nanocomposites were also able to induce cell death in spheroids, which was confirmed by live/dead dual staining results. Furthermore, when EMT-induced TNBC cells were treated with nanocomposites, they generated reactive oxygen species (ROS), depolarized the mitochondrial membrane potential, and induced apoptosis. Gene expression by real-time PCR indicated that treatment of EMT-induced TNBC cells with nanocomposites facilitated mesenchymal to epithelial transition (MET). In MDA-MB-468 cells, treatment with nanocomposites resulted in a 1.35-fold rise in E-cadherin an epithelial marker and a 1.36-fold decrease in vimentin a mesenchymal marker. Similarly, 2.87-fold and 1.76-fold decrease in stemness markers ALDH1A3 and EpCAM were observed in MDA-MB-231. Furthermore, 4.63-fold decrease in expression of ABCC1, a prominent contributor of MDR, was observed in MDA-MB-231. Protein expression studies revealed that nanocomposites reduced p-STAT-3 by 1.61-fold in MDA-MB-231 and by 7.8-fold in MDA-MB-468. Importantly, nanocomposites downregulated the expression of ß-catenin by 3-fold in MDA-MB-231 and by 3.11-fold in MDA-MB-468. Downregulation of EMT with concomitant alteration of STAT-3 and ß-catenin signaling pathways led to reduced migration ability of the TNBC cells.

Adjunctive Antioxidant Therapy in Neurologic Wilson's Disease Improves the Outcomes.

Oxidative stress has been reported in Wilson's disease with neurological manifestation (WDNM), but there is a paucity of studies on the role of adjunctive antioxidant therapy. This study aims to evaluate the efficacy of adjunctive vitamin C and E treatment in reducing oxidative stress and improving clinical outcomes. Forty-nine patients with WDNM were included and their clinical details were noted. Glutathione (GSH), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured using spectrophotometer at baseline and follow-up. All patients received zinc with or without chelating therapy, and 32 of them prescribed vitamin C (500 mg/day) and E (400 mg/day). Clinical outcomes at 6, 12, and 24 months were categorized as improved, static, or worsened based on improvement in Burke-Fahn-Marsden (BFM) score (>10%) and/or severity grade (> 1). Baseline parameters were similar between two groups; except BFM score was higher in the antioxidant group. At follow-up, the antioxidant group had higher GSH, TAC, and lower MDA levels compared with baseline. Patients on antioxidant treatment experienced improvement more frequently at 6 (53.1% vs. 29.4%), 12 (62.5% vs. 29.4%), and 24 months (68.8% vs. 35.3%) compared with those without antioxidant treatment. In WDNM, adjunctive vitamin C and E treatment reduce oxidative stress and improve clinical outcome.

[Diagnosis and treatment of Wilson disease in Japan].

Wilson disease is an autosomal recessive disorder based on inborn error of copper metabolism. The copper accumulates in the liver, brain, cornea, kidney, and other organs. This disease should be considered any individual with liver abnormality except infant, any patient older than teenage with neurological (especially for extra pyramidal signs) or neuropsychiatric disorder with or without liver disease and sibling of Wilson disease patient. Typically, a combination of low serum ceruloplasmine levels and high levels of urinary copper contents is sufficient to establish a diagnosis. As other diagnostic tests, measurement of hepatic copper content and ATP7B gene analysis are available. The key strategy of treatment is to reduce the amount of copper in the liver and other tissues by administering both copper-chelating agents, such as D-penicillamine or Trientine, and/or zinc acetate. The author recommend zinc acetate monotherapy for mild to moderate hepatic disorder, Trientine mono therapy for mild to moderate neurologic disorder and combination therapy of Trientine and zinc acetate for sever hepatic or neurologic disorder.

Effect of increasing doses of cystine-binding thiol drugs on cystine capacity in patients with cystinuria.

Appropriate dosing of cystine-binding thiol drugs in the management of cystinuria has been based on clinical stone activity. When new stones form, the dose is increased. Currently, there is no method of measuring urinary drug levels to guide the titration of therapy. Increasing cystine capacity, a measure of cystine solubility, has been promoted as a method of judging the effects of therapy. In this study, we gave increasing doses of tiopronin or D-penicillamine, depending on the patients' own prescriptions, to ten patients with cystinuria and measured cystine excretion and cystine capacity. The doses were 0, 1, 2, 3 g per day, given in two divided doses, and administered in a random order. Going from 0 to 1 g/day led to an increase in cystine capacity from - 39.1 to 130.4 mg/L (P < 0.009) and decreased 24 h cystine excretion from 1003.9 to 834.8 mg/day (P = 0.039). Increasing the doses from 1 to 2 to 3 g/day had no consistent or significant effect to further increase cystine capacity or decrease cystine excretion. Whether doses higher than 1 g/day have additional clinical benefit is not clear from this study. Limiting doses might be associated with fewer adverse effects without sacrificing the benefit of higher doses if higher doses do not offer clinical importance. However, trials with stone activity as an outcome would be desirable.

Hepatic manifestations of Wilson's disease: 12-year experience in a Swiss tertiary referral centre.

BACKGROUND AND AIM: Wilson’s disease is an inherited disorder of hepatic copper metabolism, leading to the accumulation of copper in the liver as well as the brain, cornea and other organs. Here, we describe the adult cases of hepatic Wilson’s disease diagnosed at the Division of Gastroenterology and Hepatology of the University Hospital Lausanne, Switzerland between September 2004 and August 2016. METHODS: Clinical manifestations, results of diagnostic tests, management and outcomes of adult patients with hepatic Wilson’s disease were assessed based on standardised medical records. In addition, liver histology was reviewed and the lesional patterns were recorded. RESULTS: Ten new adult cases of hepatic Wilson’s disease were diagnosed in our centre between September 2004 and August 2016. Male to female ratio was 1:1 and median age at diagnosis was 26 (range 18–56) years. Four patients presented with acute liver failure, four with persistently elevated liver function tests, and two with decompensated cirrhosis; none had neurological manifestations. Only one patient had a Kayser-Fleischer corneal ring. Median ceruloplasmin level at diagnosis was 0.13 (range <0.03–0.30) g/l, median 24-hour urinary copper excretion was 2.8 (range 0.3–77.3) μmol, and median hepatic copper concentration was 789 (range 284–1677) μg/g. At least one mutation in the ATP7B gene was identified in eight patients. Allelic frequency of the common H1069Q mutation was 19%. Leipzig score was ≥5 in all patients. Three patients presenting with acute liver failure and the two with decompensated cirrhosis underwent successful liver transplantation. One patient with acute liver failure recovered under chelation therapy, as predicted by a Dhawan score <11. D-penicillamine was used as first-line chelator treatment, with a subsequent switch to trientine due to adverse effects in three out of six patients. CONCLUSIONS: The clinical presentation of hepatic Wilson’s disease is highly variable. Three out of 10 patients were diagnosed at an age >35 years. A high index of suspicion in clinically compatible situations is key.

Epigenetic changes of the thioredoxin system in the tx-j mouse model and in patients with Wilson disease.

Wilson disease (WD) is caused by mutations in the copper transporter ATP7B, leading to copper accumulation in the liver and brain. Excess copper inhibits S-adenosyl-L-homocysteine hydrolase, leading to variable WD phenotypes from widespread alterations in DNA methylation and gene expression. Previously, we demonstrated that maternal choline supplementation in the Jackson toxic milk (tx-j) mouse model of WD corrected higher thioredoxin 1 (TNX1) transcript levels in fetal liver. Here, we investigated the effect of maternal choline supplementation on genome-wide DNA methylation patterns in tx-j fetal liver by whole-genome bisulfite sequencing (WGBS). Tx-j Atp7b genotype-dependent differences in DNA methylation were corrected by choline for genes including, but not exclusive to, oxidative stress pathways. To examine phenotypic effects of postnatal choline supplementation, tx-j mice were randomized to one of six treatment groups: with or without maternal and/or continued choline supplementation, and with or without copper chelation with penicillamine (PCA) treatment. Hepatic transcript levels of TXN1 and peroxiredoxin 1 (Prdx1) were significantly higher in mice receiving maternal and continued choline with or without PCA treatment compared to untreated mice. A WGBS comparison of human WD liver and tx-j mouse liver demonstrated a significant overlap of differentially methylated genes associated with ATP7B deficiency. Further, eight genes in the thioredoxin (TXN) pathway were differentially methylated in human WD liver samples. In summary, Atp7b deficiency and choline supplementation have a genome-wide impact, including on TXN system-related genes, in tx-j mice. These findings could explain the variability of WD phenotype and suggest new complementary treatment options for WD.

A clinical study of bone mesenchymal stem cells for the treatment of hepatic fibrosis induced by hepatolenticular degeneration.

The efficacy of bone marrow mesenchymal stem cell (BMSC) on liver fibrosis in animal has been proven, but a few studies have been made in human body and few such researches in China. This study was designed to investigate the effect of BMSC treatment on hepatic fibrosis induced by hepatolenticular degeneration and the influence on serological indicators. Sixty patients with liver fibrosis induced by hepatolenticular degeneration were randomly divided into two groups, a penicillamine group and a BMSCs plus penicillamine group, with 30 patients in each. The therapeutic effects on hepatic fibrosis, liver function, and serological indicators were recorded before and after the treatment, and the data were compared. After treatment, serum levels of HA, PCIII, LN, CIV, TIMP-1, and MMP-1 were reduced in both groups (P < 0.05). However, cytokine levels in the BMSCs plus penicillamine group were significantly lower than those in the penicillamine group (P < 0.05). Combination therapy with BMSCs and penicillamine had a significant positive effect on liver fibrosis induced by hepatolenticular degeneration.

Radiolabeled D-Penicillamine Magnetic Nanocarriers for Targeted Purposes.

The aim of this study is to synthesize D-Penicillamine (D-PA) conjugated magnetic nanocarriers for targeted purposes. Magnetic nanoparticles were prepared by partial reduction method and surface modification was done with an amino silane coupling agent's (structural properties), AEAPS, the particles were characterized by Scanning Electron Microscope (SEM), X-ray Diffraction (XRD). After that D-PA was linked with the magnetic nanoparticles (MNPs) and has been radiolabeled with [99mTc(CO)3]+ core. Quality controls of [99mTc(CO)3-MNP-D-PA] were established by Cd(Te) detector. The radiolabeling efficiency of magnetic nanoparticles ([99mTc(CO)3-MNP-D-PA]) was about 97.05% with good in vitro stability during the 24 hour period. As a parallel study, radiolabeled D-PA complex ([99mTc(CO)3-D-PA]) was prepared with a radiolabeling yield of 97.93%. At the end, biologic activities of binding complexes were investigated on MCF7 human breast cancer cells. Our results show that, radiolabeled magnetic nanoparticles with core [99mTc(CO)3]+ ([99mTc(CO)3-MNP-D-PA]) showed the highest uptake on MCF7 cells which were applied magnetic field in the wells. In that case, result of this study emphasizes that radiolabeled magnetic nanoparticles with core [99mTc(CO)3]+ would support new occurrences of new agents.

[WILSON-KONOVALOV'S DISEASE IN TWO SISTERS: DIFFERENCES IN THE CLINICAL PICTURE AND SUCCESSFUL THERAPY].

Wilson-Konovalov's disease is a rare genetic pathology of copper metabolism that in the first place affects liver and CNS. Due to autosomal-recessive inheritance of this condition, it most frequently occurs in sibs. We report a case of Wilson-Konovalov's disease in two sisters differing in its clinical course: severe abdominal variant in the younger sister and largely neurologic form in the elder one. This observation demonstrates clinical variability of Wilson-Konovalov's disease, the possibility of its late clinical manifestation (at the age 45 years), the necessity of examination of all sibs of a proband regardless of age, and the possibility of radical improvement of prognosis even when the disease is diagnosed at the stage of decompensated liver cirrhosis.

Mechanistic basis of a combination D-penicillamine and platinum drugs synergistically inhibits tumor growth in oxaliplatin-resistant human cervical cancer cells in vitro and in vivo.

The platinum-based regimen is the front-line treatment of chemotherapy. However, development of platinum resistance often causes therapeutic failure in this disease. We previously have generated an oxaliplatin-resistant subline, named S3, from human cervical carcinoma SiHa cells, and its resistant phenotype was well-characterized. In the present study, we aimed to identify the novel therapeutic strategy by combining copper chelator D-penicillamine with oxaliplatin, and to elucidate the underlying mechanisms for overcoming oxaliplatin resistance. As the result, D-penicillamine exerted synergistic killing effects only in S3 cells when combined with oxaliplatin and cisplatin by using Chou-Talalay method. Further study showed that the amounts of platinum DNA adduct formed were positively correlated to the percentage of cell death in S3 cells when co-treated D-penicillamine with oxaliplatin and cisplatin. D-penicillamine promoted copper influx transporter hCtr1 expression through upregulation of Sp1. Sp1 overexpression induced p53 translocation from nucleus to cytosol and caused p53 degradation through ubiquitination, which subsequently suppressed the expression of the copper efflux transporter ATP7A. Importantly, co-treatment of cisplatin with D-penicillamine enhanced oxaliplatin-elicited antitumor effect in the oxalipatin-resistant S3 xenograft tumors, but not found in SiHa xenograft model. Notably, Mice received D-penicillamine alone or in combination of D-penicillamine ad oxalipatin, increased hCtrl protein level in S3 xenograft tumor, however, the protein level of ATP7A was decreased. Taken together, this study provides insight into that the co-manipulation of hCtrl and ATP7A by D-penicillamine could increase the therapeutic efficacy of platinum drugs in oxaliplatin resistant tumors, especially in resistant phenotype with downexpression of hCtrl and overexpression of ATP7A.

Addition of D-penicillamine, hypotaurine, and epinephrine (PHE) mixture to IVF medium maintains motility and longevity of bovine sperm and enhances stable production of blastocysts in vitro.

The present study aimed to establish an efficient system for bovine embryo production by in vitro fertilization (IVF) that can achieve stable normal fertilization and blastocyst developmental rates in any bull without optimization of the sperm concentration in IVF medium. We examined the effects of a PHE mixture (20 µM D-penicillamine, 10 µM hypotaurine and 1 µM epinephrine), theophylline (2.5 mM), and sperm concentration (1, 2 or 5 × 10(6) cells/ml) on fertilization and blastocyst developmental rates. High cleavage rates (78.3 to 92.4%) and blastocyst developmental rates (31.9 to 62.0%) at day 7 were obtained in the presence of PHE and theophylline in IVF medium with a sperm concentration of 2 × 10(6) cells/ml using sperm from 9 bulls. In addition, the synergistic effect of PHE and theophylline on normal fertilization (2 pronuclei) was clarified at 12 h after IVF with a sperm concentration of 1 × 10(6) cells/ml. Moreover, high linearity, high flagellar beat cross frequency, and low amplitude of lateral head of motile sperm were found by computer-assisted sperm analysis. In conclusion, the combination of the PHE mixture and theophylline synergistically accelerates sperm motility and sperm penetration of bovine oocytes. Theophylline activates sperm motility with increasing intracellular cAMP. However, PHE prevents an excessive increase of cAMP and maintains sperm motility without hyperactivation. When the combination of PHE and theophylline is added to IVF medium at a sperm concentration of 2 × 10(6) cells/ml, we can achieve stable normal fertilization and blastocyst development in any bull.

Controlled administration of penicillamine reduces radiation exposure in critical organs during 64Cu-ATSM internal radiotherapy: a novel strategy for liver protection.

PURPOSE: (64)Cu-diacetyl-bis (N (4)-methylthiosemicarbazone) ((64)Cu-ATSM) is a promising theranostic agent that targets hypoxic regions in tumors related to malignant characteristics. Its diagnostic usefulness has been recognized in clinical studies. Internal radiotherapy (IRT) with (64)Cu-ATSM is reportedly effective in preclinical studies; however, for clinical applications, improvements to reduce radiation exposure in non-target organs, particularly the liver, are required. We developed a strategy to reduce radiation doses to critical organs while preserving tumor radiation doses by controlled administration of copper chelator penicillamine during (64)Cu-ATSM IRT. METHODS: Biodistribution was evaluated in HT-29 tumor-bearing mice injected with (64)Cu-ATSM (185 kBq) with or without oral penicillamine administration. The appropriate injection interval between (64)Cu-ATSM and penicillamine was determined. Then, the optimal penicillamine administration schedule was selected from single (100, 300, and 500 mg/kg) and fractionated doses (100 mg/kg×3 at 1- or 2-h intervals from 1 h after (64)Cu-ATSM injection). PET imaging was performed to confirm the effect of penicillamine with a therapeutic (64)Cu-ATSM dose (37 MBq). Dosimetry analysis was performed to estimate human absorbed doses. RESULTS: Penicillamine reduced (64)Cu accumulation in the liver and small intestine. Tumor uptake was not affected by penicillamine administration at 1 h after (64)Cu-ATSM injection, when radioactivity was almost cleared from the blood and tumor uptake had plateaued. Of the single doses, 300 mg/kg was most effective. Fractionated administration at 2-h intervals further decreased liver accumulation at later time points. PET indicated that penicillamine acts similarly with the therapeutic (64)Cu-ATSM dose. Dosimetry demonstrated that appropriately scheduled penicillamine administration reduced radiation doses to critical organs (liver, ovaries, and red marrow) below tolerance levels. Laxatives reduced radiation doses to the large intestine. CONCLUSIONS: We developed a novel strategy to reduce radiation exposure in critical organs during (64)Cu-ATSM IRT, thus promoting its clinical applications. This method could be beneficial for other (64)Cu-labeled compounds.

[INFLUENCE OF HYPERICUM PERFORATUM L. HERB POLYPHENOLS PREPARATION WITH MINERALS ON THE STATE OF PERIODONTAL CONNECTIVE TISSUE MATRIX OF RATS IN CONDITION OF PERIODONTITIS MODELING].

In experiments on 22 white 1.5-month-old rats-males there were studied influence of Hypericum perforatum L. and minerales from Dyovit® on periodont's tissues under periodontits modelling. Examined preparation normalizes level of glicosaminoglicanes in gum, but did not completely show protective effects relative to collagen's fraction. In periodont's bone preparation decreases resorbrtion; increases activity of AlP and in the same time normalizes activity of AcP.

Orthopaedic problems about the ankle in hemophilia.

Hemophilia is an inherited recessive, sex-linked bleeding disorder. The lack of sufficient coagulation factor VIII produces hemophilia A, and the lack of factor IX causes hemophilia B. The prevention and treatment of the disease requires intravenous infusion of the deficient factor. Hemophilic patients present with multiarticular joint degeneration (hemophilic arthropathy), secondary to recurrent hemarthroses. With the availability of deficient factors, hemophilic patients requiring elective ankle surgery can undergo such surgery with a high expectation of success. A thorough analysis of each case by a multidisciplinary team will increase the likelihood of successful surgical intervention in the hemophilic patient. Radiosynovectomy decreases both the frequency and the intensity of recurrent ankle bleeding episodes related to ankle synovitis. The general recommendation is that when 3 early consecutive radiosynovectomies (repeated every 6 months) fail to halt synovitis, arthroscopic synovectomy should be considered. For advanced hemophilic arthropathy of the ankle, the first alternative for treatment, in our opinion, is arthroscopic ankle debridement. In the most severe cases, we recommend either ankle arthrodesis or total ankle replacement. In every other case, we feel that the best therapy is prophylaxis and radiosynovectomy in order to avoid hemophilic synovitis and ankle arthropathy.

Polypeptide conjugates of D-penicillamine and idarubicin for anticancer therapy.

We investigated anticancer therapy with a novel combination of D-penicillamine (D-pen) and Idarubicin (Ida) in a synthetic dual drug conjugate (DDC). D-pen and Ida were covalently linked to poly(α)-L-glutamic acid (PGA) via reducible disulfide and acid-sensitive hydrazone bonds, respectively. The DDCs showed cell uptake and sustained release of the bound drugs in conditions mimicking the intracellular release media (10mM glutathione and pH 5.2). The in-vitro cytotoxicity of DDCs was comparable to unconjugated Ida in several sensitive and resistant cancer cell lines and correlated with the rate of cell uptake. In a single equivalent-dose pharmacokinetic study, DDCs enhanced the drug exposure by 7-fold and prolonged the plasma circulation half-life (t(1/2)) by 5-fold over unconjugated Ida. The therapeutic index of DDCs was 2-3-fold higher than unconjugated drugs. DDCs caused 89% tumor growth inhibition compared to 60% by unconjugated Ida alone and led to significant enhancement in the median survival (17%) of athymic nu/nu mice bearing NCI-H460 tumor xenografts.

Topical application of L-arginine blocks advanced glycation by ascorbic acid in the lens of hSVCT2 transgenic mice.

PURPOSE: Previous experiments from our laboratory showed that the oral intake of selected guanidino compounds could block the formation of crystallin-bound advanced ascorbylation products. Here we tested whether these were also active when applied as eye drops. METHODS: Two month old hSVCT2 transgenic mice (n=10) were treated twice daily with one drop of 0.1% L-arginine, γ-guanidinobutyric acid (GBA), penicillamine (PA) or N-acetylcysteine (NAC) in one eye and vehicle only in the other eye. After seven months, lens crystallins were isolated, dialyzed, and proteolytically digested to determine the protein-bound fluorescence at 335/385 and 370/440 nm excitation/emission and the advanced glycation/ascorbylation endproducts carboxymethyl-lysine (CML), carboxyethyl-lysine (CEL), glucosepane, glyoxal, and methylglyoxal hydroimidazolones G-H1 and MG-H1. The topical uptake of L-arginine and NAC was also evaluated in vitro and in vivo in rabbit lens. RESULTS: In hSVCT2 mice, L-arginine decreased 335/385 and 370/440 nm fluorescence by 40% (p<0.001), CML, CEL, and glucosepane crystallin crosslinks by 35% (p<0.05), 30% (p<0.05), and 37% (p<0.05), respectively, without affecting MG-H1 and G-H1. NAC decreased 335/385 nm fluorescence by 50% (p<0.001) but, like PA and GBA, had no effect on other modifications. L-Arginine uptake into rabbit eyes treated topically reached identical lenticular plateau levels (~400 nmol/g wet weight) at 0.5% and 2.0% but levels remained three times higher at 5 h at 2% versus 0.5% concentration, respectively. In vitro studies showed a 100 fold higher L-arginine level than NAC levels, implicating high affinity uptake of the former. CONCLUSIONS: L-Arginine when applied both orally and topically is a potent and broad suppressor of advanced ascorbylation in the lens. Its uptake in rabbit lens upon topical application suggests transcorneal uptake into the human lens should be feasible for testing its potential anticataract properties in clinical trials.

Administration of a novel penicillamine-bound membrane: a preventive and therapeutic treatment for abdominal adhesions.

BACKGROUND: Adhesions formation is a significant postsurgical complication. At present, there is no effective method for preventing adhesions formation 1, although barrier products such as Dextran (Dex) 2 and sodium hyaluronate (SH) 3 have proved the most clinically successful 456, This study is designed to investigate the preventive and therapeutic potential of a novel penicillamine-bound membrane for abdominal adhesions formation. METHODS: 150 rats were involved in the present study. All animals were randomly divided into 6 groups (1 vehicle group and 5 test groups respectively treated with dextran, sodium hyaluronate, penicillamine, penicillamine-bound membrane or non-penicillamine-bound membrane). The occurrence, grade and score of abdominal adhesions were compared between the different groups. The breaking strength of incision was compared between the vehicle group and the penicillamine, membrane with/without penicillamine - treated groups. Expression of collagen type I was compared between the vehicle and penicillamine-treated group. The occurrence of adhesions was compared between the Dextran (Dex), sodium hyaluronate (SH), penicillamine-treated group and membrane with or without penicillamine- treated groups. RESULTS: Penicillamine and penicillamine-bound membrane had significant preventive effects on abdominal adhesions formation, better than dextran, sodium hyaluronate and non-penicillamine-bound membrane. However, neither of them influenced incision healing, although they insignificantly decreased the breaking strength of the incision. Penicillamine-bound membrane, which can be loaded locally and more efficaciously, shows greater advantages than penicillamine. CONCLUSIONS: Penicillamine-bound membrane can be applied as an effective therapeutic intervention for abdominal adhesions with inconsequential side effects.