Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.

Pharmacotherapy used for alcohol and cocaine use disorders in a CAPS-AD of Minas Gerais

Abstract Substance use disorder is one of the major social and public health problems in the world. The present study analyzed the pharmacoepidemiological profile of patients treated at the Psychosocial Treatment Center for Alcohol and Substance Use Disorders (CAPS-AD) for treatment of alcohol use disorders (AUD), cocaine use disorders (CUD) and concomitant alcohol and cocaine use disorders (A-CUD) in the city of Betim-MG. The study used quantitative and descriptive data and was based on the evaluation of medical records of patients attended from January to December 2016. After analyzing 295 medical records, the majority of study participants were male (83.7 %) with an average age of 46.26 for AUD, 28.88 for CUD and 34.29 for A-CUD. The most prescribed drugs for AUD were diazepam (54.1 %), thiamine (37 %), complex B vitamins (29.5 %), and disulfiram (2.7 %); for CUD, diazepam (26.9 %) and haloperidol (23.1 %). It should be noticed that although contraindicated by the guidelines, chlorpromazine (42.3 %, 25.3 %, 20.3 %) was prescribed for CUD, AUD, and A-CUD respectively. Knowing the pharmacoepidemiological profile of CAPS-AD patients is extremely important for making decisions regarding which medicines to make available to the population.

Disulfiram, a Re-positioned Aldehyde Dehydrogenase Inhibitor, Enhances Radiosensitivity of Human Glioblastoma Cells In Vitro / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Glioblastoma, the most common brain tumor in adults, has poor prognosis. The purpose of this study was to determine the effect of disulfiram (DSF), an aldehyde dehydrogenase inhibitor, on in vitro radiosensitivity of glioblastoma cells with different methylation status of O⁶-methylguanine-DNA methyltransferase (MGMT) promoter and the underlying mechanism of such effect. MATERIALS AND METHODS: Five human glioblastoma cells (U138MG, T98G, U251MG, U87MG, and U373MG) and one normal human astrocyte (NHA) cell were cultured and treated with DSF or 6MV X-rays (0, 2, 4, 6, and 8 Gy). For combined treatment, cells were treated with DSF before irradiation. Surviving fractions fit from cell survival based on colony forming ability. Apoptosis, DNA damage repair, and cell cycle distributionwere assayed bywestern blot for cleaved caspase-3, γH2AX staining, and flow cytometry, respectively. RESULTS: DSF induced radiosensitization in most of the glioblastoma cells, especially, in the cells with radioresistance as wildtype unmethylated promoter (MGMT-wt), but did not in normal NHA cell. DSF augmented or induced cleavage of caspase-3 in all cells after irradiation. DSF inhibited repair of radiation-induced DNA damage in MGMT-wt cells, but not in cells with methylated MGMT promoter. DSF abrogated radiation-induced G2/M arrest in T98G and U251MG cells. CONCLUSION: Radiosensitivity of glioblastoma cells were preferentially enhanced by pre-irradiation DSF treatment compared to normal cell, especially radioresistant cells such as MGMT-wt cells. Induction of apoptosis or inhibition of DNA damage repair may underlie DSF-induced radiosensitization. Clinical benefit of combining DSF with radiotherapy should be investigated in the future.

Epileptic Seizure Due to Disulfiram Treatment / 가정의학회지

Disulfiram has been used for the treatment of alcohol dependence for nearly 65 years and is approved by the Food and Drug Administration. It causes negative reinforcement by accumulating toxic acetaldehyde due to irreversible inhibition of aldehyde dehydrogenase. Disulfiram has very few side effects when taken without alcohol. Epileptic seizure induction is a rare side effect in therapeutic doses, and its mechanism is unknown. We present a patient with a single epileptic seizure which was thought to be due to disulfiram used in the treatment of alcohol dependence. We did not find it ethical to administer disulfiram again because the patient discontinued alcohol use and was afraid of epileptic seizures.

Disulfram Treatment of NUP98-PHF23 AML Is Not Effective In Vivo: Potential Role for Hematopoietic Stem Cells Niche / 임상소아혈액종양

BACKGROUND: NUP98 has numerous partner genes of which plant homeodomain (PHD) finger protein 23 (PHF23) fusion with NUP98 (NP23) can be detected by RT-PCR in patients with cytogenetically normal acute myelogenous leukemia (AML). In this fusion transcript of NP23 PHD of PHF23 is known to specifically bind H3K4me3 residues and act as a chromatic modifier. Disulfiram (DSF) which inhibits the binding of PHD to H3K4me3 residues selectively killed NP23 myeloblasts in vitro and therefore, we planned to evaluate the efficacy of DSF in vivo. METHODS: Cultured 961C cells (CD45.2), NP23 myeloblast cells were transplanted into B57BL/6 mice (CD45.1). Using limit dilution assay the number of leukemic stem cells (LSCs) could be calculated. A certain amount of 961C cells were transplanted into B57BL/6 mice and DSF was treated after 1 week. The engraftment level was monitored with CD45.2. Kaplan Meier survival curve was used to compare the survival between therapeutic and control group. RESULTS: 961C cells could be transplanted without radiation in recipient mice. Calculated LSC was estimated to be 1 out of 184 cells (95% CI range, 56–609). When treated with DSF of different doses and administration routes in 961C recipient mice no survival advantage of DSF was observed in 961C transplanted immunocompetent mouse, however it was evident that engraftment level was consistent in both groups. CONCLUSION: No survival advantage of DSF in 961C transplanted immunocompetent mouse was observed, however it was evident that 961C cells shared niche with normal hematopoietic stem cells (HSCs). We expect that 961C cells and transplanted recipient mice have the potential to be used as in vivo system for new drugs development as well as for research dealing with niche for normal HSCs and LSCs.

Disulfiram Induced Psychosis

Disulfiram is the commonly prescribed drug for the treatment of alcohol dependence. It's major metabolite (diethyldithiocarbamate) is an inhibitor of dopamine-betahydroxylase, an enzyme that catalyzes the metabolism of dopamine to norepinephrine resulting in psychosis. We recommend that disulfiram should be used at the lowest effective dose, possibly 250 mg daily and caution should be taken while prescribing disulfiram for patients with personal and familial antecedents of psychosis.

Comment on: Disulfiram Induced Psychosis (Mohapatra and Rath, Clin Psychopharmacol Neurosci 2017;15:68-69)

No abstract available.

Nutritional Supports in Patients with Inflammatory Bowel Disease

Underweight and specific nutrient deficiencies are frequent in adult patients with inflammatory bowel disease (IBD). In addition, a significant number of children with IBD, particularly Crohn's disease (CD) have impaired linear growth. Nutritional support is important in patients with IBD and nutritional problems. Enteral nutrition (EN) can reduce CD activity and maintain remission in both adults and children. Given that the ultimate goal in the treatment of CD is mucosal healing, this advantage of EN over corticosteroid treatment is valuable in therapeutic decision-making. EN is indicated in active CD, in cases of steroid intolerance, in patient's refusal of steroids, in combination with steroids in undernourished individuals, and in patients with inflammatory stenosis of the small intestine. EN should be the first choice compared to total parenteral nutrition. However, EN does not have a primary therapeutic role in ulcerative colitis. In conclusion, it appears that the role of nutrition as supportive care in patients with IBD should not be underestimated. The aim of this comprehensive review is to provide the reader with an update on the role of nutritional support in IBD patients.

Liquid chromatography for determination of disulfiramin workplace atmosphere / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To establish a method for determination of disulfiram in the workplace atmosphere by liquid chromatography.</p><p><b>METHODS</b>Sampling with glass fiber filter, eluting with methanol, separating with C18 column, and determination with liquid chromatography.</p><p><b>RESULTS</b>The bearing capacity of glass fiber filter exceeded 3.45 mg per piece. The elution efficiency was 97.8%∼101.0% The relative standard deviation varied from 1.09% to 1.44%. The limit of detection was 0.1 µg/ml. The minimum detectable concentration was 0.011 mg/m³ (with sampled air volume of 45 L).</p><p><b>CONCLUSION</b>The method has high selectivity, accuracy, and precision and strong applicability.</p>

The role of interleukin-18 in glioblastoma pathology implies therapeutic potential of two old drugs-disulfiram and ritonavir / 癌症

Based on reporting in the last several years, an impressive but dismal list of cytotoxic chemotherapies that fail to prolong the median overall survival of patients with glioblastoma has prompted the development of treatment protocols designed to interfere with growth-facilitating signaling systems by using non-cytotoxic, non-oncology drugs. Recent recognition of the pro-mobility stimulus, interleukin-18, as a driver of centrifugal glioblastoma cell migration allows potential treatment adjuncts with disulfiram and ritonavir. Disulfiram and ritonavir are well-tolerated, non-cytotoxic, non-oncology chemotherapeutic drugs that are marketed for the treatment of alcoholism and human immunodeficiency virus (HIV) infection, respectively. Both drugs exhibit an interleukin-18-inhibiting function. Given the favorable tolerability profile of disulfiram and ritonavir, the unlikely drug-drug interaction with temozolomide, and the poor prognosis of glioblastoma, trials of addition of disulfiram and ritonavir to current standard initial treatment of glioblastoma would be warranted.

Factors associated with Problem Drinking in Korean Male Employees for Drinking Motivation, Job Stress, and Drinking Refusal Self-efficacy / 한국직업건강간호학회지

PURPOSE: The purpose of this study was to examine relationships between drinking motivation, drinking refusal self-efficacy, job stress and problem drinking, and identify contributing factors on employees' problem drinking. METHODS: A total of 191 employees recruited from two worksites. Data were analyzed using descriptive statistics, t-test, ANOVA, and Pearson's correlation coefficient, and multiple regression. RESULTS: A 65.5% of employees has shown as hazardous drinking. Employees' problem drinking was significantly influenced by coping motives as a sub-factors of drinking motives (beta=.25) and social pressure as a sub-factors of drinking refusal self-efficacy(beta =-.57), explained 51.2% of the total variance. CONCLUSION: Considering the results of this study, healthy workplace culture for preventing employees' problem drinking should be builded. In addition, alcohol education program and effective employee assistance program need to be developed.

How to Improve Eating Behaviour during Early Childhood / 대한소아소화기영양학회지

Eating behaviour disorder during early childhood is a common pediatric problem. Many terminologies have been used interchangeably to describe this condition, hindering implementation of therapy and confusing a common problem. The definition suggests an eating behaviour which has consequences for family harmony and growth. The recent Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition does not cover the entire spectrum seen by pediatricians. Publications are substantive but level of evidence is most of the time low. This purpose of this review is to clarify terminology of eating behaviour problems during early childhood; including benign picky eating, limited diets, sensory food aversion, selective eating, food avoidance emotional disorder, pervasive refusal syndrome, tactile defensiveness, functional dysphagia, neophobia and toddler anorexia. This tool is proposed only to ease the clinical management for child care providers. Diagnostic criteria are set and management tools are suggested. The role of dietary counselling and, where necessary, behavioural therapy is clarified. It is hoped that the condition will make its way into mainstream pediatrics to allow these children, and their families, to receive the help they deserve.

Multivariate Analysis of Risk Factors Associated With the Nonreversal Ileostomy Following Sphincter-Preserving Surgery for Rectal Cancer

PURPOSE: A loop ileostomy is used to protect an anastomosis after anal sphincter-preserving surgery, especially in patients with low rectal cancer, but little information is available concerning risk factors associated with a nonreversal ileostomy. The purpose of this study was to identify risk factors of ileostomy nonreversibility after a sphincter-saving resection for rectal cancer. METHODS: Six hundred seventy-nine (679) patients with rectal cancer who underwent sphincter-preserving surgery between January 2004 and December 2011 were evaluated retrospectively. Of the 679, 135 (19.9%) underwent a defunctioning loop ileostomy of temporary intent, and these patients were divided into two groups, that is, a reversal group (RG, 112 patients) and a nonreversal group (NRG, 23 patients) according to the reversibility of the ileostomy. RESULTS: In 23 of the 135 rectal cancer patients (17.0%) that underwent a diverting ileostomy, stoma reversal was not possible for the following reasons; stage IV rectal cancer (11, 47.8%), poor tone of the anal sphincter (4, 17.4%), local recurrence (2, 8.7%), anastomotic leakage (1, 4.3%), radiation proctitis (1, 4.3%), and patient refusal (4, 17.4%). The independent risk factors of the nonreversal group were anastomotic leakage or fistula, stage IV cancer, local recurrence, and comorbidity. CONCLUSION: Postoperative complications such as anastomotic leakage or fistula, advanced primary disease (stage IV), local recurrence and comorbidity were identified as risk factors of a nonreversal ileostomy. These factors should be considered when drafting prudential guidelines for ileostomy closure.

Transfusion free radical antegrade modular pancreaticosplenectomy of metastatic neuroendocrine tumor of the pancreas in Jehovah's Witness patient

In a popular sense, Jehovah's Witnesses (JW) have their creeds, one of which is refusal of blood transfusion. Such refusal may impinge on their proper management, especially in critical situations. We present a case of successful bloodless multimodality therapy, which was performed for a JW. The patient was a 49-year-old woman and JW who had general weakness 7 days before admission. She was diagnosed with a pancreatic neuroendocrine tumor (PNET) with hepatic metastases. Transcatheter arterial chemoembolization and Sandostatin LAR injection were performed, and then she was given a transfusion-free Radical antegrade modular pancreatosplenectomy sequentially. We gave recombinant human erythropoietin and iron hydroxide sucrose complex daily for five days after surgery. She was discharged at postoperative day 12 without any surgical complications. Multimodality therapy is very important for optimal treatment of PNET. Along with intimate interdepartmental cooperation, careful patient selection and appropriate perioperative management could possibly enhance the surgical outcome.

Impact of a "TED-Style" presentation on potential patients' willingness to accept dental implant therapy: a one-group, pre-test posttest study

PURPOSE: A survey was conducted to assess the impact of a TED-like educational session on participants' willingness to accept dental implant therapy. MATERIALS AND METHODS: Volunteers interested in having information about dental implant therapies were recruited and asked to complete a two-part survey before and after an educational session. The initial survey elicited demographic information, self-perceived knowledge on dental implants and willingness to this kind of treatment. A "TED-style" presentation that provided information about dental implant treatments was conducted before asking the participants to complete a second set of questions assessing the impact of the session. RESULTS: The survey was completed by 104 individuals, 78.8% were women and the mean age was 66.5+/-10.8. Before the educational session, 76.0% of the participants refused dental implants mainly due to lack of knowledge. After the educational session, the rejection of dental implants decreased by almost four folds to 20.2%. CONCLUSION: This study proved that an educational intervention can significantly increase willingness to accept treatment with dental implants in a segment of the population who is interested in having information about dental implant therapy. Furthermore, educational interventions, such as TED-like talks, might be useful to increase popular awareness on dental implant therapy.

Usefulness of Minimally Invasive Posterior Foraminotomy using Tubular Retractor for Lumbar Spinal Stenosis with Foraminal Stenosis

STUDY DESIGN: Retrospective study. OBJECTIVES: The aim of this study was to report the usefulness of lumbar posterior foraminotomy and central decompression using tubular retractor with minimally invasive technique. SUMMARY OF LITERATURE REVIEW: Posterior decompression and arthrodesis for the treatment of lumbar spinal stenosis with foraminal stenosis is a classical surgical method. It is inappropriate for patients who have rejection to arthrodesis or medical problems, because it may have several complications. MATERIALS AND METHODS: Clinical results were obtained from 12 patients who underwent posterior foraminotomy and central decompression from January 2009 to April 2011 and were assessed using a Visual analogue scale, Oswestry disability index and the Prolo outcome scale. RESULTS: Six Of 12 patients showed immediate relief of radiculopathy. Postoperative posterior lumbar pain and spasm were negligible, and no surgically related complication was noted. During the follow-up period, the Oswestry disability index decreased from 24.25+/-2.89(pre-op) to 19.33+/-3.02(Last F/U)(p=0.28, paired t-test) in 8 of 12 patients. CONCLUSIONS: A minimally invasive posterior foraminotomy and central decompression could be an alternative surgical option for the treatment of lumbar spinal stenosis with foraminal stenosis, especially in subjects with old age, having medical problems and refusal of arthrodesis.

Comparison between Natives and Foreigners who Visited an Emergency Center due to Suicidal Attempt

PURPOSE: In an effort to determine the characteristics of foreign suicides who visit an emergency center, this study analyzed suicidal attempt between natives and foreigners. METHODS: We conducted a retrospective analysis of 1,218 Korean and 149 foreign suicidal attempters who visited a regional emergency center from January 1, 2009 to December 31, 2013. We compared two groups according to age, sex, selected suicidal methods, past psychiatric history, medical examination and treatment acceptance, elapsed time to visit an emergency center after suicidal attempt, emergency center residence time, and hospitalization period. RESULTS: No difference in medical exam acceptance and tetanus vaccination was observed between the two groups. However, we found a difference in hospitalization acceptance. The prevalence rate of psychiatric disorders was lower in foreign suicides, and the refusal rate of psychiatric treatment was higher in foreign patients. CONCLUSION: In foreign suicides, social support including finance is required for easy access to health care service. In addition, more active interdisciplinary cooperation with the department of psychiatry and close observation is needed.

Reversible Motor Neuropathy Following Disulfiram Therapy

No abstract available.

Disulfiram Implantation for the Treatment of Alcoholism: Clinical Experiences from the Plastic Surgeon's Point of View

BACKGROUND: Disulfiram implantation is a widely used treatment alternative for alcohol abuse, yet reports on the surgical aspect of disulfiram implantation with respect to patient and drug-related treatment efficacy and wound complications are very limited. We present our clinical experiences with disulfiram implantation and discuss the surgical outcomes obtained with different anatomical planes for implantation. METHODS: Medical records of all patients referred to our clinic from the psychiatry department between 2007 and 2013 for disulfiram implantation were retrospectively analyzed. Implantation was carried out using 10 sterile Disulfiram tablets (WZF Polfa S.A.), each tablet containing 100 mg of disulfiram. The procedure was carried out by implanting the tablets randomly in either a subcutaneous or an intramuscular plane. The location and the plane of implantation and the complications were recorded for each patient and compared to determine the differences in the outcomes. RESULTS: A total of 32 implantation procedures were evaluated for this study. Twenty-five implants were placed in the intramuscular plane (78.2%), while seven implants were placed subcutaneously (21.8%). Exposure was encountered in three of the seven subcutaneous implants (42.9%), while no exposure was seen with the intramuscular implants. Incomplete absorption of the tablets was encountered in one patient with a previous subcutaneous implant who presented 1 year later for re-implantation as part of the continuation of therapy. CONCLUSIONS: To overcome the issue of treatment continuation in the case of disulfiram therapy, which may be ceased due to frequently encountered wound complications, we believe that implantation in the subscapular intramuscular plane allows both uneventful healing and an out-of-reach implant location.

Outcome of Local Excision Following Preoperative Chemoradiotherapy for Clinically T2 Distal Rectal Cancer: A Multicenter Retrospective Study (KROG 12-06) / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The aim of this study was to examine the clinical implications of a pathologically complete response after neoadjuvant chemoradiotherapy (CRT) followed by local excision for patients with cT2 rectal cancer who refused radical surgery. MATERIALS AND METHODS: Seventeen patients with cT2 primary rectal cancer within 6 cm from the anal verge who received neoadjuvant CRT and local excision because of patient refusal of radical surgery or poor performance status were included. Two patients had clinical involvement of a regional lymph node. Preoperative radiotherapy was delivered to the whole pelvis at a dose of 44 to 50.4 Gy in 22 to 28 fractions. All patients underwent transanal excision and eight patients (47%) received postoperative chemotherapy. RESULTS: Ten patients (59%) achieved ypT0. At a median follow-up period of 75 months (range, 22 to 126 months), four (24%) patients developed recurrence (two locoregional and two distant). The 5-year disease-free survival of all patients was 82%, and was higher in patients with ypT0 (90%) than in patients with ypT1-2 (69%, p=0.1643). Decreased disease-free survival was also observed in patients receiving capecitabine compared with 5-fluorouracil (54% vs. 100%, p=0.0298). CONCLUSION: Local excision could be a feasible alternative to radical surgery in patients with ypT0 after neoadjuvant CRT for cT2 distal rectal cancer without further radical surgery.