High Concentrations of Sodium Chloride Improve Microbicidal Activity of Ibuprofen against Common Cystic Fibrosis Pathogens.

Pharmaceuticals (Basel). 2018 May 17;11(2):

Authors: Muñoz AJ, Alasino RV, Garro AG, Heredia V, García NH, Cremonezzi DC, Beltramo DM

Abstract
Ibuprofen (IBU-H), a widely used anti-inflammatory, also shows a marked antimicrobial effect against several bacterial species, including those involved in cystic fibrosis such as Pseudomona aeruginosa, methicillin resistant Staphylococcus aureus and Burkholderia cepacia complex. Additionally, our results show significant synergy between water soluble Na-ibuprofen (IBU-Na) and ionic strength. Salt concentrations above 0.5 M modify the zeta potential promoting the action of Na-IBU; thus, with 1 M sodium chloride, IBU-Na is ten times more efficient than in the absence of ionic strength, and the minimum effective contact time is reduced from hours to minutes. In short time periods, where neither IBU-Na nor controls with 1 M NaCl show activity, the combination of both leads to a reduction in the bacterial load. We also analyzed whether the changes caused by salt on the bacterial membrane also promoted the activity of other microbicide compounds used in cystic fibrosis like gentamicin, tobramycin and phosphomycin. The results show that the presence of ionic strength only enhanced the bactericidal activity of the amphipathic molecule of IBU-Na. In this respect, the effect of saline concentration was also reflected in the surface properties of IBU-Na, where, in addition to the clear differences observed between 145 mM and 1 M, singular behaviors were also found, different in each condition. The combination of anti-inflammatory activity and this improved bactericidal effect of Na-IBU in hypertonic solution provides a new alternative for the treatment of respiratory infections of fibrotic patients based on known and widely used compounds.

PMID: 29772761 [PubMed]

Bethlem myopathy in a Portuguese patient - case report.

Acta Myol. 2017 Sep;36(3):178-181

Authors: Martins AI, Maarque C, Pinto-Basto J, Negrão L

Abstract
Mutations of the encoding genes of collagen VI (COL6A1, COL6A2 and COL6A3), are responsible for two classical phenotypes (with a wide range of severity), the Ullrich congenital muscular dystrophy (UCMD) and the Bethlem myopathy (BM). We present a male patient of 49 years old, with symptoms of muscle weakness beginning in childhood and of very slowly progression. At the age of 42, the neurological examination revealed proximal lower limb muscle weakness and contractures of fingers flexors muscles, positive Gowers manoeuvre and a waddling gait. Serum creatine kinase (CK) values were slightly elevated, electromyographic study revealed myopathic changes and muscle MRI of the lower limbs showed a specific pattern of muscle involvement, with peripheral fat infiltration in vastus lateralis and intermedius and anterocentral infiltration in rectus femoris. Respiratory and cardiac functions were unremarkable. Whole exome sequencing identified the homozygous mutation c.1970-9G>A in COL6A2 gene.

PMID: 29774307 [PubMed - in process]

Independent Tumor Origin in Two Cases of Synchronous Bilateral Clear Cell Renal Cell Carcinoma.

Sci Rep. 2016 07 07;6:29267

Authors: Ji Z, Zhao J, Zhao T, Han Y, Zhang Y, Ye H

Abstract
Bilateral renal cell carcinomas (RCCs) pose a challenge for clinical treatment and management. Most bilateral RCCs are sporadic, and do not show a hereditary pattern indicative of VHL syndrome or other inherited cancers. The origin and evolution of these sporadic bilateral RCCs remains elusive. We obtained normal and tumor samples from two male patients suffering from early stage synchronous bilateral clear cell RCC (ccRCC), and analyzed genomic DNA using whole exome sequencing and bisulfite pyrosequencing. We detected distinct 3p loss of heterozygosity (LOH) in both tumors in each patient. Two tumors within the same patient harbored distinct driver mutations and different CpG hypermethylation sites in the VHL promoter. Moreover, tumors exhibit independent evolutionary trajectories. Therefore, distinct 3p LOH, combined with contingent driver gene mutations and independent VHL hypermethylation, led to independent tumor origin and parallel evolution of bilateral ccRCC in these two patients. Our results indicate that tumors in these two cases were not due to common germline oncogenic mutations. They were results of multiple de novo mutations in each kidney, rather than primary ccRCC with contralateral renal metastasis. Therefore, histopathologic and genetic profiling from single tumor specimen may underestimate the mutational burden and somatic heterogeneity of bilateral ccRCCs.

PMID: 27383411 [PubMed - indexed for MEDLINE]

Cefepime vs. cefoperazone/sulbactam in combination with amikacin as empirical antibiotic therapy in febrile neutropenia.

Support Care Cancer. 2018 May 17;:

Authors: Ponraj M, Dubashi B, Harish BH, Kayal S, Cyriac SL, Pattnaik J, Ranjith K, Pillai US, Jadhav N, Matta KK, Singh J, Jaffa E, Prakash B

Abstract
PURPOSE: Beta lactams are standard empirical therapy for febrile neutropenia (FN). The aim of this study was to evaluate the efficacy and safety of cefepime monotherapy compared with cefoperazone/sulbactam plus amikacin (CS + A) for empirical treatment of high risk FN.
METHODS: One hundred seventy-five patients with 336 FN episodes were randomized to receive either cefepime (2 g q8h for adults and 50 mg/kg q8h for children) or CS (2 g q8h for adults and 50 mg/kg q8h for children) plus amikacin (15 mg/kg once a day). Positive response was defined as afebrile within 72 h of starting antibiotics, persistent afebrile status more than 48 h and no requirement of second-line antibiotics and antifungal agents.
RESULTS: Three hundred thirty-six episodes were assessable for efficacy (168 cefepime, 168 CS + A). The positive response to antibiotics was identical for cefepime (53%) and CS + A (53%). Positive response was similar in MDI (microbiologically documented infection), 50 vs. 35% (p = 0.248), CDI (clinically documented infection), 50 vs. 35% (p = 0.259), combination CDI + MDI, 25 vs. 15% (p = 0.400), FUO (fever of unknown origin), 68 vs. 72% (p = 0.577) respectively in the two groups. The successful discontinuation of antibiotics at 72 h in FUO was similar in both groups (60 vs. 59%, p = 0.544). Total drug-related adverse events were similar in both groups (8 vs. 6%) except renal dysfunction was high in CS + A (1 vs. 7 events). Mortality was the same between two groups (8 vs 7%).
CONCLUSIONS: Cefepime monotherapy and CS + A had similar efficacy as first-line therapy for FN. Discontinuation of empirical antibiotics is safe and feasible approach in selected group of FUO patients.

PMID: 29774477 [PubMed - as supplied by publisher]

Phase 2 study of everolimus for relapsed or refractory classical Hodgkin lymphoma.

Exp Hematol Oncol. 2018;7:12

Authors: Johnston PB, Pinter-Brown LC, Warsi G, White K, Ramchandren R

Abstract
Background: The current standard of care for classical Hodgkin lymphoma (HL) is multiagent chemotherapy with or without radiation. In patients who relapse or fail to respond, additional high-dose chemotherapy with autologous hematopoietic stem cell transplantation (AHSCT) can improve progression-free survival (PFS). Novel therapies are required for patients refractory to chemotherapy and AHSCT. The mammalian target of rapamycin inhibitor everolimus has shown preliminary activity in preclinical models of HL and promising efficacy in patients with relapsed or refractory HL.
Methods: This was an open-label, two-stage, phase 2 study that enrolled 57 patients aged ≥ 18 years with classic HL that had progressed after standard therapy. Patients received everolimus 10 mg daily until disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was overall response rate; secondary endpoints included PFS, overall survival, time to response, duration of response, and safety.
Results: Overall response rate was 45.6% (95% confidence interval [CI] 32.4-59.3%); five patients (8.8%) experienced a complete response and 21 patients had a partial response (36.8%). Median PFS was 8.0 months (95% CI 5.1-11.0 months). Seven patients (12%) were long-term responders (≥ 12 months). The most common study drug-related adverse events were thrombocytopenia (45.6%), fatigue (31.6%), anemia (26.3%), rash (24.6%), and stomatitis (22.8%).
Conclusions: Everolimus 10 mg/day demonstrated favorable results in patients with heavily pretreated, relapsed, or refractory classical HL. These findings support the further evaluation of everolimus in this indication.Trial registration ClinicalTrials.gov NCT01022996. Registered November 25, 2009.

PMID: 29774169 [PubMed]

Constipation and other common symptoms reported by women and men in methadone and buprenorphine maintenance treatment.

Drug Alcohol Depend. 2017 Dec 01;181:132-139

Authors: Haber PS, Elsayed M, Espinoza D, Lintzeris N, Veillard AS, Hallinan R

Abstract
BACKGROUND: Opioid substitution treatment (OST) is often continued long-term and, therefore, opioid-associated symptoms are of interest. Symptoms associated with methadone maintenance treatment (MMT) in men are well described, but there are fewer reports concerning symptoms associated with buprenorphine maintenance treatment (BMT) and very few reports among women.
METHOD: Recipients of BMT (n=113) and MMT (n=184), non-opioid users (n=105) and opioid users not receiving OST (n=87) completed the Patient Assessment of Constipation (PAC-SYM) and a general symptom checklist. Multivariate analysis included other potential moderators of opioid-associated symptoms.
FINDINGS: Opioid users reported a higher frequency and severity of symptoms than non-opioid users. Constipation, dry mouth, decreased appetite, sweating and fatigue were highly prevalent in the previous 30days (51-80%). Nausea, itchy skin, trouble urinating, menstrual problems, lightheadedness, blurred vision, heart racing were also common (30-50%). Non-OST opioid users had significantly higher frequency and severity than OST recipients of nausea, vomiting, diarrhoea, decreased appetite, sweating and itchy skin. Sweating was significantly more common in MMT than BMT. Constipation scores were higher in women, otherwise most sex differences were small. Higher PAC-SYM scores were associated with vomiting (OR=1.04) and sweating (OR=1.06). Cannabis use was associated with vomiting (OR=2.19). Constipation (OR=1.07), insomnia (OR=2.5) and depression (OR=2.82) were associated with fatigue.
CONCLUSION: Men and women receiving OST report similarly high rates of somatic symptoms, though less than opioid users not receiving OST. There were few differences between BMT and MMT. Buprenorphine might be preferred where sweating is problematic. Several modifiable factors were identified.

PMID: 29054032 [PubMed - indexed for MEDLINE]

Managing morbidity and treatment-related toxicity in patients with ankylosing spondylitis.

Rheumatology (Oxford). 2018 03 01;57(3):419-428

Authors: Bergman M, Lundholm A

Abstract
AS is the prototypical member of the family of spondyloarthropathies, and is characterized by seronegativity, axial predominance and new bone formation, which underlie symptoms of inflammatory back pain, enthesopathy and extra-articular manifestations, including anterior uveitis, psoriasis and colitis. Patients with AS typically experience a wide variety of morbidities. These include both morbidities related to the disease itself-most prominently progressive, irreversible, structural damage to the axial or peripheral skeleton-and morbidities stemming from treatments for the disease, including toxicities from NSAID use, and increased risk of infections and immunogenicity concerns with biologics. AS is also associated with a number of comorbidities. We review the risks associated with AS, its comorbidities and its treatments, as well as strategies that can be used to mitigate these risks in patients with AS.

PMID: 28977661 [PubMed - indexed for MEDLINE]

An analysis of redactions in Canada's Common Drug Review Clinical Review Reports and how they relate to the patients' voice.

BMJ Open. 2017 Sep 11;7(9):e015497

Authors: Soprovich A, El Kurdi S, Eurich DT

Abstract
IMPORTANCE: Canada's Common Drug Review (CDR) evaluates drug data from published and unpublished research, as well as input from patient groups, to recommend provincial coverage. Currently, the CDR process gives manufacturers the opportunity to redact information in the final publicly available report. Patients often have strong feelings regarding the efficacy, harms, health-related quality of life (HRQL), and cost associated with the drugs under review and their redacted data. Highlighting Canada's approach will hopefully build on the growing international concern regarding transparency of clinical study data.
OBJECTIVE: The purpose was to objectively examine and classify completed, publicly available CDR-Clinical Review Reports (CRR) for redactions, and compare them to the patients' reported interests as patient-centred outcomes.
METHODS: Two independent reviewers searched for and examined publicly available CDR-CRR from November 2013-September 2016 through the Canadian Agency for Drugs and Technologies in Health (CADTH) on-line database. Both reviewers separately classified the redactions and patient-reported interests into the following categories: efficacy, harms, HRQL and costs. All discrepancies were rectified by consensus involving a third reviewer.
RESULTS: Fifty-two completed CDR-CRR were reviewed. 48 (92%) included patient-reported interests and 40 (77%) had redactions classified in the following categories: efficacy (75%), costs (48%), harms (38%), HRQL (23%). 89% of redactions were outcomes identified as patient-reported interests (69% efficacy, 42% harms, 36% cost, 33% HRQL). When examining drug characteristics, biological agents were statistically associated with increased odds of redactions with respect to either efficacy (OR 3.4, 95% CI 1.0 to 11.6) or harms (OR 3.5, 95% CI 1.02 to 12.4) compared with non-biological agents.
CONCLUSIONS: Whether data from the CDR-CRR used in the decision-making should be fully disclosed to the public is controversial. Our findings suggest clinical data (efficacy, harms, HRQL) matters to patients and should be publicly available within the CDR-CRR. Canada trails Europe and the USA regarding the transparency of clinical study data. This lack of transparency relates to the patient voice, and limits movement towards patient-centred care and patient-engaged research, restricting real-world value measurement.

PMID: 28893743 [PubMed - indexed for MEDLINE]

Medication-related visits in a pediatric emergency department: an 8-years retrospective analysis.

Ital J Pediatr. 2017 Jun 13;43(1):55

Authors: Rosafio C, Paioli S, Del Giovane C, Cenciarelli V, Viani N, Bertolani P, Iughetti L

Abstract
BACKGROUND: There are limited data on the characterization of medication-related visits (MRVs) to the emergency department (ED) in pediatric patients in Italy. We have estimated the frequency, severity, and classification of MRVs to the ED in pediatric patients.
METHODS: We retrospectively analyzed data for children seeking medical evaluation for a MRV over an 8 years period. A medication-related ED visit was identified by using a random pharmacist assessment, emergency physician assessment, and in case of conflicting events, by a third investigators random assessment.
RESULTS: In this study, regarding a single tertiary center in Italy, on a total of 147,643 patients from 0 to 14 years old, 497 medication-related visits were found, 54% of which occurred in children from 0 to 2 years of age. Severity was classified as mild in 21.6% of cases, moderate in 67.2% of cases, and severe in 11.2% of cases. The most common events were related to drug use without indication (51%), adverse drug reactions (30.3%), supratherapeutic dosage (13.2%) and improper drug selection (4.5%). The medication classes most frequently implicated in an ADE were anti-infective drugs for systemic use (28.9%), central nervous system agents (22.3%) and respiratory system drugs (10.8%). The most common symptom manifestations were dermatologic conditions (46.1%), general disorder and administration site conditions (29.7%) and gastrointestinal symptoms (16.0%).
CONCLUSIONS: To our knowledge, this is the first study in Italy evaluating the epidemiologic characteristics of MRVs confirming a significant cause of healthcare contact resulting in ED visits and hospital admissions with associated resource utilization. Our results suggests further future prospective, large-sample sized, and multicenter research is necessary to better understand the impact of MRVs and to develop strategies to provide care plans and monitor patients to prevent medication-related visits.
TRIAL REGISTRATION: Not applicable.

PMID: 28610634 [PubMed - indexed for MEDLINE]

Antibiotic complications during the treatment of Mycobacterium ulcerans disease in Australian patients.

Intern Med J. 2017 Sep;47(9):1011-1019

Authors: O'Brien DP, Friedman D, Hughes A, Walton A, Athan E

Abstract
BACKGROUND: Antibiotics are the recommended first-line treatment for Mycobacterium ulcerans disease. Antibiotic toxicity is common in Australian patients, yet antibiotic complication rates and their risk factors have not been determined.
AIM: To determine the incidence rate and risk factors for antibiotic toxicity in Australian patients treated for M. ulcerans disease.
METHODS: An analysis of severe antibiotic complications was performed using data from a prospective cohort of M. ulcerans cases managed at Barwon Health from 1 January 1998 to 30 June 2016. A severe antibiotic complication was defined as an antibiotic adverse event that required its cessation. Antibiotic complication rates and their associations were assessed using a Poisson regression model.
RESULTS: A total of 337 patients was included; 184 (54.6%) males and median age 57 years (interquartile range (IQR) 36-73 years). Median antibiotic treatment duration was 56 days (IQR 49-76 days). Seventy-five (22.2%) patients experienced severe antibiotic complications after a median 28 days (IQR 17-45 days) at a rate of 141.53 per 100 person-years (95% confidence interval (CI) 112.86-177.47). Eleven (14.7%) patients required hospitalisation. Compared with rifampicin/clarithromycin combinations, severe complication rates were not increased for rifampicin/ciprofloxacin (rate ratio (RR) 1.49, 95% CI 0.89-2.50, P = 0.13) or rifampicin/moxifloxacin (RR 2.54, 95% CI 0.76-8.50, P = 0.13) combinations, but were significantly increased for 'other' combinations (RR 2.53, 95% CI 1.13-5.68, P = 0.03). In a multivariable analysis, severe complication rates were significantly increased with reduced estimated glomerular filtration rates (EGFR) (adjusted rate ratio (aRR) 2.65, 95% CI 1.24-5.65 for EGFR 60-89 mL/min and aRR 1.31, 95% CI 0.49-3.53 for EGFR 0-59 mL/min compared with EGFR ≥90 mL/min, P < 0.01) and female gender (aRR 2.15, 95% CI 1.38-3.30, P < 0.01).
CONCLUSIONS: Severe antibiotic complications during M. ulcerans treatment are high with increased rates independently associated with reduced renal function and female gender.

PMID: 28585259 [PubMed - indexed for MEDLINE]

Characteristics of dyspnoea and associated clinical outcomes in the CHAMPION PHOENIX study.

Thromb Haemost. 2017 Jun 02;117(6):1093-1100

Authors: Parker WA, Bhatt DL, Prats J, Day JRS, Steg PG, Stone GW, Hamm CW, Mahaffey KW, Price MJ, Gibson CM, White HD, Storey RF, CHAMPION PHOENIX Investigators

Abstract
Dyspnoea may be induced by some reversibly-binding P2Y12 inhibitors, including cangrelor and ticagrelor. Dyspnoea was not associated with any compromise to the efficacy of ticagrelor in the PLATO study. The CHAMPION PHOENIX study (NCT01156571) compared initial treatment with cangrelor versus initial treatment with clopidogrel in patients undergoing PCI. We investigated the incidence, characteristics, and associated clinical outcomes in patients with dyspnoea in CHAMPION PHOENIX. Adverse events (AEs) of dyspnoea to 48 hours were recorded in patients randomised to cangrelor or clopidogrel in CHAMPION PHOENIX. The composite primary endpoint of death, myocardial infarction, ischaemia-driven revascularisation, or stent thrombosis as well its individual components were assessed in patients who did or did not report dyspnoea. A total of 68 (1.2 %) cangrelor-treated patients and 18 (0.3 %) clopidogrel-treated patients reported dyspnoea (p<0.001). Most dyspnoea events in cangrelor-treated patients were considered mild (71 %) or moderate (28 %) and only one event was considered severe and led to discontinuation of cangrelor. The dyspnoea events in the clopidogrel-treated patients were mild (78 %) or moderate (22 %). Characteristics of dyspnoea were consistent with those seen in the CHAMPION programme as a whole. In the modified intention-to-treat population, rates of the composite primary outcome and its individual components were not affected by the presence of dyspnoea in cangrelor-treated patients. Cangrelor-related dyspnoea is transient, usually mild or moderate, and unlikely to lead to discontinuation of therapy. The occurrence of dyspnoea does not seem to be associated with any reduction in the efficacy of cangrelor compared with clopidogrel as initial therapy in PCI patients.

PMID: 28382371 [PubMed - indexed for MEDLINE]

[Analysis and exploration on adverse reactions of four kinds of andrographolide injections].

Zhongguo Zhong Yao Za Zhi. 2016 Jun;41(12):2350-2355

Authors: Xiang D, Wang MD, Wang WQ, Shi CY, Xie XJ, Fang JG

Abstract
Concerned literature on four kinds of andrographolide injections in recent 15 years were searched in CNKI, Wanfang and VIP databases. The adverse drug reaction(ADR) cases of Chuanhuning, Yanhuning, Xiyanping and Lianbizhi injections were classified and analyzed statistically, including a total of 194 articles and 3 479 cases. The ADR clinical characteristics and occurrence regularity of these four andrographolide injections were analyzed and compared from the gender, age, primary disease, emergence time of ADR, clinical manifestation, allergy history, dosage, prognosis and combined medication of the patients. It is useful to provide valuable references for rational use of these andrographolide injections in clinical practice.

PMID: 28901084 [PubMed - indexed for MEDLINE]

[Frequency of prescriptions of off-label drugs and drugs not approved for pediatric use in primary health care in a southern municipality of Brazil].

Rev Paul Pediatr. 2016 Jan-Mar;34(1):11-7

Authors: Gonçalves MG, Heineck I

Abstract
OBJECTIVE: To determine the frequency of prescriptions of off-label drugs and drugs not approved for pediatric use in primary health care in medium-sized municipality of Rio Grande do Sul, Brazil.
METHODS: Cross-sectional study with retrospective data collection, which analyzed prescriptions issued to 326 patients from August to December/2012 in two basic health units in the city of Viamão, state of Rio Grande do Sul. It included all prescriptions of patients whose medical records or service records were available and complete in relation to the date of presence, weight and date of birth. Off-label prescriptions were those which, in relation to the drug leaflet, showed dose different the recommended range, frequency of prescription and/or different form of administration and younger age than the indicated range. Descriptive statistics with absolute frequencies, means and standard deviations were used.
RESULTS: During the study period, a total of 731 drug prescriptions were issued and the frequency of off-label medications prescribed was 31.7%, especially antihistamines and antiasthmatics (32.3% and 31.5%, respectively). The main type of off-label prescription was dose (38.8%), followed by age range (31.5%) and frequency of administration (29.3%). Regarding the dose off-label prescription, overdose was more frequent (93.3%) than the underdose (6.7%). Prescriptions of unapproved drugs were not identified.
CONCLUSIONS: The study showed that off label prescription is common in both assessed units. The observed percentage of off label prescription was higher than that reported by European studies carried out in primary care. On the other hand, the prescription of drugs not approved for children was not observed.

PMID: 26530249 [PubMed - indexed for MEDLINE]

24 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/05/18

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica.

Nat Commun. 2018 May 16;9(1):1929

Authors: Estrada K, Whelan CW, Zhao F, Bronson P, Handsaker RE, Sun C, Carulli JP, Harris T, Ransohoff RM, McCarroll SA, Day-Williams AG, Greenberg BM, MacArthur DG

Abstract
Neuromyelitis optica (NMO) is a rare autoimmune disease that affects the optic nerve and spinal cord. Most NMO patients ( > 70%) are seropositive for circulating autoantibodies against aquaporin 4 (NMO-IgG+). Here, we meta-analyze whole-genome sequences from 86 NMO cases and 460 controls with genome-wide SNP array from 129 NMO cases and 784 controls to test for association with SNPs and copy number variation (total N = 215 NMO cases, 1244 controls). We identify two independent signals in the major histocompatibility complex (MHC) region associated with NMO-IgG+, one of which may be explained by structural variation in the complement component 4 genes. Mendelian Randomization analysis reveals a significant causal effect of known systemic lupus erythematosus (SLE), but not multiple sclerosis (MS), risk variants in NMO-IgG+. Our results suggest that genetic variants in the MHC region contribute to the etiology of NMO-IgG+ and that NMO-IgG+ is genetically more similar to SLE than MS.

PMID: 29769526 [PubMed - in process]

Functional characterization of 21 allelic variants of dihydropyrimidine dehydrogenase identified in 1,070 Japanese individuals.

Drug Metab Dispos. 2018 May 16;:

Authors: Hishinuma E, Narita Y, Saito S, Maekawa M, Akai F, Nakanishi Y, Yasuda J, Nagasaki M, Yamamoto M, Yamaguchi H, Mano N, Hirasawa N, Hiratsuka M

Abstract
Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2), encoded by the DPYD gene, is the rate-limiting enzyme in the degradation pathway of endogenous pyrimidine and fluoropyrimidine drugs such as 5-fluorouracil (5-FU). DPD catalyzes the reduction of uracil, thymine, and 5-FU. In Caucasians, DPYD mutations, including DPYD*2A, DPYD*13, c.2846A>T, and 1129-5923C>G/hapB3, are known to contribute to interindividual variations in the toxicity of 5-FU. However, none of these DPYD polymorphisms have been identified in the Asian population. Recently, 21 DPYD allelic variants, including some novel-single nucleotide variants (SNVs), were identified in 1,070 healthy Japanese individuals by analyzing their whole-genome sequences (WGS), but the functional alterations caused by these variants remain unknown. In this study, in vitro analysis was performed on 22 DPD allelic variants by transiently expressing wild-type DPD and 21 DPD variants in 293FT cells and characterizing their enzymatic activities, using 5-FU as a substrate. DPD expression levels and dimeric forms were determined using immunoblotting and blue native-PAGE, respectively. Additionally, the values of three kinetic parameters, the Michaelis constant (Km), maximum velocity (Vmax), and intrinsic clearance (CLint = Vmax/Km), were determined for the reduction of 5-FU. We found that 10 variants exhibited significantly decreased intrinsic clearance in comparison to wild-type DPD. Moreover, the band patterns observed in the immunoblots of blue native gels indicated that DPD dimerization is required for enzymatic activity in DPD. Thus, the detection of rare DPYD variants might facilitate severe adverse effect prediction of 5-FU-based chemotherapy in the Japanese population.

PMID: 29769267 [PubMed - as supplied by publisher]

Peptide inhibitors of chloride channels for treating secretory diarrhea.

Front Biosci (Landmark Ed). 2018 Jun 01;23:1780-1788

Authors: Ma J, Ding X, Yin Y, Huang P

Abstract
Morbidity and mortality associated with diarrheal diseases remain significant burdens on global health. In the developing world, the major sources of secretory diarrhea are infectious, including those caused by bacteria such as enterotoxic Escherichia coli, and viruses such as rotavirus. In many cases of secretory diarrhea, activation of pathways for cyclic nucleotides and/or Ca2+ signaling in the apical membrane of enterocytes increases the conductance of Cl- channels at the enterocyte lumen-facing membrane. Those channels include the cystic fibrosis transmembrane conductance regulator (CFTR) and Ca2+-activated Cl- channel (CaCC). Inhibition of enterocyte Cl- channels is an effective strategy for anti-secretory drug therapy. Small molecules and natural peptides with Cl- channel inhibitory activity have shown efficacy in diarrhea models. Screening of natural peptides via the patch-clamp technique provides evidence that such channel inhibition by an extract of black tea may be responsible for its anti-diarrhea benefits.

PMID: 29772528 [PubMed - in process]