The past decade in bench research into pulmonary infectious diseases: What do clinicians need to know?

Respirology. 2017 Jun 28;:

Authors: Finch S, Keir HR, Dicker AJ, Chalmers JD

Abstract
Respiratory infections are primarily treated with antibiotics, drugs that are mostly inexpensive and have been widely available since the 1940s and 1950s. Nevertheless, despite antibiotics, the burden of disease in pneumonia, bronchiectasis, cystic fibrosis, COPD and rare respiratory infections remains exceptionally high. There is an urgent need for translational studies to develop new treatments or new biomarkers to improve outcomes in these conditions. The 'translational gaps' between bench science and clinical practice are particularly challenging in respiratory infections. This is partly due to the poor representativeness of animal models of infection to human disease, and a long-term lack of investment into pulmonary infection research. The revolution in genomics and other omics technologies, however, is beginning to unlock clinically important information about the host response to infection, the behaviour of bacterial communities and the development of new antibiotics. It is not possible to review the extensive progress made in the last decade into the pathophysiology of the different respiratory infections and so here, we focus on major technologies that are now changing respiratory infection research, specifically bacterial whole-genome sequencing, the microbiota, personalized medicine with omics technologies, new antibiotic development and host inflammatory cell biology.

PMID: 28657170 [PubMed - as supplied by publisher]

Corticosteroid-resistant inflammatory signalling in Pseudomonas-infected bronchial cells.

ERJ Open Res. 2017 Apr;3(2):

Authors: Mizutani M, Bérubé J, Ahlgren HG, Bernier J, Matouk E, Nguyen D, Rousseau S

Abstract
Decreasing the inflammatory response that leads to tissue damage during cystic fibrosis (CF) lung disease has been a long-standing goal of CF therapy. While corticosteroids are widely used anti-inflammatory drugs, their efficacy in CF lung disease remains debated. The complex interaction between the colonising bacteria and the host environment may impact corticosteroid responsiveness. In this study, sputum samples from adult CF patients were collected at baseline and during pulmonary exacerbation episodes. Lung function measurements and sputum microbiological analyses were performed. In parallel, the inflammatory response and corticosteroid sensitivity of airway epithelial cells to Pseudomonas-derived exoproducts was investigated. We report that adult CF patients colonised with mucoid Pseudomonas aeruginosa have higher levels of baseline inflammation, more frequent exacerbations and worse lung function compared with patients colonised with nonmucoid P. aeruginosa. Moreover, mucoid P. aeruginosa activates NF-κB via Toll-like receptor (TLR) 2, which acts in an additive manner to TLR5 to drive inflammation in airway epithelial cells. Furthermore, TLR2-mediated intracellular signalling is more resistant to the anti-inflammatory effects of corticosteroid when compared with other TLR signalling pathways. Overall, these results suggest that airway inflammation triggered by mucoid P. aeruginosa is less responsive to the anti-inflammatory action of corticosteroids. Whether this translates into a diminished response of CF patients to corticosteroid therapy should be examined in future clinical studies.

PMID: 28656134 [PubMed - in process]

Stabilization of a nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator yields insight into disease-causing mutations.

J Biol Chem. 2017 Jun 27;:

Authors: Vernon RM, Chong PA, Lin H, Yang Z, Zhou Q, Aleksandrov AA, Dawson JE, Riordan JR, Brouillette CG, Thibodeau PH, Forman-Kay JD

Abstract
Characterization of the second nucleotide binding domain (NBD2) of the cystic fibrosis transmembrane conductance regulator (CFTR) has lagged behind research into the NBD1 domain, in part because NBD1 contains the F508del mutation which is the dominant cause of cystic fibrosis. Research on NBD2 has also been hampered by the overall instability of the domain and the difficulty of producing reagents. Nonetheless multiple disease-causing mutations reside in NBD2 and the domain is critical to CFTR function, since channel gating involves NBD1:NBD2 dimerization and NBD2 contains the catalytically active ATPase site in CFTR. Recognizing the paucity of structural and biophysical data on NBD2, here, we have defined a bioinformatics-based method for manually identifying stabilizing substitutions in NBD2, and used an iterative process of screening single substitutions against thermal melting points to both produce minimally mutated stable constructs and individually characterize mutations. We present a range of stable constructs with minimal mutations to help inform further research on NBD2. We have used this stabilized background to study the effects of NBD2 mutations identified in CF patients, demonstrating that mutants such as N1303K and G1349D are characterized by lower stability, as previously demonstrated for some NBD1 mutations, suggesting a potential role for NBD2 instability in the pathology of CF.

PMID: 28655774 [PubMed - as supplied by publisher]

Diabetes of the exocrine pancreas: American Diabetes Association-compliant lexicon.

Pancreatology. 2017 Jun 19;:

Authors: Petrov MS

Abstract
Multidisciplinary teams, including gastroenterologists, endocrinologists, surgeons, dietitians, primary care physicians, and other health professionals, are involved in management of individuals with diabetes of the exocrine pancreas (DEP). This necessitates introduction of a uniform terminology to ensure proper communication and reporting. Because DEP is a form of secondary diabetes mellitus, it makes sense to align the evolving DEP lexicon with nomenclature and diagnostic standards advocated by a world leading professional body in the field of diabetes such as the American Diabetes Association. This Editorial offers a historical excursus on the terms used and proposes a new concise nomenclature and diagnostic criteria. This new taxonomy of DEP, compliant with the American Diabetes Association standards of diagnosis and care for patients with diabetes mellitus, will ensure standardisation of reporting in future clinical studies on DEP and enable a dynamic incorporation of glucose dysregulation mechanisms related specifically to diseases of the exocrine pancreas as new evidence emerges.

PMID: 28655595 [PubMed - as supplied by publisher]

A Model for the Transient Subdiffusive Behavior of Particles in Mucus.

Biophys J. 2017 Jan 10;112(1):172-179

Authors: Ernst M, John T, Guenther M, Wagner C, Schaefer UF, Lehr CM

Abstract
In this study we have applied a model to explain the reported subdiffusion of particles in mucus, based on the measured mean squared displacements (MSD). The model considers Brownian diffusion of particles in a confined geometry, made from permeable membranes. The applied model predicts a normal diffusive behavior at very short and long time lags, as observed in several experiments. In between these timescales, we find that the "subdiffusive" regime is only a transient effect, MSD∝τ(α),α<1. The only parameters in the model are the diffusion-coefficients at the limits of very short and long times, and the distance between the permeable membranes L. Our numerical results are in agreement with published experimental data for realistic assumptions of these parameters. Finally, we show that only particles with a diameter less than 40 nm are able to pass through a mucus layer by passive Brownian motion.

PMID: 28076809 [PubMed - indexed for MEDLINE]

The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery.

Nat Genet. 2016 Jun;48(6):648-56

Authors: Toriyama M, Lee C, Taylor SP, Duran I, Cohn DH, Bruel AL, Tabler JM, Drew K, Kelly MR, Kim S, Park TJ, Braun DA, Pierquin G, Biver A, Wagner K, Malfroot A, Panigrahi I, Franco B, Al-Lami HA, Yeung Y, Choi YJ, University of Washington Center for Mendelian Genomics, Duffourd Y, Faivre L, Rivière JB, Chen J, Liu KJ, Marcotte EM, Hildebrandt F, Thauvin-Robinet C, Krakow D, Jackson PK, Wallingford JB

Abstract
Cilia use microtubule-based intraflagellar transport (IFT) to organize intercellular signaling. Ciliopathies are a spectrum of human diseases resulting from defects in cilia structure or function. The mechanisms regulating the assembly of ciliary multiprotein complexes and the transport of these complexes to the base of cilia remain largely unknown. Combining proteomics, in vivo imaging and genetic analysis of proteins linked to planar cell polarity (Inturned, Fuzzy and Wdpcp), we identified and characterized a new genetic module, which we term CPLANE (ciliogenesis and planar polarity effector), and an extensive associated protein network. CPLANE proteins physically and functionally interact with the poorly understood ciliopathy-associated protein Jbts17 at basal bodies, where they act to recruit a specific subset of IFT-A proteins. In the absence of CPLANE, defective IFT-A particles enter the axoneme and IFT-B trafficking is severely perturbed. Accordingly, mutation of CPLANE genes elicits specific ciliopathy phenotypes in mouse models and is associated with ciliopathies in human patients.

PMID: 27158779 [PubMed - indexed for MEDLINE]

Drug-related problems and medication reviews among old people with dementia.

BMC Pharmacol Toxicol. 2017 Jun 27;18(1):52

Authors: Pfister B, Jonsson J, Gustafsson M

Abstract
BACKGROUND: Drug-related problems, including medication errors and adverse drug events, are common among old people. Due to, for example, greater susceptibility to side effects, people with dementia are even more at risk of drug-related problems. The objectives of this study were to assess the occurrence and character of drug-related problems found among old people with dementia or cognitive impairment.
METHODS: Data from a randomized controlled clinical trial exploring the effects of a pharmacist intervention as part of a hospital ward team in patients 65 years and older with dementia or cognitive impairment were used. The study was conducted between 2012 and 2014 in the orthopedic and medicine wards in two hospitals located in Northern Sweden. Drug-related problems identified in this patient group were classified and described, and associations with different factors were investigated.
RESULTS: Clinical pharmacists identified at least one DRP in 66% (140/212) of participants in the intervention group, for a total of 310 DRPs. Ineffective drug/inappropriate drug and unnecessary drug therapy were the most common drug-related problems. Discontinuation of drug therapy was the most common action carried out. Drug-related problems were more common among people prescribed a larger number of drugs and among people with an earlier stroke.
CONCLUSIONS: Drug-related problems are common among people with dementia and cognitive impairment. Comprehensive medication reviews conducted by clinical pharmacists as part of a health care team might be important to prevent, identify and solve these problems.

PMID: 28655357 [PubMed - in process]

Treatment outcomes of fixed-dose combination versus separate tablet regimens in pulmonary tuberculosis patients with or without diabetes in Qatar.

BMC Infect Dis. 2017 Feb 02;17(1):118

Authors: Al-Shaer MH, Mansour H, Elewa H, Salameh P, Iqbal F

Abstract
BACKGROUND: Tuberculosis is considered the second most common cause of death due to infectious agent. The currently preferred regimen for treatment of pulmonary tuberculosis (PTB) is isoniazid, rifampin, pyrazinamide, and ethambutol, which has been used either as separate tablets (ST) or as fixed-dose combination (FDC). To date, no studies have compared both regimens in Qatar. We aim to evaluate the safety and effectiveness of FDC and ST regimen for treating PTB, in addition to comparing safety and efficacy of FDC and ST regimens in patients with diabetes treated for TB.
METHODS: A retrospective observational study was conducted in two general hospitals in Qatar. Patients diagnosed with PTB received anti-tuberculosis medications (either as FDC or ST) administered by the nurse. Sputum smears were tested weekly. We assessed the time to negative sputum smear and incidence of adverse events among FDC and ST groups.
RESULTS: The study included 148 patients. FDC was used in 90 patients (61%). Effectiveness was not different between FDC and ST regimens as shown by mean time to sputum conversion (29.9 ± 18.3 vs. 35.6 ± 23 days, p = 0.12). Similarly, there was no difference in the incidence of adverse events, except for visual one that was higher in ST group. Among the 33 diabetic patients, 19 received the FDC and had faster sputum conversion compared to those who received ST (31 ± 12 vs. 49.4 ± 30.9 days, p = 0.05). Overall, diabetic patients needed longer time for sputum conversion and had more hepatotoxic and gastric adverse events compared to non-diabetics.
CONCLUSION: ST group had higher visual side effects compared to FDC. FDC may be more effective in diabetic patients; however, further studies are required to confirm such finding.

PMID: 28152986 [PubMed - indexed for MEDLINE]

Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation.

J Am Coll Cardiol. 2016 Oct 18;68(16):1756-1764

Authors: Lorberbaum T, Sampson KJ, Chang JB, Iyer V, Woosley RL, Kass RS, Tatonetti NP

Abstract
BACKGROUND: QT interval-prolonging drug-drug interactions (QT-DDIs) may increase the risk of life-threatening arrhythmia. Despite guidelines for testing from regulatory agencies, these interactions are usually discovered after drugs are marketed and may go undiscovered for years.
OBJECTIVES: Using a combination of adverse event reports, electronic health records (EHR), and laboratory experiments, the goal of this study was to develop a data-driven pipeline for discovering QT-DDIs.
METHODS: 1.8 million adverse event reports were mined for signals indicating a QT-DDI. Using 1.6 million electrocardiogram results from 380,000 patients in our institutional EHR, these putative interactions were either refuted or corroborated. In the laboratory, we used patch-clamp electrophysiology to measure the human ether-à-go-go-related gene (hERG) channel block (the primary mechanism by which drugs prolong the QT interval) to evaluate our top candidate.
RESULTS: Both direct and indirect signals in the adverse event reports provided evidence that the combination of ceftriaxone (a cephalosporin antibiotic) and lansoprazole (a proton-pump inhibitor) will prolong the QT interval. In the EHR, we found that patients taking both ceftriaxone and lansoprazole had significantly longer QTc intervals (up to 12 ms in white men) and were 1.4 times more likely to have a QTc interval above 500 ms. In the laboratory, we found that, in combination and at clinically relevant concentrations, these drugs blocked the hERG channel. As a negative control, we evaluated the combination of lansoprazole and cefuroxime (another cephalosporin), which lacked evidence of an interaction in the adverse event reports. We found no significant effect of this pair in either the EHR or in the electrophysiology experiments. Class effect analyses suggested this interaction was specific to lansoprazole combined with ceftriaxone but not with other cephalosporins.
CONCLUSIONS: Coupling data mining and laboratory experiments is an efficient method for identifying QT-DDIs. Combination therapy of ceftriaxone and lansoprazole is associated with increased risk of acquired long QT syndrome.

PMID: 27737742 [PubMed - indexed for MEDLINE]

Therapeutic efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria from three highly malarious states in India.

Malar J. 2016 Oct 13;15(1):498

Authors: Bharti PK, Shukla MM, Ringwald P, Krishna S, Singh PP, Yadav A, Mishra S, Gahlot U, Malaiya JP, Kumar A, Prasad S, Baghel P, Singh M, Vadadi J, Singh MP, Bustos MD, Ortega LI, Christophel EM, Kashyotia SS, Sonal GS, Singh N

Abstract
BACKGROUND: Anti-malarial drug resistance continues to be a leading threat to malaria control efforts and calls for continued monitoring of waning efficacy of artemisinin-based combination therapy (ACT). Artesunate + sulfadoxine/pyrimethamine (AS + SP) is used for the treatment of uncomplicated Plasmodium falciparum malaria in India. However, resistance against AS + SP is emerged in northeastern states. Therefore, artemether-lumefantrine (AL) is the recommended first line treatment for falciparum malaria in north eastern states. This study investigates the therapeutic efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in three malaria-endemic states in India. The data generated through this study will benefit the immediate implementation of second-line ACT as and when required.
METHODS: This was a one-arm prospective evaluation of clinical and parasitological responses for uncomplicated falciparum malaria using WHO protocol. Patients diagnosed with uncomplicated mono P. falciparum infection were administered six-dose regimen of AL over 3 days and subsequent follow-up was carried out up to 28 days. Molecular markers msp-1 and msp-2 were used to differentiate recrudescence and re-infection and K13 propeller gene was amplified and sequenced covering the codon 450-680.
RESULTS: A total of 402 eligible patients were enrolled in the study from all four sites. Overall, adequate clinical and parasitological response (ACPR) was 98 % without PCR correction and 99 % with PCR correction. At three study sites, ACPR rates were 100 %, while at Bastar, cure rate was 92.5 % on day 28. No early treatment failure was found. The PCR-corrected endpoint finding confirmed that one late clinical failure (LCF) and two late parasitological failures (LPF) were recrudescences. The PCR corrected cure rate was 96.5 %. The mean fever clearance time was 27.2 h ± 8.2 (24-48 h) and the mean parasite clearance time was 30.1 h ± 11.0 (24-72 h). Additionally, no adverse event was recorded. Analysis of total 186 samples revealed a mutation in the k13 gene along with non-synonymous mutation at codon M579T in three (1.6 %) samples.
CONCLUSION: AL is an efficacious drug for the treatment of uncomplicated falciparum malaria. However, regular monitoring of AL is required in view of malaria elimination initiatives, which will be largely dependent on therapeutic interventions, regular surveillance and targeted vector control.

PMID: 27737665 [PubMed - indexed for MEDLINE]

Metamizole (Dipyrone) as an Alternative Agent in Postoperative Analgesia in Patients with Contraindications for Nonsteroidal Anti-Inflammatory Drugs.

Pain Pract. 2017 Mar;17(3):402-408

Authors: Konijnenbelt-Peters J, van der Heijden C, Ekhart C, Bos J, Bruhn J, Kramers C

Abstract
PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) play an important role in multimodal pain management. In patients with a contraindication for NSAIDs, pain management is challenging. A recent Dutch anesthesiology guideline propagates the use of metamizole (dipyrone) in these patients. Metamizole is a controversial drug, its use being previously discouraged because of the risk for agranulocytosis. We discuss whether metamizole could be an alternative to classical NSAIDs and opioids in postoperative pain management despite this drawback.
METHOD: Literature review and pharmacovigilance research based on World Health Organization adverse effect registrations.
RESULTS: Metamizole causes fewer gastric and duodenal ulcers than other nonselective NSAIDs, and the risk for bleeding is limited. It is unknown whether it is safer than a nonselective NSAID combined with a proton pump inhibitor. Although the drug appears to be safe for renal function in healthy volunteers, data in high-risk patients (eg, those with heart or renal failure) are lacking. The incidence of metamizole-induced agranulocytosis is controversial, but the risk is likely to be limited with short-term postoperative use in this selected group of patients.
CONCLUSION: Although firm evidence is lacking, metamizole may be safer for the upper intestinal tract and kidneys than other NSAIDs, and could alternatively be used in patients with an increased risk for stomach or renal problems. Hereby, improved postoperative pain relief can potentially be achieved. The risk for metamizole-induced agranulocytosis is judged to be acceptable.

PMID: 27346584 [PubMed - indexed for MEDLINE]

Pharmacological Treatment of Pain in Cancer Patients: The Role of Adjuvant Analgesics, a Systematic Review.

Pain Pract. 2017 Mar;17(3):409-419

Authors: van den Beuken-van Everdingen MH, de Graeff A, Jongen JL, Dijkstra D, Mostovaya I, Vissers KC, national guideline working group “Diagnosis treatment of cancer pain”

Abstract
CONTEXT: In patients with cancer, pain is one of the most feared and burdensome symptoms. Adjuvant analgesics are an important cornerstone on which treatment of pain in patients with cancer is based.
OBJECTIVES: To update our guidelines for the treatment of pain in patients with cancer, we performed a systematic review on the use of adjuvant analgesics in pain in cancer.
METHODS: A systematic search of the literature was performed searching for articles that studied the effect of (1) antidepressants, (2) anti-epileptics, (3) N-methyl-d-aspartate (NMDA) receptor antagonists, and (4) other adjuvant analgesics in patients with cancer pain and described their effects on pain intensity and/or side effects.
RESULTS: Based on the keywords and after reading the full papers, we could include 12 papers on anticonvulsants, 10 papers on antidepressants, four on NMDA receptor antagonists, and 10 papers on other adjuvant analgesics. The methodological quality of the included papers was graded as low to very low. Overall, there was a low quality of evidence that gabapentin, pregabalin, amitriptyline, and venlafaxine were effective in reducing pain intensity in patients with cancer pain. There was insufficient evidence on the effectiveness of lamotrigine, levetiracetam, NMDA antagonists, cannabinoids, corticosteroids, and local anesthetics on reducing pain intensity in patients with cancer pain.
CONCLUSION: The quality of currently available evidence on the effectiveness of adjuvant analgesics in the treatment of cancer pain is low. The treatment of pain associated with cancer should be tailored to the patient's personal preferences.

PMID: 27207115 [PubMed - indexed for MEDLINE]

Endocervical gastric-type adenocarcinoma, an unrelated HPV tumour: difficulties in screening and diagnosis.

BMJ Case Rep. 2017 Apr 11;2017:

Authors: Lima PC, Teixeira J, Aires GN, Andrade LA

Abstract
Gastric-type adenocarcinoma of the cervix (GAS) is an uncommon and aggressive tumour unrelated to human papillomavirus (HPV) infection with distinctive histological and immunohistochemical characteristics. GAS may be associated with lobular endocervical glandular hyperplasia (LEGH), another unusual lesion. We report a case of a 59-year-old woman with screening cytology 'AGC-Neo' and cervical conisation exhibiting cervical intraepithelial neoplasia grade 1, extensive LEGH and canal sampling with abundant mucinous cells. Based on the possible association between LEGH and GAS, a total hysterectomy was performed. The histological diagnosis revealed a morphological gradient of lesions: LEGH, minimal deviation adenocarcinoma and GAS with lymphatic invasion. Immunohistochemistry revealed strong MUC6 expression and no p16 staining. After pelvic radiotherapy, the patient continues follow-up evaluation. The diagnostic difficulties of GAS and its relationship with LEGH are discussed. This rare tumour is important because it is poorly symptomatic and potentially aggressive. In addition, the methods for cancer control related to HPV do not affect this tumour.

PMID: 28404551 [PubMed - indexed for MEDLINE]

A clustering approach to identify and characterize the asthma and chronic obstructive pulmonary disease overlap phenotype.

Clin Exp Allergy. 2017 Jun 28;:

Authors: Hirai K, Shirai T, Suzuki M, Akamatsu T, Suzuki T, Hayashi I, Yamamoto A, Akita T, Morita S, Asada K, Tsuji D, Inoue K, Itoh K

Abstract
BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. The phenotypes that have clinical features of both asthma and COPD are still incompletely understood.
OBJECTIVE: To clarify the best discriminators of the asthma-COPD overlap phenotype from asthma and COPD subgroups using a clustering approach.
METHODS: This study assessed pathophysiological parameters, including mRNA expression levels of T helper cell-related transcription factors, namely, TBX21 (Th1), GATA3 (Th2), RORC (Th17), and FOXP3 (Treg), in peripheral blood mononuclear cells in asthma patients (n = 152) and in COPD patients (n = 50). Clusters were determined using k-means clustering. Exacerbations of asthma and COPD were recorded during the 1-year follow-up period.
RESULTS: The cluster analysis revealed four biological clusters: cluster 1, predominantly patients with COPD; cluster 2, patients with an asthma-COPD overlap phenotype; cluster 3, patients with non-atopic and late-onset asthma; and cluster 4, patients with early-onset atopic asthma. Hazard ratios for exacerbation were 2.5 (95% confidence interval [CI], 1.1-5.6) in cluster 1 and 2.3 (95% CI, 1.0-5.0) in cluster 2 compared with patients in other clusters. Cluster 2 was discriminated from other clusters by total serum IgE level ≥ 310 IU/mL, blood eosinophil counts ≥ 280 cells/μL, a higher ratio of TBX21/GATA3, FEV1 /FVC ratio < 0.67, and smoking ≥ 10 pack-years with an area under the curve of 0.94 (95% CI, 0.90-0.98) in the receiver operating characteristic analysis.
CONCLUSIONS & CLINICAL RELEVANCE: The asthma-COPD overlap phenotype was characterized by peripheral blood eosinophilia and higher levels of IgE despite the Th2-low endotype. This article is protected by copyright. All rights reserved.

PMID: 28658564 [PubMed - as supplied by publisher]

Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal-induced hyperexcitability of sensory neurons due to Nav1.7 mutation I234T.

Br J Pharmacol. 2017 Jun 28;:

Authors: Yang Y, Adi T, Effraim P, Chen L, Dib-Hajj SD, Waxman SG

Abstract
BACKGROUND AND PURPOSE: Pharmacotherapy for pain currently involves trial-and-error. A previous study on inherited erythromelalgia (a genetic model of neuropathic pain due to mutations in voltage-gated sodium channel Nav1.7) used genomics, structural modeling, biophysical and pharmacological analyses to guide pharmacotherapy, and showed that carbamazepine normalizes voltage-dependence of activation of the Nav1.7-S241T mutant channel, reducing pain in patients carrying this mutation. However, whether this approach is applicable to other Nav mutations is still unknown.
EXPERIMENTAL APPROACH: We used structural modeling, patch-clamp, and multi-electrode recording (MEA) to assess the effects of carbamazepine on Nav1.7-I234T mutant channel, and on the firing of DRG sensory neurons expressing Nav1.7-I234T mutant channel.
KEY RESULTS: In a reverse engineering approach, we show by structural modeling that the I234T mutation is located in atomic proximity to the carbamazepine-responsive S241T mutation, and show that activation of Nav1.7-I234T mutant channel, from patients who are known to respond to carbamazepine, is partially normalized with a clinically-relevant concentration (30 μM) of carbamazepine. We further demonstrate significantly higher firing in intact sensory neurons expressing Nav1.7-I234T compared to neurons expressing Nav1.7-WT, and show that preincubation with 30 μM carbamazepine significantly reduces firing of intact DRG sensory neurons expressing Nav1.7-I234T. Additionally, while we confirmed the expected use-dependent inhibition of Nav1.7-WT by carbamazepine, we show that carbamazepine does not enhance use-dependent inhibition of Nav1.7-I234T mutant channel.
CONCLUSION AND IMPLICATIONS: These results support the utility of a pharmacogenomic approach to treatment of pain in patients carrying sodium channel variants.

PMID: 28658526 [PubMed - as supplied by publisher]

Safety profile of biological therapies for treating rheumatoid arthritis.

Expert Opin Biol Ther. 2017 Jun 28;:

Authors: Cañete JD, Hernández V, Sanmartí R

Abstract
INTRODUCTION: Biological agents such as tumor necrosis factor inhibitors (TNFi), abatacept, rituximab and tocilizumab have proven efficacy in RA. However, these agents are also associated with adverse events so further data is essential to detect them at the earliest stage possible. Areas covered: Herein, the authors review the safety profile of biological therapy, including TNFi and non-TNF agents including abatacept (ABA), rituximab (RTX) and tocilizumab (TCZ). The authors analyze both published articles and congress communications including clinical trials, meta-analyses, observational studies, data from registries and spontaneous clinical reports. The authors classify studies according to the most common and relevant adverse events associated with biological agents. Expert opinion: Biological therapies have a reasonable safety profile and, globally, the benefits far outweigh the possible risk of adverse events. Currently, the risk of serious infections is low and no increased risk in solid malignancies or cardiovascular events have been found after a long clinical experience with these therapies. However, there are still potential risks as well as concerns of immunogenicity induced by TNFi. More studies are required to understand these risks, design safer drugs, and implement pharmacogenomics into the clinic. This will lead to a more personalized medicine in the future.

PMID: 28657381 [PubMed - as supplied by publisher]

Apigenin overcomes drug resistance by blocking the signal transducer and activator of transcription 3 signaling in breast cancer cells.

Oncol Rep. 2017 Jun 26;:

Authors: Seo HS, Ku JM, Choi HS, Woo JK, Lee BH, Kim DS, Song HJ, Jang BH, Shin YC, Ko SG

Abstract
Drug resistance in chemotherapy is a serious obstacle for the successful treatment of cancer. Drug resistance is caused by various factors, including the overexpression of P‑glycoprotein (P‑gp, MDR1). The development of new, useful compounds that overcome drug resistance is urgent. Apigenin, a dietary flavonoid, has been reported as an anticancer drug in vivo and in vitro. In the present study, we investigated whether apigenin is able to reverse drug resistance using adriamycin‑resistant breast cancer cells (MCF‑7/ADR). In our experiments, apigenin significantly decreased cell growth and colony formation in MCF‑7/ADR cells and parental MCF‑7 cells. This growth inhibition was related to the accumulation of cells in the sub‑G0/G1 apoptotic population and an increase in the number of apoptotic cells. Apigenin reduced the mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance‑associated proteins (MRPs) in MCF‑7/ADR cells. Apigenin also downregulated the expression of P‑gp. Apigenin reversed drug efflux from MCF‑7/ADR cells, resulting in rhodamine 123 (Rho123) accumulation. Inhibition of drug resistance by apigenin is related to the suppression of the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Apigenin decreased STAT3 activation (p‑STAT3) and its nuclear translocation and inhibited the secretion of VEGF and MMP‑9, which are STAT3 target genes. A STAT3 inhibitor, JAK inhibitor I and an HIF‑1α inhibitor decreased cell growth in MCF‑7 and MCF‑7/ADR cells. Taken together, these results demonstrate that apigenin can overcome drug resistance.

PMID: 28656316 [PubMed - as supplied by publisher]

DNMT3A and TET2 dominate clonal hematopoiesis, demonstrate benign phenotypes and different genetic predisposition.

Blood. 2017 Jun 27;:

Authors: Buscarlet M, Provost S, Feroz Zada Y, Barhdadi A, Bourgoin V, Lépine G, Mollica L, Szuber N, Dubé MP, Busque L

Abstract
Age-associated clonal hematopoiesis caused by acquired mutations in myeloid cancer associated genes is highly prevalent in the normal population. Its etiology, biological impact on hematopoiesis and oncogenic risk is poorly defined at this time. To gain insight into this phenomenon, we analyzed a cohort of 2530 related and unrelated hematologically normal individuals (aged 55 to 101). We used a sensitive gene targeted deep sequencing approach to gain precision on the exact prevalence of driver mutations and the proportions of affected genes. Mutational status was correlated with biological parameters. We report a higher overall prevalence of driver mutations (13.7%) which occurred mostly (93%) in DNMT3A or TET2 and were highly age-correlated. Mutation in these two genes had some distinctive effects on endpoints. TET2 mutations were more age-dependent, associated with a modest neutropenic effect (9%, P = .012), demonstrated familial aggregation and were associated with chronic obstructive pulmonary disease. Mutations in DNMT3A had no impact on blood counts or indices. Mutational burden of both genes correlated with X-inactivation skewing but no significant association with age-adjusted telomere length reduction was documented. The discordance between the high prevalence of mutations in these 2 genes and their limited biological impact raise the question of the potential role of dysregulated epigenetic modifiers in normal aging hematopoiesis, which may include support to failing hematopoiesis.

PMID: 28655780 [PubMed - as supplied by publisher]

UPLC-MS/MS method for the simultaneous quantification of three new antiretroviral drugs, dolutegravir, elvitegravir and rilpivirine, and other thirteen antiretroviral agents plus cobicistat and ritonavir boosters in human plasma.

J Pharm Biomed Anal. 2017 May 10;138:223-230

Authors: Simiele M, Ariaudo A, De Nicolò A, Favata F, Ferrante M, Carcieri C, Bonora S, Di Perri G, De Avolio A

Abstract
Rilpivirine (RPV), dolutegravir (DTG) and elvitegravir (EVG) are the latest antiretroviral drugs approved for treatment of HIV infection. Currently, poor information is currently available concerning their pharmacokinetic and pharmacodynamic properties, thus making the use of therapeutic drug monitoring for these drugs not useful. This lack of information is partially due to the absence of an high-throughput method for their simultaneous quantification together with other antiretroviral drugs. In this work, we describe the development and validation of a new UPLC-MS/MS method to quantify these drugs, together with other fourteen antiretroviral agents, in human plasma. One hundred microliters of plasma samples were added with internal standard (6,7-Dimethyl- 2,3-di(2-pyridyl) quinoxaline), underwent a simple protein precipitation with methanol:acetonitrile (50:50v/v) followed by sample dilution with water. Chromatographic separation was performed on a Acquity(®) UPLC HSS T3 column (150mm x 2.1mm I.D) with a particle size of 1.8μm and compounds were detected with a tandem mass detector, monitoring two ion transitions for each drugs. The mean recovery of RPV, DTG and EVG were 101%, 87% and 112.3% respectively. Accuracy and precision inter/intra-day were below 15% for all drugs, in accordance to Food and Drug Administration guidelines requirements. The UPLC-MS/MS method reported here could be used routinely to monitor plasma concentrations of antiviral drugs, including RPV, DTG and EVG.

PMID: 28219799 [PubMed - indexed for MEDLINE]

A rapid and robust UHPLC-DAD method for the quantification of amphotericin B in human plasma.

J Pharm Biomed Anal. 2017 May 10;138:142-145

Authors: Barco S, Zunino A, D'Avolio A, Barbagallo L, Maffia A, Tripodi G, Castagnola E, Cangemi G

Abstract
Amphotericin B is an antifungal drug widely used in Intensive Care Units. Therapeutic drug monitoring (TDM) of amphotericin B is recommended for the assessment of toxicity surveillance and treatment optimization. In this paper we described the development and validation of a new Ultra High Performance Liquid Chromatography coupled to Diode Array Detection (UHPLC-DAD) method for the quantification of Amphotericin B in 200μL human plasma over a wide range of concentrations (0.125-10mg/L). The new method has been validated following international guidelines on bioanalytical method validation and showed high selectivity, high accuracy and precision and high process efficiency. The new UHPLC-DAD method that we describe is robust, rapid, cost effective and suitable for application to the routine TDM analyses.

PMID: 28199895 [PubMed - indexed for MEDLINE]