Related Articles

De Novo Coding Variants Are Strongly Associated with Tourette Disorder.

Neuron. 2017 May 03;94(3):486-499.e9

Authors: Willsey AJ, Fernandez TV, Yu D, King RA, Dietrich A, Xing J, Sanders SJ, Mandell JD, Huang AY, Richer P, Smith L, Dong S, Samocha KE, Tourette International Collaborative Genetics (TIC Genetics), Tourette Syndrome Association International Consortium for Genetics (TSAICG), Neale BM, Coppola G, Mathews CA, Tischfield JA, Scharf JM, State MW, Heiman GA

Abstract
Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. VIDEO ABSTRACT.

PMID: 28472652 [PubMed - indexed for MEDLINE]

Reported Complications Following Laser Vitreolysis.

JAMA Ophthalmol. 2017 Jul 27;:

Authors: Hahn P, Schneider EW, Tabandeh H, Wong RW, Emerson GG, American Society of Retina Specialists Research and Safety in Therapeutics (ASRS ReST) Committee

Abstract
Importance: Use of laser vitreolysis for symptomatic floaters has increased in recent years, but prospective studies are not available and the complication profile is poorly understood.
Objective: To analyze cases of complications following laser vitreolysis as voluntarily reported to the American Society of Retina Specialists Research and Safety in Therapeutics (ASRS ReST) Committee, an independent task force formed to monitor device-related and drug-related safety events.
Design, Setting, and Participants: A retrospective assessment was performed of all cases of complications following laser vitreolysis that were voluntarily reported by practitioners throughout the United States to the ASRS ReST Committee from the first report on September 19, 2016, through March 16, 2017, the date of data analysis and manuscript writing.
Main Outcomes and Measures: Complications reported to the ASRS ReST Committee following laser vitreolysis were analyzed by type to gain an understanding of the spectrum of potential complications.
Results: A total of 16 complications following laser vitreolysis were reported in 15 patients by 7 US vitreoretinal specialists during the study period. Complications included elevated intraocular pressure leading to glaucoma; cataracts, including posterior capsule defects requiring cataract surgery; retinal tear; retinal detachment; retinal hemorrhages; scotomas; and an increased number of floaters.
Conclusions and Relevance: This report presents a spectrum of complications reported to the ASRS ReST Committee across 6 months. The rate of complications cannot be determined because the denominator of total cases is unknown. Also, these findings cannot determine whether there is a causal association between these complications and laser vitreolysis. Prospective studies are warranted to better understand the efficacy of this procedure and the frequency of attendant complications. Until then, practitioners should be aware of the profile of potential complications to properly inform patients during the consent process. The ASRS ReST Committee will continue to monitor device-related and drug-related adverse events and encourages active surveillance and reporting by all physicians.

PMID: 28750116 [PubMed - as supplied by publisher]

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Evaluation of Mitochondrial Respiration in Cultured Rat Hepatocytes.

Methods Mol Biol. 2017;1641:297-308

Authors: Marchandeau JP, Labbe G

Abstract
Mitochondrial dysfunction is a major mechanism whereby drugs can induce liver injury and other serious side effects, such as lactic acidosis and rhabdomyolysis, in some patients. Several in vitro and in vivo investigations can be performed in order to determine if drugs can disturb mitochondrial fatty acid oxidation (FAO) and the oxidative phosphorylation (OXPHOS) process, deplete hepatic mitochondrial DNA (mtDNA), or trigger the opening of the mitochondrial permeability transition pore (MPT). Among these investigations, mitochondrial respiration is a relatively easy test to measure the potential toxicity of a drug. The use of cells instead of isolated mitochondria allows one to test the toxic effect of a parent compound and its metabolites. The use of rat hepatocytes can detect drugs involved in drug-induced liver injuries (DILI). The method consists in measuring oxygen consumption by using a Clark electrode in a chamber containing a suspension of hepatocytes preincubated with drug.

PMID: 28748471 [PubMed - in process]

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Therapeutic Effects of Topical Tranexamic Acid in Comparison with Hydroquinone in Treatment of Women with Melasma.

Dermatol Ther (Heidelb). 2017 Jul 26;:

Authors: Atefi N, Dalvand B, Ghassemi M, Mehran G, Heydarian A

Abstract
INTRODUCTION: Few studies have focused on therapeutic as well as side effects of tranexamic acid (TXA) as a topical drug compared to other topical drugs in treating melasma. The present study aimed to assess and compare the beneficial therapeutic effects and also side effects of local TXA in comparison with hydroquinone in treating women with melasma.
METHODS: This randomized double-blinded clinical trial was performed on 60 women who suffered from melasma and were referred to the skin disorders clinic at the Rasoul-e-Akram hospital in Tehran in 2015. The patients were then randomly assigned via computerized randomization to two groups: group A received TXA%5 (topically twice a day for 12 weeks in the location of the melasma) and group B (received hydroquinone 2% with the same treatment order). Prior to intervention and at 12 weeks after intervention, the intensity and extension of melasma were assessed based on the Melasma Area and Severity Index (MASI) scoring method.
RESULTS: The mean MASI score in both treatment groups decreased considerably after completion of treatment and was not significant between the two groups. No side effects were detected in group A, but 10% of those in group B complained of drug-related side effects including erythema and skin irritation (p = 0.131). Regarding the level of patient satisfaction, the patients in group A had a significantly higher level of satisfaction level of 33.3% compared with 6.7% in group B (p = 0.015) (Fig. 9). Multivariate linear regression modeling with the presence of age, history of systemic disorder, drug history, and family history of melasma demonstrated no difference in the mean MASI between the two groups.
CONCLUSION: Topical use of TXA significantly reduced both melanin level and MASI score. Given its high efficiency and low drug side effects, this regimen results in high patient satisfaction compared with topical hydroquinone. IRCT code: IRCT2016040627220N2.

PMID: 28748406 [PubMed - as supplied by publisher]

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[My eReport, an application for the benefit of public health].

Rev Infirm. 2017 May;66(231):35-36

Authors: Touche C

Abstract
Positioning themselves more and more as players in their own health care alongside health professionals, citizens demand reliable, transparent and safe health information. The eVeDrug application now enables them to contribute to the practice of pharmacovigilance by reporting side effects of medication, while also keeping themselves informed of these same effects.

PMID: 28460730 [PubMed - indexed for MEDLINE]

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Pharmacogenetics-based personalized therapy: Levels of evidence and recommendations from the French Network of Pharmacogenetics (RNPGx).

Therapie. 2017 Apr;72(2):185-192

Authors: Picard N, Boyer JC, Etienne-Grimaldi MC, Barin-Le Guellec C, Thomas F, Loriot MA, French National Network of Pharmacogenetics (RNPGx)

Abstract
More than 50 laboratories offer pharmacogenetic testing in France. These tests are restricted to a limited number of indications: prevention of serious adverse drug reactions; choice of most appropriate therapeutic option; dose adjustment for a specific drug. A very small proportion of these tests are mentioned in drug information labeling and the data provided (if any) are generally insufficient to ascertain whether a test is required and if it is useful. This article discusses the rationale for evaluating the performance and clinical usefulness of pharmacogenetics and provides, on behalf of the French national network of pharmacogenetics (RNPGx), three levels of recommendation for testing: essential, advisable, and possibly helpful.

PMID: 28237406 [PubMed - indexed for MEDLINE]

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[Clinical characteristics and therapeutic effect of drug-resistant tuberculosis in children].

Zhonghua Er Ke Za Zhi. 2017 Feb 02;55(2):100-103

Authors: Liao Q, Tan S, Zhu Y, Wan CM, Deng SY, Shu M

Abstract
Objective: To explore the clinical characteristics of drug-resistant tuberculosis (TB) in children and to study the effectiveness of second-line anti-TB therapy for children and to examine the incidence of adverse drug reactions. Method: Retrospective research was conducted. The clinical records of children in West China Second Hospital diagnosed as drug-resistant TB from January 2010 to June 2014 were investigated.The clinical characteristics and risk factors were analyzed retrospectively. Treatment effect at discharge was examined as a short-term outcome indicator to evaluate the effectiveness of second-line anti-TB therapy and the incidence of adverse drug reactions. χ(2) test was used. Result: Forty-six patients were diagnosed as drug-resistant TB in 443 children infected with TB, with a 10.4% resistance rate. The 46 children included 26 male and 20 female patients, aged from one month and 28 days to 17 years and 5 months, with the average age (8.4±4.5) years, >7 to 14 years old patients as the biggest part(25 patients, 54.3%). Among the 46 children, 20 patients(43.5%)had close contact with TB patients, of whom 12 patients (60.0%) contacted with family members (including parents, brothers and sisters and grandparents living together) and 8 patients(40.0%) contacted with patients from outside family (such as relatives or neighbors). Moreover, 11 cases (23.9%) were under initial treatment and 35 cases (76.1%) were retreated.From 2010 to 2014, the number of cases of initial and retreated patients had no significant difference(0 and 1, 1 and 13, 4 and 7, 4 and 11, 2 and 3 cases, χ(2)=3.255, P=0.196). Among retreated patients, 31.4% (11/35) had irregular treatment before.Until discharge, the effective rate was 87.0% (40/46), while the incidence rate of adverse drug reaction was 10.9%(5/46). Conclusion: The therapy for drug-resistant TB is effective and the incidence of adverse drug reaction is relatively low.

PMID: 28173646 [PubMed - indexed for MEDLINE]

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Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial.

PLoS Negl Trop Dis. 2017 Jun;11(6):e0005706

Authors: Romero GAS, Costa DL, Costa CHN, de Almeida RP, de Melo EV, de Carvalho SFG, Rabello A, de Carvalho AL, Sousa AQ, Leite RD, Lima SS, Amaral TA, Alves FP, Rode J, Collaborative LVBrasil Group

Abstract
BACKGROUND: There is insufficient evidence to support visceral leishmaniasis (VL) treatment recommendations in Brazil and an urgent need to improve current treatments. Drug combinations may be an option.
METHODS: A multicenter, randomized, open label, controlled trial was conducted in five sites in Brazil to evaluate efficacy and safety of (i) amphotericin B deoxycholate (AmphoB) (1 mg/kg/day for 14 days), (ii) liposomal amphotericin B (LAMB) (3 mg/kg/day for 7 days) and (iii) a combination of LAMB (10 mg/kg single dose) plus meglumine antimoniate (MA) (20 mg Sb+5/kg/day for 10 days), compared to (iv) standard treatment with MA (20 mg Sb+5/kg/day for 20 days). Patients, aged 6 months to 50 years, with confirmed VL and without HIV infection were enrolled in the study. Primary efficacy endpoint was clinical cure at 6 months. A planned efficacy and safety interim analysis led to trial interruption.
RESULTS: 378 patients were randomized to the four treatment arms: MA (n = 112), AmphoB (n = 45), LAMB (n = 109), or LAMB plus MA (n = 112). A high toxicity of AmphoB prompted an unplanned interim safety analysis and this treatment arm was dropped. Per intention-to-treat protocol final analyses of the remaining 332 patients show cure rates at 6 months of 77.5% for MA, 87.2% for LAMB, and 83.9% for LAMB plus MA, without statistically significant differences between the experimental arms and comparator (LAMB: 9.7%; CI95% -0.28 to 19.68, p = 0.06; LAMB plus MA: 6.4%; CI95% -3.93 to 16.73; p = 0.222). LAMB monotherapy was safer than MA regarding frequency of treatment-related adverse events (AE) (p = 0.045), proportion of patients presenting at least one severe AE (p = 0.029), and the proportion of AEs resulting in definitive treatment discontinuation (p = 0.003).
CONCLUSIONS: Due to lower toxicity and acceptable efficacy, LAMB would be a more suitable first line treatment for VL than standard treatment. ClinicalTrials.gov identification number: NCT01310738.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01310738.

PMID: 28662034 [PubMed - indexed for MEDLINE]

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Test systems in drug discovery for hazard identification and risk assessment of human drug-induced liver injury.

Expert Opin Drug Metab Toxicol. 2017 Jul;13(7):767-782

Authors: Weaver RJ, Betts C, Blomme EAG, Gerets HHJ, Gjervig Jensen K, Hewitt PG, Juhila S, Labbe G, Liguori MJ, Mesens N, Ogese MO, Persson M, Snoeys J, Stevens JL, Walker T, Park BK

Abstract
INTRODUCTION: The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered: The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized. The test systems highlighted herein cover mostly in vitro and some in vivo models and endpoint measurements used in the assessment of small molecule toxic liabilities. Opportunities for research efforts in areas necessitating the development of specific tests and improved mechanistic understanding are highlighted. Expert Opinion: Use of in vitro test systems for safety optimization will remain a core activity in drug discovery. Substantial inroads have been made with a number of assays established for human Drug-induced Liver Injury. There nevertheless remain significant gaps with a need for improved in vitro tools and novel tests to address specific mechanisms of human Drug-Induced Liver Injury. Progress in these areas will necessitate not only models fit for application, but also mechanistic understanding of how chemical insult on the liver occurs in order to identify translational and quantifiable readouts for decision-making.

PMID: 28604124 [PubMed - indexed for MEDLINE]

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Hepatotoxicity associated to synthetic cannabinoids use.

Eur Rev Med Pharmacol Sci. 2017 Mar;21(1 Suppl):1-6

Authors: Solimini R, Busardò FP, Rotolo MC, Ricci S, Mastrobattista L, Mortali C, Graziano S, Pellegrini M, di Luca NM, Palmi I

Abstract
Synthetic cannabinoids (SCs) are psychotropic compounds, chemically created in laboratory to mimic cannabinergic brain activity of delta-9 tetrahydrocannabinol. The consumption of these compounds for recreational purposes can lead to a variety of adverse effects on health including overdose and deaths. Increasingly popular as substances of abuse since the 2000s, SCs were produced initially to bind and study cannabinoid receptors (they also can be called synthetic cannabimimetics) failing in eliminating the psychoactive effects. Currently, SCs are misused by students and young adults as "natural products" because of their herbal aspect. Actually, these apparently innocuous recreational substances hide toxic effects to health. Reported side effects are cardiovascular, gastrointestinal, neurological, renal, metabolic, ophthalmologic, pulmonary and psychoactive including dependence and withdrawal. A few cases of SCs ingestion have also been associated with liver failure. We herein review the recent literature on the SCs toxicity with particular attention to liver damage aspects.

PMID: 28379600 [PubMed - indexed for MEDLINE]

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Sildenafil-associated hepatoxicity: a review of the literature.

Eur Rev Med Pharmacol Sci. 2017 Mar;21(1 Suppl):17-22

Authors: Graziano S, Montana A, Zaami S, Rotolo MC, Minutillo A, Busardò FP, Marinelli E

Abstract
Sildenafil citrate (Viagra®) is a vasoactive agent available worldwide since 1998 for the treatment of male erectile dysfunction. It is a selective phosphodiesterase type 5-enzyme inhibitor able to potentiate the downstream effects of nitric oxide on smooth muscle relaxation and vasodilation through its effects on the cyclic guanosine monophosphate (c-GMP) pathway in the erectile tissue of the penis. When sildenafil is orally administered, it is rapidly absorbed with a maximum plasma concentration achieved within 1 h and has a terminal half-life of between 3 to 6 h. The drug is extensively and rapidly metabolized by the liver, primarily by the CYP3A4 enzyme. Although the drug is well tolerated, specific adverse events have been observed, like flushing, headaches, dyspepsia, and visual disturbances. Liver toxicity related to sildenafil consumption has been considered a very rare event. However, in the last decade, some cases of sildenafil-associated hepatotoxicity have been reported. Furthermore, some hepatic intoxications have been reported after the intake of "natural" or "herbal" aphrodisiac supplements sold through Internet, sex shops, social media, and by word-of-mouth found to contain sildenafil and other phosphodiesterase type 5 (PDE-5) inhibitors. Studies investigating a possible link between sildenafil use and liver damage are limited, and the underlying mechanism responsible for hepatotoxicity is still missing. Studies in animals evidence that the hematopoietic function of the liver may have severely been affected as a result of a probable toxic effect of sildenafil. Here, the studies reporting liver toxicity by sildenafil in humans and in animals are reported and discussed.

PMID: 28379598 [PubMed - indexed for MEDLINE]

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Flutamide-induced hepatotoxicity: ethical and scientific issues.

Eur Rev Med Pharmacol Sci. 2017 Mar;21(1 Suppl):69-77

Authors: Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A

Abstract
OBJECTIVE: Flutamide (FLU) is a non-steroidal antiandrogen drug approved for the treatment of advanced prostate cancer. While this indication limits the use to male patients, FLU is widely prescribed to women, off-label, for the treatment of polycystic ovary syndrome (POCS) related hirsutism and acne. According to the literature, its assumption is associated with a higher incidence of adverse events in women than in male patients.
MATERIALS AND METHODS: A literature search was conducted in main databases targeting unwilling FLU effects in hepatic and reproductive function. References in the selected paper were also considered as an additional source of data. Human- and animal-based studies were separately considered.
RESULTS: Twenty-three human-based studies were evaluated: ten were case reports, six were retrospective studies, four were prospective, two were surveillance studies, while the last was an observational study. Nine animal-based studies were also evaluated.
CONCLUSIONS: Scientific contributions highlight that FLU is responsible for specific hepatotoxic profiles in the female gender. From the ethical point of view, off-label prescribing of FLU in women is not only substantially unlawful, but also, without major safeguards being granted, a potential source of liability for prescribers.

PMID: 28379593 [PubMed - indexed for MEDLINE]

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Systolic Blood Pressure Intervention Trial (SPRINT) and Target Systolic Blood Pressure in Future Hypertension Guidelines.

Hypertension. 2016 Aug;68(2):318-23

Authors: Egan BM, Li J, Wagner CS

Abstract
The Systolic Blood Pressure (SBP, mm Hg) Intervention Trial (SPRINT) showed that targeting SBP <120 mm Hg (intensive treatment, mean SBP: 121.5 mm Hg) versus <140 (standard treatment, mean SBP: 134.6 mm Hg) reduced cardiovascular events 25%. SPRINT has 2 implicit assumptions that could impact future US hypertension guidelines: (1) standard therapy controlled SBP similarly to that in adults with treated hypertension and (2) intensive therapy produced a lower mean SBP than in adults with treated hypertension and SBP <140 mm Hg. To examine these assumptions, US National Health and Nutrition Examination Survey 2009 to 2012 data were analyzed on 3 groups of adults with treated hypertension: group 1 consisted of SPRINT-like participants aged ≥50 years; group 2 consisted of participants all aged ≥18 years; and group 3 consisted of participants aged ≥18 years excluding group 1 but otherwise similar to SPRINT-like participants except high cardiovascular risk. Mean SBPs in groups 1, 2, and 3 were 133.0, 130.1, and 124.6, with 66.2%, 72.2%, and 81.9%, respectively, controlled to SBP <140; 68.3%, 74.8%, and 83.4% of the controlled subset had SBP <130. Mean SBPs in those controlled to <140 were 123.3, 120.9, and 118.9, respectively. Among US adults with treated hypertension, (1) the SPRINT-like group had higher mean SBP than comparison groups, yet lower than SPRINT standard treatment group and (2) among groups 1 to 3 with SBP <140, SBP values were within <3 mm Hg of SPRINT intensive treatment. SPRINT results suggest that treatment should be continued and not reduced when treated SBP is <130, especially for the SPRINT-like subset. Furthermore, increasing the percentage of treated adults with SBP <140 could approximate SPRINT intensive treatment SBP without lowering treatment goals.

PMID: 27354422 [PubMed - indexed for MEDLINE]

Related Articles

Medication Regimen Complexity and Number of Medications as Factors Associated With Unplanned Hospitalizations in Older People: A Population-based Cohort Study.

J Gerontol A Biol Sci Med Sci. 2016 Jun;71(6):831-7

Authors: Wimmer BC, Bell JS, Fastbom J, Wiese MD, Johnell K

Abstract
BACKGROUND: Adverse drug events are a leading cause of hospitalization among older people. Up to half of all medication-related hospitalizations are potentially preventable. The objective of this study was to investigate and compare the association between medication regimen complexity and number of medications with unplanned hospitalizations over a 3-year period.
METHODS: Data were analyzed for 3,348 participants aged 60 years or older in Sweden. Regimen complexity was assessed using the 65-item Medication Regimen Complexity Index (MRCI) and number of medications was assessed as a continuous variable. Cox proportional hazard models were used to compute unadjusted and adjusted hazard ratios with 95% confidence intervals (CIs) for associations between regimen complexity and number of medications with unplanned hospitalizations over a 3-year period. Receiver operating characteristics curves with corresponding areas under the curve were calculated for regimen complexity and number of medications in relation to unplanned hospitalizations. The population attributable fraction of unplanned hospitalizations was calculated for MRCI and number of medications.
RESULTS: In total, 1,125 participants (33.6%) had one or more unplanned hospitalizations. Regimen complexity (hazard ratio 1.22; 95% CI 1.14-1.34) and number of medications (hazard ratio 1.07; 95% CI 1.04-1.09) were both associated with unplanned hospitalizations and had similar sensitivity and specificity (area under the curve 0.641 for regimen complexity and area under the curve 0.644 for number of medications). The population attributable fraction was 14.08% (95% CI 9.62-18.33) for MRCI and 17.61% (95% CI 12.59-22.35) for number of medications.
CONCLUSIONS: There was no evidence that using a complex tool to assess regimen complexity was better at predicting unplanned hospitalization than number of medications.

PMID: 26707381 [PubMed - indexed for MEDLINE]

In vivo FRET-FLIM reveals cell-type-specific protein interactions in Arabidopsis roots.

Nature. 2017 Jul 26;:

Authors: Long Y, Stahl Y, Weidtkamp-Peters S, Postma M, Zhou W, Goedhart J, Sánchez-Pérez MI, Gadella TWJ, Simon R, Scheres B, Blilou I

Abstract
During multicellular development, specification of distinct cell fates is often regulated by the same transcription factors operating differently in distinct cis-regulatory modules, either through different protein complexes, conformational modification of protein complexes, or combinations of both. Direct visualization of different transcription factor complex states guiding specific gene expression programs has been challenging. Here we use in vivo FRET-FLIM (Förster resonance energy transfer measured by fluorescence lifetime microscopy) to reveal spatial partitioning of protein interactions in relation to specification of cell fate. We show that, in Arabidopsis roots, three fully functional fluorescently tagged cell fate regulators establish cell-type-specific interactions at endogenous expression levels and can form higher order complexes. We reveal that cell-type-specific in vivo FRET-FLIM distributions reflect conformational changes of these complexes to differentially regulate target genes and specify distinct cell fates.

PMID: 28746306 [PubMed - as supplied by publisher]

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Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice.

EMBO Mol Med. 2017 Jul 25;:

Authors: Wehr MC, Hinrichs W, Brzózka MM, Unterbarnscheidt T, Herholt A, Wintgens JP, Papiol S, Soto-Bernardini MC, Kravchenko M, Zhang M, Nave KA, Wichert SP, Falkai P, Zhang W, Schwab MH, Rossner MJ

Abstract
Enhanced NRG1-ERBB4 signaling is a risk pathway in schizophrenia, and corresponding mouse models display several endophenotypes of the disease. Nonetheless, pathway-directed treatment strategies with clinically applicable compounds have not been identified. Here, we applied a cell-based assay using the split TEV technology to screen a library of clinically applicable compounds to identify modulators of NRG1-ERBB4 signaling for repurposing. We recovered spironolactone, known as antagonist of corticosteroids, as an inhibitor of the ERBB4 receptor and tested it in pharmacological and biochemical assays to assess secondary compound actions. Transgenic mice overexpressing Nrg1 type III display cortical Erbb4 hyperphosphorylation, a condition observed in postmortem brains from schizophrenia patients. Spironolactone treatment reverted hyperphosphorylation of activated Erbb4 in these mice. In behavioral tests, spironolactone treatment of Nrg1 type III transgenic mice ameliorated schizophrenia-relevant behavioral endophenotypes, such as reduced sensorimotor gating, hyperactivity, and impaired working memory. Moreover, spironolactone increases spontaneous inhibitory postsynaptic currents in cortical slices supporting an ERBB4-mediated mode-of-action. Our findings suggest that spironolactone, a clinically safe drug, provides an opportunity for new treatment options for schizophrenia.

PMID: 28743784 [PubMed - as supplied by publisher]

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Kinome Profiling Identifies Druggable Targets for Novel Human Cytomegalovirus (HCMV) Antivirals.

Mol Cell Proteomics. 2017 Apr;16(4 suppl 1):S263-S276

Authors: Arend KC, Lenarcic EM, Vincent HA, Rashid N, Lazear E, McDonald IM, Gilbert TS, East MP, Herring LE, Johnson GL, Graves LM, Moorman NJ

Abstract
Human cytomegalovirus (HCMV) is a significant cause of disease in immune-compromised adults and immune naïve newborns. No vaccine exists to prevent HCMV infection, and current antiviral therapies have toxic side effects that limit the duration and intensity of their use. There is thus an urgent need for new strategies to treat HCMV infection. Repurposing existing drugs as antivirals is an attractive approach to limit the time and cost of new antiviral drug development. Virus-induced changes in infected cells are often driven by changes in cellular kinase activity, which led us to hypothesize that defining the complement of kinases (the kinome), whose abundance or expression is altered during infection would identify existing kinase inhibitors that could be repurposed as new antivirals. To this end, we applied a kinase capture technique, multiplexed kinase inhibitor bead-mass spectrometry (MIB-MS) kinome, to quantitatively measure perturbations in >240 cellular kinases simultaneously in cells infected with a laboratory-adapted (AD169) or clinical (TB40E) HCMV strain. MIB-MS profiling identified time-dependent increases and decreases in MIB binding of multiple kinases including cell cycle kinases, receptor tyrosine kinases, and mitotic kinases. Based on the kinome data, we tested the antiviral effects of kinase inhibitors and other compounds, several of which are in clinical use or development. Using a novel flow cytometry-based assay and a fluorescent reporter virus we identified three compounds that inhibited HCMV replication with IC50 values of <1 μm, and at doses that were not toxic to uninfected cells. The most potent inhibitor of HCMV replication was OTSSP167 (IC50 <1.2 nm), a MELK inhibitor, blocked HCMV early gene expression and viral DNA accumulation, resulting in a >3 log decrease in virus replication. These results show the utility of MIB-MS kinome profiling for identifying existing kinase inhibitors that can potentially be repurposed as novel antiviral drugs.

PMID: 28237943 [PubMed - indexed for MEDLINE]

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Antifungal adjuvants: Preserving and extending the antifungal arsenal.

Virulence. 2017 Feb 17;8(2):198-210

Authors: Butts A, Palmer GE, Rogers PD

Abstract
As the rates of systemic fungal infections continue to rise and antifungal drug resistance becomes more prevalent, there is an urgent need for new therapeutic options. This issue is exacerbated by the limited number of systemic antifungal drug classes. However, the discovery, development, and approval of novel antifungals is an extensive process that often takes decades. For this reason, there is growing interest and research into the possibility of combining existing therapies with various adjuvants that either enhance activity or overcome existing mechanisms of resistance. Reports of antifungal adjuvants range from plant extracts to repurposed compounds, to synthetic peptides. This approach would potentially prolong the utility of currently approved antifungals and mitigate the ongoing development of resistance.

PMID: 27459018 [PubMed - indexed for MEDLINE]