Pharmacogenomics and drug therapy.

Aust Prescr. 2018 Feb;41(1):6

Authors: Goh S

PMID: 29507452 [PubMed]

Model-based Dosage Individualization of Ganciclovir in Neonates and Young Infants with Congenital Cytomegalovirus Infection: A Pilot Study.

Antimicrob Agents Chemother. 2018 Mar 05;:

Authors: Dong Q, Leroux S, Shi HY, Xu HY, Kou C, Khan MW, Jacqz-Aigrain E, Zhao W

Abstract
Background: Newborns with congenital cytomegalovirus (CMV) infection are at high risk for developing permanent sequelae. Intravenous ganciclovir therapy is frequently used for the treatment of congenital CMV infection. Target area under the concentration versus time curve (AUC0-24) of 40-50 μg·h/mL is recommended. The standard dose resulted in a large variability in ganciclovir exposure in newborns, indicating the unmet need of dosage individualization in this vulnerable population, but the implementation of this strategy remains challenging in clinical practice. We aim to evaluate the clinical utility of model-based dosage individualization of ganciclovir in newborns using an opportunistic sampling approach.Methods: The predictive performance of a published ganciclovir population pharmacokinetic model was evaluated using an independent patient cohort. The individual dose was adjusted based on the target AUC0-24 to ensure the efficacy.Results: A total of 26 newborns with congenital CMV infection were included in the present study. Only 11 (42.3%) patients achieved the target AUC0-24 after giving the standard dose. For all the subtherapeutic (below 80% target AUC) patients (n=5), model-based dosage adjustment was performed using Bayesian estimation method combined with the opportunistic sampling strategy. The adjusted doses were increased 28.6% - 60.0% in these five patients and all adapted AUC0-24 achieved the target (range: 48.6-66.1 μg·h/mL).Conclusion: The clinical utility of model-based dosing individualization of ganciclovir was demonstrated in newborns with congenital CMV infection. Population pharmacokinetic model combined with the opportunistic sampling strategy provides a clinical feasible method to adapt ganciclovir dose in neonatal clinical practice.

PMID: 29507070 [PubMed - as supplied by publisher]

Screening and identifying antioxidants from Oplopanax elatus using 2,2'-diphenyl-1-picrylhydrazyl with off-line two-dimensional HPLC coupled with diode array detection and tandem time-of-flight mass spectrometry.

J Sep Sci. 2016 Nov;39(22):4269-4280

Authors: Shao L, Nie MK, Chen MY, Wang J, Wang CZ, Huang WH, Yuan CS, Zhou HH

Abstract
The root of Oplopanax elatus (Nakai) Nakai has a well-known history of use for the treatment of diseases such as neurasthenia, cardiovascular disorders, and cancer by the native people in northeast China. It is important to screen and identify the bioactive molecules from its root rapidly. Hereby, an off-line two-dimensional high performance liquid chromatography coupled with diode array detection and tandem time-of-flight mass spectrometry together with 2,2'-diphenyl-1-picrylhydrazyl was established to screen antioxidants from the root of O. elatus. A Waters cyanogen column (150 × 3.9 mm, id, 4 μm) was used for the first dimensional liquid chromatography, while a Hypersil BDS-C18 column (250 × 4.6 mm, id, 5 μm) was installed for the second dimension liquid chromatographic analysis. Twenty-eight compounds had been tentatively identified from the methanol extract of the air-dried root of O. elatus including six polyynes and eight phenolic derivatives were screened with antioxidant activity. The developed method could be expedient for screening and identifying antioxidants from O. elatus.

PMID: 27624907 [PubMed - indexed for MEDLINE]

The accessibility of topical treatment in the paranasal sinuses on operated cystic fibrosis patients assessed by scintigraphy.

Rhinology. 2018 Mar 06;:

Authors: Aanaes K, Alanin MC, Nielsen KG, Moller Jorgensen M, von Buchwald C, Hoiby N, Johansen HK, Johannesen HH, Mortensen J

Abstract
BACKGROUND: Nasal irrigations with antibiotics are used to eradicate Pseudomonas aeruginosa from the upper airways in patients with cystic fibrosis (CF) and thereby avoid lung colonisations; nevertheless, the efficacy is uncertain.
METHODOLOGY: The aim of this study was to investigate the accessibility and durability of solutions in the sinuses before and after sinus surgery. The participants irrigated their noses with radioactively marked saline and were evaluated using a dynamic SPECT/CT scan. The preoperative and postoperative (after 30 days) examinations were compared.
RESULTS: Twelve CF patients were included. In 10 out of the 24 scanned maxillary sinuses an improvement was seen postoperatively compared with the preoperative fluid volume. Notably, in 7 out of the 24 sinuses the mucosa was so swollen postoperatively that no fluid was detected. Ten patients had developed their frontal sinuses. We observed no fluid in the frontal or sphenoid sinuses, neither before nor after surgery. At best, a mean of 23% of the maxillary sinuses were filled with fluid; thus, all sinuses had postoperatively areas of the mucosa that did not have contact with the fluid. A mean of 76% of the initial volume was present after 30 min in the maxillary sinuses.
CONCLUSION: Fluid-depositing using nasal irrigation will not sufficiently or not at all get in contact with all the sinus mucosa despite of sinus surgery. Thus, the efficacy of topical deposition of antibiotics is presumably reduced.

PMID: 29509830 [PubMed - as supplied by publisher]

Mechanical insufflation-exsufflation for airway clearance in adults with cystic fibrosis.

Respirol Case Rep. 2018 May;6(4):e00307

Authors: Gaynor M, Wood J

Abstract
In cystic fibrosis (CF), acute exacerbations can decrease the effectiveness of patients' usual airway clearance techniques (ACT). In order to maintain effective airway clearance and preserve lung function, these ACT must be adapted to prevent further dyspnoea and fatigue and improve ease of expectoration. Mechanical insufflation-exsufflation (MI-E) is widely used in neuromuscular disorders to facilitate airway clearance and augment cough but has rarely been used in CF despite potential indications. The NIPPY Clearway, an airway clearance device with multiple modes including MI-E, can be set to deliver multiple insufflations prior to a single exsufflation. We present two cases where this modified version of MI-E was used as an adjunct to traditional ACT in adults during an acute exacerbation of CF.

PMID: 29507722 [PubMed]

Killed but metabolically active Pseudomonas aeruginosa-based vaccine induces protective humoral- and cell-mediated immunity against Pseudomonas aeruginosa pulmonary infections.

Vaccine. 2018 Mar 02;:

Authors: Meynet E, Laurin D, Lenormand JL, Camara B, Toussaint B, Le Gouëllec A

Abstract
Pseudomonas aeruginosa (Pa) is a significant cause of morbidity and mortality, especially in cystic fibrosis patients. Its eradication is difficult due to a wide phenotypic adaptability and an increase of its resistance to antibiotics. After the failure of several recombinant vaccines which mainly triggered humoral response, live-attenuated vaccines received attention thanks to their ability to elicit a broad immunity with both humoral- and cell-mediated responses, essential to fight this pathogen. In this study, we developed an innovative and safer live-attenuated Pa vaccine based on a Killed But Metabolically Active (KBMA) attenuation method. KBMA Pa has been further rationally designed to overexpress beneficial effectors like the type 3 secretion system apparatus. We demonstrated that KBMA Pa elicits a high and broad humoral response in mice against several antigens of particular interest such as OprF and PcrV proteins. Moreover, we assessed cytokines in the serum of immunized mice and showed that KBMA Pa elicits Th1, Th2 and especially Th17 pathways of cell-mediated immune responses. Th17 pathway involvement was also confirmed after specific stimulation of helper T cells in immunized mice. Finally, we showed that this vaccine is safe and has a protective effect in a murine acute pulmonary infectious challenge. In conclusion, KBMA Pa is a new platform with high potential for the development of a vaccine against Pa.

PMID: 29506924 [PubMed - as supplied by publisher]

ECFS best practice guidelines: the 2018 revision.

J Cyst Fibros. 2018 Mar 02;:

Authors: Castellani C, Duff AJA, Bell SC, Heijerman HGM, Munck A, Ratjen F, Sermet-Gaudelus I, Southern KW, Barben J, Flume PA, Hodková P, Kashirskaya N, Kirszenbaum MN, Madge S, Oxley H, Plant B, Schwarzenberg SJ, Smyth AR, Taccetti G, Wagner TOF, Wolfe SP, Drevinek P

Abstract
Developments in managing CF continue to drive dramatic improvements in survival. As newborn screening rolls-out across Europe, CF centres are increasingly caring for cohorts of patients who have minimal lung disease on diagnosis. With the introduction of mutation-specific therapies and the prospect of truly personalised medicine, patients have the potential to enjoy good quality of life in adulthood with ever-increasing life expectancy. The landmark Standards of Care published in 2005 set out what high quality CF care is and how it can be delivered throughout Europe. This underwent a fundamental re-write in 2014, resulting in three documents; center framework, quality management and best practice guidelines. This document is a revision of the latter, updating standards for best practice in key aspects of CF care, in the context of a fast-moving and dynamic field. In continuing to give a broad overview of the standards expected for newborn screening, diagnosis, preventative treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support, this consensus on best practice is expected to prove useful to clinical teams both in countries where CF care is developing and those with established CF centres. The document is an ECFS product and endorsed by the CF Network in ERN LUNG and CF Europe.

PMID: 29506920 [PubMed - as supplied by publisher]

Oscillating devices for airway clearance in people with cystic fibrosis.

Int J Nurs Stud. 2018 Feb 23;:

Authors: Wilson A

PMID: 29506758 [PubMed - as supplied by publisher]

[Italian Cystic Fibrosis Registry. Report 2011-2014].

Epidemiol Prev. 2018 Jan-Feb;42(1S1):1-32

Authors: Giordani B, Amato A, Majo F, Ferrari G, Quattrucci S, Minicucci L, Padoan R, Floridia G, Puppo Fornaro G, Taruscio D, Salvatore M, Gruppo di lavoro RIFC

Abstract
INTRODUCTION: The Italian Cystic Fibrosis Registry (ICFR) is based on a new agreement about the data flow towards the Registry signed on October, 4th 2016 by the Centre for Rare Diseases of the Italian National Institute of Health (NIH), the clinicians of the Italian National Referral and Support Centres for Cystic Fibrosis, the Paediatric Hospital "Bambino Gesù" (Rome), the Italian Cystic Fibrosis Society, and the Italian League for Cystic Fibrosis.
OBJECTIVES: The aim of the present Report is to improve the knowledge on cystic fibrosis (CF) through the epidemiological description of Italian patients. The members of the Scientific and Technical Committee have to write a report on data collected by ICFR, in order to contribute to achieve the aims of ICFR itself, i.e., to improve the care of CF patients. In particular, the Report should contribute to the following objectives: - to analyze the medium and long-term clinical and epidemiological trends of the disease; - to identify the main healthcare needs at regional and national level in order to contribute to the healthcare programmes and to the distribution of resources; - to compare Italian data with the international ones.
DESIGN: Analyses and results described in the present Report are referred to patients in charge to the Italian National Referral and Support Centres for Cystic Fibrosis in the period 2011-2014. Data were sent by Centres by means of a specific software (Camilla, Ibis Informatica) and has undergone a double quality control (QC): the first by NIH and the second at a European level (before the inclusion of the Italian data within the European Cystic Fibrosis Registry). These QCs assure the completeness and accuracy of data as well as their consistency with European core data.
SETTING AND PARTICIPANTS: A total of 29 different CF centres (referral, support, and Paediatric Hospital "Bambino Gesù") sent their data to ICFR; data referred to the period 2011-2014. Data regarding Sardinia Region (Southern Italy) are missing; data from Molise (Southern Italy) CF centre refer only to 2014.
RESULTS: The present Report has been organized into 10 sections. 1. Demography - number of Italian patients with cystic fibrosis (CF) in 2014 was 4,981 and their median age was 20.4 years; estimated 2014 CF prevalence was 8.2/100,000 residents in Italy; on average, 52.1% of the patients were male and CF distribution showed higher frequency in patients aged from 7 to 35 years. On average, 53.7% of CF patients are aged more than 18 years. 2. Diagnoses - most of the CF patients were diagnosed before two years of age (around 66%); a significant proportion of patients (on average, 12%) was diagnosed in adult age. 3. New diagnoses - new diagnoses were 187 in 2011, 200 in 2012, 160 in 2013, and 135 in 2014. Estimated incidence was 1/4,052 live births in 2011; 1/4,313 in 2012; 1/5,189 in 2013 and 1/8,243 in 2014. 4. Genetics - 99.5% of patients was studied at the molecular level, with identification of 90.1% of Cystic Fibrosis Transmembrane Regulator CFTR mutations; [delta]508F was the most frequent mutation (44.8% in 2014). 5. Lung function - FEV₁ (Forced Expiratory Volume in the first second) scores progressively decreased shortly before the start of adult age, in accordance with the natural history of the disease. Most of the patients between 6 and 17 years of age reported a FEV₁ % ≥ 70% of the predicted value, while the proportion of patients with severe lung disease (FEV₁ % <40% of the predicted value) is <2% over the period 2011-2014. 6. Nutrition - most critical periods come out during the first 6 months of life and during adolescence. Prevalence of malnourished male aged 12-17 years decreases over the period 2011-2014; an increasing percentage of patient (both male and female) with a suboptimal body mass index value is observed among patients aged more than 18 years 7. Complications - the presence of missing data represents an obstacle in the correct evaluation of prevalence value of complications related to Italian patients within ICFR. Nevertheless, it was estimated that, in 2014, the principal complication in patients aged <18 years was hepatopathies (15%), while in patients aged more than 18 years the principal complications were due to hepatopathies (25%) and diabetes (22%). 8. Transplantation - during the period 2011-2014, 135 patients ageed between 7 and 53 years received a double lung transplant; median age at transplantation was 32.5 years. Median duration of waiting list for transplantation is estimated in 11 months. 9. Microbiology - analyses were referred to test performed in 2014. Prevalence of adult patients with Pseudomonas aeruginosa chronic infection is 49.4% compared to 14.5% of paediatric patients; Staphylococcus aureus chronic infection is present in 48% of adult patients and 45.6% of paediatric patients; Burkholderia Cepacia complex is present almost exclusively in adult patients (4.9%); Nontuberculous mycobacteria is present in 0.9% and 0.3% of adult and paediatric patients, respectively; Stenotrophomonas maltophilia infection is present in 4.6% of patients (both adults and paediatric). 10. Mortality - RIFC data show that 176 patients (median age 32 years; 81 males and 95 females) died in the period 2011-2014.
CONCLUSIONS: The present Report shows that CF population is growing (median age), so paediatric mortality is decreasing. A very low percentage of paediatric population is characterized by complication of pulmonary functions; adult patients are characterized by an increase of age at death (more than 30 years of age). ICFR Report may represent an important tool to analyze clinical and epidemiological trends of the disease as well as to identify the main healthcare needs at regional and national level to contribute to the healthcare programmes and to the distribution of the resources.

PMID: 29506377 [PubMed - in process]

Low Alcohol and Cigarette Use Is Associated to the Risk of Developing Chronic Pancreatitis.

Pancreas. 2017 Feb;46(2):225-229

Authors: Di Leo M, Leandro G, Singh SK, Mariani A, Bianco M, Zuppardo RA, Goni E, Rogger TM, Di Mario F, Guslandi M, De Cobelli F, Del Maschio A, Testoni PA, Cavestro GM

Abstract
OBJECTIVES: The aim of this study was to investigate the contribution of smoking and alcohol intake and pancreas divisum on the risk of developing chronic pancreatitis (CP).
METHODS: Consecutive patients with CP who underwent secretin-enhanced magnetic resonance cholangiopancreatography were compared with consecutive patients without pancreatic disease who underwent secretin-enhanced magnetic resonance cholangiopancreatography for irritable bowel syndrome.
RESULTS: We enrolled 145 consecutive CP patients and 103 irritable bowel syndrome patients from 2010 to 2014. In a univariate analysis, statistically significant differences in sex, mean age, and the duration and amount of cigarette and alcohol use were found. Per a receiver operating characteristic curve analysis, thresholds for cigarette and alcohol consumption were, respectively, 5.5 cigarettes and 13.5 g daily. In a multivariate analysis, independent risk factors for CP were male sex (odds ratio [OR], 2.05), smoking more than 5.5 cigarettes per day (OR, 2.72), and drinking more than 13.5 g/d (OR, 6.35).
CONCLUSIONS: In an Italian population, we confirmed smoking and alcohol as cofactors in the development of CP. This study shows that alcohol intake and smoking habits are 2 of the most important risk factors for the development of CP.

PMID: 27846144 [PubMed - indexed for MEDLINE]

Expanding the phenotypic spectrum associated with OPHN1 mutations: Report of 17 individuals with intellectual disability but no cerebellar hypoplasia.

Eur J Med Genet. 2018 Mar 03;:

Authors: Moortgat S, Lederer D, Deprez M, Buzatu M, Clapuyt P, Boulanger S, Benoit V, Mary S, Guichet A, Ziegler A, Colin E, Bonneau D, Maystadt I

Abstract
Mutations in the oligophrenin 1 gene (OPHN1) have been identified in patients with X-linked intellectual disability (XLID) associated with cerebellar hypoplasia and ventriculomegaly, suggesting it could be a recognizable syndromic intellectual disability (ID). Affected individuals share additional clinical features including speech delay, seizures, strabismus, behavioral difficulties, and slight facial dysmorphism. OPHN1 is located in Xq12 and encodes a Rho-GTPase-activating protein involved in the regulation of the G-protein cycle. Rho protein members play an important role in dendritic growth and in plasticity of excitatory synapses. Here we report on 17 individuals from four unrelated families affected by mild to severe intellectual disability due to OPHN1 mutations without cerebellar anomaly on brain MRI. We describe clinical, genetic and neuroimaging data of affected patients. Among the identified OPHN1 mutations, we report for the first time a missense mutation occurring in a mosaic state. We discuss the intrafamilial clinical variability of the disease and compare our patients with those previously reported. We emphasize the power of next generation techniques (X-exome sequencing, whole-exome sequencing and targeted multi-gene panel) to expand the phenotypic and mutational spectrum of OPHN1-related ID.

PMID: 29510240 [PubMed - as supplied by publisher]

Targeted exome sequencing and chromosomal microarray for the molecular diagnosis of nevoid basal cell carcinoma syndrome.

J Dermatol Sci. 2017 Jun;86(3):206-211

Authors: Matsudate Y, Naruto T, Hayashi Y, Minami M, Tohyama M, Yokota K, Yamada D, Imoto I, Kubo Y

Abstract
BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder mainly caused by heterozygous mutations of PTCH1. In addition to characteristic clinical features, detection of a mutation in causative genes is reliable for the diagnosis of NBCCS; however, no mutations have been identified in some patients using conventional methods.
OBJECTIVE: To improve the method for the molecular diagnosis of NBCCS.
METHODS: We performed targeted exome sequencing (TES) analysis using a multi-gene panel, including PTCH1, PTCH2, SUFU, and other sonic hedgehog signaling pathway-related genes, based on next-generation sequencing (NGS) technology in 8 cases in whom possible causative mutations were not detected by previously performed conventional analysis and 2 recent cases of NBCCS. Subsequent analysis of gross deletion within or around PTCH1 detected by TES was performed using chromosomal microarray (CMA).
RESULTS: Through TES analysis, specific single nucleotide variants or small indels of PTCH1 causing inferred amino acid changes were identified in 2 novel cases and 2 undiagnosed cases, whereas gross deletions within or around PTCH1, which are validated by CMA, were found in 3 undiagnosed cases. However, no mutations were detected even by TES in 3 cases. Among 3 cases with gross deletions of PTCH1, deletions containing the entire PTCH1 and additional neighboring genes were detected in 2 cases, one of which exhibited atypical clinical features, such as severe mental retardation, likely associated with genes located within the 4.3Mb deleted region, especially.
CONCLUSION: TES-based simultaneous evaluation of sequences and copy number status in all targeted coding exons by NGS is likely to be more useful for the molecular diagnosis of NBCCS than conventional methods. CMA is recommended as a subsequent analysis for validation and detailed mapping of deleted regions, which may explain the atypical clinical features of NBCCS cases.

PMID: 28342698 [PubMed - indexed for MEDLINE]

Germline and somatic DICER1 mutations in familial and sporadic liver tumors.

J Hepatol. 2017 Apr;66(4):734-742

Authors: Caruso S, Calderaro J, Letouzé E, Nault JC, Couchy G, Boulai A, Luciani A, Zafrani ES, Bioulac-Sage P, Seror O, Imbeaud S, Zucman-Rossi J

Abstract
BACKGROUND & AIMS: Growing evidence suggests that genetic predisposition significantly increases the risk of hepatocellular carcinoma (HCC), independently from the presence of other risk factors. Here, we report a novel germline DICER1 mutation associated with familial recurrent liver tumors. We then aimed to investigate the contribution of constitutional and somatic DICER1 mutations on HCC occurrence.
METHODS: We investigated two individuals of a single family that developed recurrent well-differentiated hepatocellular tumors over the years. Histological slides from surgically resected tumors were reviewed. Exome sequencing was performed on constitutional DNA from circulating lymphocytes in both patients. The presence of somatic DICER1 mutations was analyzed in 243 liver tumors. MicroRNA (miRNA) sequencing was performed in 50 liver tumors to identify groups of tumors with similar profiles and differentially expressed miRNAs (DEMs).
RESULTS: A pathological study identified hepatocellular adenomas and well-differentiated carcinomas in both patients. Tumors exhibited Wnt/β-catenin pathway activation, with strong and diffuse glutamine synthetase expression. Interestingly, non-tumor liver tissues showed abnormal liver zonation as previously reported in Dicer1 knockout mouse livers. Screening for DICER1 mutations in 243 sporadic liver tumors identified six tumors with somatic DICER1 mutations. In HCCs, DICER1 mutations were significantly associated with CTNNB1 mutations (p=0.03). miRNA profiling identified a specific expression profile in DICER1-mutated tumors with a decreased expression of mature miRNAs compared to the other samples. Among the DEMs, downregulation of let-7a and miR-365b was closely related to DICER1 mutations.
CONCLUSIONS: Our results highlight the role of DICER1 mutations in liver carcinogenesis in a specific subtype of familial and sporadic hepatocellular carcinomas associated with β-catenin activation.
LAY SUMMARY: DICER1 germline mutations are known to predispose individuals to the development of malignant tumors, mainly pleuropulmonary blastoma and ovarian Sertoli-Leydig cell tumor. Here, we described familial HCC associated with a novel DICER1 germline mutation and altered liver zonation. Familial and sporadic HCCs carrying DICER1 mutations are associated with CTNNB1 mutation and characterized by a reduced expression of specific mature miRNAs.

PMID: 28012864 [PubMed - indexed for MEDLINE]

MED12 mutations in breast phyllodes tumors: evidence of temporal tumoral heterogeneity and identification of associated critical signaling pathways.

Oncotarget. 2016 Dec 20;7(51):84428-84438

Authors: Laé M, Gardrat S, Rondeau S, Richardot C, Caly M, Chemlali W, Vacher S, Couturier J, Mariani O, Terrier P, Bièche I

Abstract
Exome sequencing has recently identified highly recurrent MED12 somatic mutations in fibroadenomas (FAs) and phyllodes tumors (PTs). In the present study, based on a large series, we confirmed the presence of MED12 exon 1 and 2 mutations in 49% (41/83) of PTs, 70% (7/10) of FAs and 9.1% (1/11) of fibromatoses. We show that MED12 mutations are associated with benign behavior of phyllodes tumors, as they are detected less frequently in malignant PTs (27.6%) compared to benign (58.3%) and borderline (63.3%) PTs, respectively (p = 0.0036). Phyllodes tumors presented marked temporal heterogeneity of MED12 mutation status, as 50% (3/6) of primary and recurrent phyllodes tumor pairs with MED12 mutation presented different MED12 mutations between the primary and recurrent tumors. There was no correlation between MED12 status and genomic profiles obtained by array-CGH. MED12 mutations are associated with altered expressions of the genes involved in the WNT (PAX3, WNT3A, AXIN2), TGFB (TAGLN, TGFBR2, CTGF) and THRA (RXRA, THRA) signaling pathways.In conclusion, this study confirmed that MED12 plays a central oncogenic role in breast fibroepithelial tumorigenesis and identified a limited number of altered signaling pathways that maybe associated with MED12 mutations. MED12 exon 1 and 2 mutation status and some of the altered genes identified in this study could constitute useful diagnostic or prognostic markers, and form the basis for novel therapeutic strategies for PTs.

PMID: 27806318 [PubMed - indexed for MEDLINE]

Drug-associated pulmonary arterial hypertension.

Clin Toxicol (Phila). 2018 Mar 06;:1-9

Authors: McGee M, Whitehead N, Martin J, Collins N

Abstract
INTRODUCTION: While pulmonary arterial hypertension remains an uncommon diagnosis, various therapeutic agents are recognized as important associations. These agents are typically categorized into "definite", "likely", "possible", or "unlikely" to cause pulmonary arterial hypertension, based on the strength of evidence.
OBJECTIVE: This review will focus on those therapeutic agents where there is sufficient literature to adequately comment on the role of the agent in the pathogenesis of pulmonary arterial hypertension.
METHODS: A systematic search was conducted using PubMed covering the period September 1970- 2017. The search term utilized was "drug induced pulmonary hypertension". This resulted in the identification of 853 peer-reviewed articles including case reports. Each paper was then reviewed by the authors for its relevance. The majority of these papers (599) were excluded as they related to systemic hypertension, chronic obstructive pulmonary disease, human immunodeficiency virus, pulmonary fibrosis, alternate differential diagnosis, treatment, basic science, adverse effects of treatment, and pulmonary hypertension secondary to pulmonary embolism. Agents affecting serotonin metabolism (and related anorexigens): Anorexigens, such as aminorex, fenfluramine, benfluorex, phenylpropanolamine, and dexfenfluramine were the first class of medications recognized to cause pulmonary arterial hypertension. Although most of these medications have now been withdrawn worldwide, they remain important not only from a historical perspective, but because their impact on serotonin metabolism remains relevant. Selective serotonin reuptake inhibitors, tryptophan, and lithium, which affect serotonin metabolism, have also been implicated in the development of pulmonary arterial hypertension. Interferon and related medications: Interferon alfa and sofosbuvir have been linked to the development of pulmonary arterial hypertension in patients with other risk factors, such as human immunodeficiency virus co-infection. Antiviral therapies: Sofosbuvir has been associated with two cases of pulmonary artery hypertension in patients with multiple risk factors for its development. Its role in pathogenesis remains unclear. Small molecule tyrosine kinase inhibitors: Small molecule tyrosine kinase inhibitors represent a relatively new class of medications. Of these dasatinib has the strongest evidence in drug-induced pulmonary arterial hypertension, considered a recognized cause. Nilotinib, ponatinib, carfilzomib, and ruxolitinib are newer agents, which paradoxically have been linked to both cause and treatment for pulmonary arterial hypertension. Monoclonal antibodies and immune regulating medications: Several case reports have linked some monoclonal antibodies and immune modulating therapies to pulmonary arterial hypertension. There are no large series documenting an increased prevalence of pulmonary arterial hypertension complicating these agents; nonetheless, trastuzumab emtansine, rituximab, bevacizumab, cyclosporine, and leflunomide have all been implicated in case reports. Opioids and substances of abuse: Buprenorphine and cocaine have been identified as potential causes of pulmonary arterial hypertension. The mechanism by which this occurs is unclear. Tramadol has been demonstrated to cause severe, transient, and reversible pulmonary hypertension. Chemotherapeutic agents: Alkylating and alkylating-like agents, such as bleomycin, cyclophosphamide, and mitomycin have increased the risk of pulmonary veno-occlusive disease, which may be clinically indistinct from pulmonary arterial hypertension. Thalidomide and paclitaxel have also been implicated as potential causes. Miscellaneous medications: Protamine appears to be able to cause acute, reversible pulmonary hypertension when bound to heparin. Amiodarone is also capable of causing pulmonary hypertension by way of recognized side effects.
CONCLUSIONS: Pulmonary arterial hypertension remains a rare diagnosis, with drug-induced causes even more uncommon, accounting for only 10.5% of cases in large registry series. Despite several agents being implicated in the development of PAH, the supportive evidence is typically limited, based on case series and observational data. Furthermore, even in the drugs with relatively strong associations, factors that predispose an individual to PAH have yet to be elucidated.

PMID: 29508628 [PubMed - as supplied by publisher]

Integration of genome-scale metabolic networks into whole-body PBPK models shows phenotype-specific cases of drug-induced metabolic perturbation.

NPJ Syst Biol Appl. 2018;4:10

Authors: Cordes H, Thiel C, Baier V, Blank LM, Kuepfer L

Abstract
Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism. The applicability of the proposed workflow is illustrated for isoniazid, a first-line antibacterial agent against Mycobacterium tuberculosis, which is known to cause idiosyncratic drug-induced liver injuries (DILI). We combined GSMN models of a human liver with N-acetyl transferase 2 (NAT2)-phenotype-specific PBPK models of isoniazid. The combined PBPK-GSMN models quantitatively describe isoniazid pharmacokinetics, as well as intracellular responses, and changes in the exometabolome in a human liver following isoniazid administration. Notably, intracellular and extracellular responses identified with the PBPK-GSMN models are in line with experimental and clinical findings. Moreover, the drug-induced metabolic perturbations are distributed and attenuated in the metabolic network in a phenotype-dependent manner. Our simulation results show that a simultaneous consideration of both drug pharmacokinetics at the whole-body and metabolism at the cellular level is mandatory to explain drug-induced injuries at the patient level. The proposed workflow extends our mechanistic understanding of the biochemistry underlying adverse events and may be used to prevent drug-induced injuries in the future.

PMID: 29507756 [PubMed]

New low-dose liquid pilocarpine formulation for treating dry mouth in Sjögren's syndrome: clinical efficacy, symptom relief, and improvement in quality of life.

J Pharm Health Care Sci. 2018;4:4

Authors: Watanabe M, Yamada C, Komagata Y, Kikuchi H, Hosono H, Itagaki F

Abstract
Background: Patients with Sjögren's syndrome (SS) typically present clinically with xerostomia (dry mouth) because of progressive damage to the exocrine glands. We developed a new, low-dose pilocarpine/sodium alginate (LPA) solution with pilocarpine hydrochloride to inhibit systemic adverse effects by administering via the oral mucosa. The purpose of this study was to assess its stability, safety, and efficacy.
Methods: The pilocarpine concentration in an LPA liquid formulation was measured 3, 7, 14, and 28 days after preparation to assess its stability. A prospective clinical trial was undertaken to assess the efficacy and safety of the LPA solution as a symptomatic treatment for dry mouth in SS. Patients (n = 24) with clinically significant xerostomia were enrolled after providing written informed consent. Whole-mouth salivary flow rate was measured twice; immediately before and 60 min after LPA application. Symptoms were assessed by questionnaire with visual analog scales or checkboxes before the first application (baseline), and then once daily for 7 days.
Results: The pilocarpine content 3, 7, 14, and 28 days after preparation showed no marked change, confirming its stability. Salivary flow was significantly increased from 0.076 ± 0.092 g/30 s to 0.122 ± 0.140 g/30 s 60 min after LPA administration (P < 0.001). Dry mouth and thirstiness showed significant improvement compared with that of baseline (P ≤ 0.01). The only adverse effect was sweating, and no serious drug-related adverse events were reported.
Conclusions: This new, low-dose pilocarpine formulation was well-tolerated and resulted in significant improvements in symptoms of dry mouth and other xerostomic conditions in patients with SS.
Trial registration: The study approval number in the institution; 08-068-2. Registered January 19, 2009. UMIN000029307. Registered 27 September 2017 (retrospectively registered).

PMID: 29507747 [PubMed]

Analysis of Adverse Drug Reaction Risk in Elderly Patients Using the Japanese Adverse Drug Event Report (JADER) Database.

Biol Pharm Bull. 2017;40(6):824-829

Authors: Chisaki Y, Aoji S, Yano Y

Abstract
In general, the risk of adverse drug reactions (ADRs) is higher in elderly patients than in younger patients. In this study, we performed a comprehensive assessment of the risks of possible drug-ADR combinations in elderly patients using the Japanese Adverse Drug Event Report (JADER) database of the Pharmaceutical and Medical Devices Agency (PMDA, Japan) using the reporting odds ratio (ROR) as an index. Data recorded from April 2004 to September 2015 in the JADER database were downloaded from the PMDA website. The patients were classified into younger (≤69 years old) and elderly (≥70 years old) groups. The ROR and 95% confidence interval (CI) were calculated for all combinations of drugs and ADRs for which there were three or more reports in the database, focusing particularly on the combinations where more than 100 cases had been reported in elderly and younger patients. The most frequently reported drug-ADR combination was methotrexate with interstitial lung disease (646 cases). The combination with the highest ROR was methotrexate with lymphoproliferative disorder (ROR: 484.6, 95% CI: 334.1-702.9). In total, 27 drug-ADR combinations were found to have high risk in elderly patients. In conclusion, the findings of this comprehensive assessment of drug-ADR combinations using the JADER database will be valuable for updating the ADR risks for elderly patients in clinical setting.

PMID: 28566626 [PubMed - indexed for MEDLINE]

Adverse effects of levamisole in cocaine users: a review and risk assessment.

Arch Toxicol. 2017 Jun;91(6):2303-2313

Authors: Brunt TM, van den Berg J, Pennings E, Venhuis B

Abstract
The immunomodulatory adjuvant and antihelminth levamisole is increasingly used as an adulterant in cocaine worldwide. An accumulating body of clinical and toxicological literature has appeared since 2010 describing neutropenia, agranulocytosis, leukoencephalopathy and vasculitis in cases associated with levamisole-adulterated cocaine. Mostly, neutropenia and agranulocytosis were reported, characterized by a decimation of neutrophils. A large proportion of cases also involved vasculopathy, characterized by pronounced black and purple skin purpura with cutaneous necrosis. Females are more susceptible for both agranulocytosis and vasculitis. Another complication reported with levamisole-adulterated cocaine is leukoencephalopathy, a disabling and potentially fatal neurological disorder caused by cerebral demyelination. In this review, all adverse effects associated with therapeutic levamisole and levamisole-adulterated cocaine are described. In addition, this review provides an update of the pharmacology of levamisole, its metabolism, including toxic metabolites and metabolites that are relevant for levamisole's addition to cocaine. Special emphasis is put on the immunopathology and the dose-effect relationship of chronic levamisole exposure. Finally, a risk assessment is provided based on the current level of levamisole adulteration in street cocaine, the dose range calculated per gram and the pattern of chronic exposure in heavy or dependent users.

PMID: 28314885 [PubMed - indexed for MEDLINE]

DTNI: a novel toxicogenomics data analysis tool for identifying the molecular mechanisms underlying the adverse effects of toxic compounds.

Arch Toxicol. 2017 Jun;91(6):2343-2352

Authors: Hendrickx DM, Souza T, Jennen DGJ, Kleinjans JCS

Abstract
Unravelling gene regulatory networks (GRNs) influenced by chemicals is a major challenge in systems toxicology. Because toxicant-induced GRNs evolve over time and dose, the analysis of global gene expression data measured at multiple time points and doses will provide insight in the adverse effects of compounds. Therefore, there is a need for mathematical methods for GRN identification from time-over-dose-dependent data. One of the current approaches for GRN inference is Time Series Network Identification (TSNI). TSNI is based on ordinary differential equations (ODE), describing the time evolution of the expression of each gene, which is assumed to be dependent on the expression of other genes and an external perturbation (i.e. chemical exposure). Here, we present Dose-Time Network Identification (DTNI), a method extending TSNI by including ODE describing how the expression of each gene evolves with dose, which is supposed to depend on the expression of other genes and the exposure time. We also adapted TSNI in order to enable inclusion of time-over-dose-dependent data from multiple compounds. Here, we show that DTNI outperforms TSNI in inferring a toxicant-induced GRN. Moreover, we show that DTNI is a suitable method to infer a GRN dose- and time-dependently induced by a group of compounds influencing a common biological process. Applying DTNI on experimental data from TG-GATEs, we demonstrate that DTNI provides in-depth information on the mode of action of compounds, in particular key events and potential molecular initiating events. Furthermore, DTNI also discloses several unknown interactions which have to be verified experimentally.

PMID: 28032149 [PubMed - indexed for MEDLINE]