The Value of Measuring Inspiratory Capacity in Subjects With Cystic Fibrosis.

Respir Care. 2018 Jul 17;:

Authors: Vilozni D, Dagan A, Lavie M, Sarouk I, Bar-Aluma BE, Ashkenazi M, Mendelovich SL, Betzalel Y, Efrati O

Abstract
BACKGROUND: Inspiratory capacity (IC) was scarely considered an important measured index of spirometry in patients with cystic fibrosis (CF). Abnormally low IC may indicate the onset of static/dynamic hyperinflation, which may be accompanied by dyspnea and an increase in the work of breathing. This cross-sectional study sought to determine whether measuring IC during spirometry, may add clinical value to FEV1 measurements in CF subjects.
METHODS: Anthropometric, clinical, spirometry, and static lung volume data were gathered retrospectively from 98 of 165 patients with CF (mean ± SD age 26.8 ± 11.0 y) registered in The Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Israel. We compared the IC (% predicted) to FEV1, static lung volumes, and hospitalization days/year.
RESULTS: IC decreased alongside FEV1 decline but at a slower pace (r2 = 0.32). Incremental trapped air, as measured by residual volume (RV), and a rapid elevation in the ratio of RV to total lung capacity occurred when IC deteriorated below 60% predicted values. The unique combination of IC < 50% predicted and FEV1 > 40% predicted induced an increase of up to 125 hospitalization days/year compared to subjects having IC > 50% predicted (up to 73 d/y, P < .001).
CONCLUSIONS: Measuring IC in CF subjects may reveal silent worsening of lung function as indicated by a decline in IC < 50% predicted while FEV1 is still > 40% predicted. This condition may lead to inefficient breathing at high lung volumes, which may explain a subjective sensation of breathlessness and lead to an increase in hospitalization days/year.

PMID: 30018173 [PubMed - as supplied by publisher]

Impact of a program ensuring consistent response to acute drops in lung function in children with cystic fibrosis.

J Cyst Fibros. 2018 Jul 13;:

Authors: Schechter MS, Schmidt HJ, Williams R, Norton R, Taylor D, Molzhon A

Abstract
BACKGROUND: Variation in CF pulmonary outcomes is multifactorial, but a significant component appears to be dependent upon differences in CF Center care. Previous investigations suggest that high performing CF centers are more consistent and proactive in the treatment of pulmonary exacerbations. We incorporated this approach into a program that could be bundled and shared with other CF Centers.
METHODS: The reorganization of CF pulmonary care at the Children's Hospital of Richmond included the development of a pulmonary algorithm to define a standard response to changes in lung function and run charts to track process and outcome measures. We calculated the rolling average of the best percent predicted FEV1 (ppFEV1) over the previous 12 months as our primary outcome measure.
RESULTS: The mean of the best ppFEV1 in the previous 12 months rose from 87% predicted (65% predicted for those 13-18 years, 97% predicted for those 6-13 years) in January 2013 to 98% predicted (95% predicted for those 13-18 years, 110% predicted for those 6-13 years) in January 2018. The ppFEV1 difference between children 6-13 years and adolescents 13-18 years dropped from 34 to 14 during that time.
CONCLUSIONS: Improvements in pulmonary outcomes can be accomplished rapidly using basic quality improvement principles, including interdisciplinary team goal setting, standardized and proactive approaches that ensure consistent recognition and treatment of pulmonary exacerbations, and the use of data to follow the effectiveness of the process. We believe that the steps involved would be easy for other CF Centers to adapt to their own settings.

PMID: 30017327 [PubMed - as supplied by publisher]

The suppression of premature termination codons and the repair of splicing mutations in CFTR.

Curr Opin Pharmacol. 2017 06;34:125-131

Authors: Oren YS, Pranke IM, Kerem B, Sermet-Gaudelus I

Abstract
Premature termination codons (PTC) originate from nucleotide substitution introducing an in-frame PTC. They induce truncated, usually non-functional, proteins, degradation of the PTC containing transcripts by the nonsense-mediated decay (NMD) pathway and abnormal exon skipping. Readthrough compounds facilitate near cognate amino-acyl-tRNA incorporation, leading potentially to restoration of a functional full-length protein. Splicing mutations can lead to aberrantly spliced transcripts by creating a cryptic splice site or destroying a normal site. Most mutations result in disruption of the open reading frame and activation of NMD. Antisense oligonucleotides are single stranded short synthetic RNA-like molecules chemically modified to improve their stability and ability to recognize their target RNAs and modify the splice site. This review focuses on recent developments in therapies aiming to improve the health of CF patients carrying nonsense or splicing mutations.

PMID: 29128743 [PubMed - indexed for MEDLINE]

Early-onset retinal dystrophy and chronic dermatitis in a girl with an undiagnosed congenital disorder of glycosylation (SRD5A3-CDG).

Ophthalmic Genet. 2018 Jul 18;:1-3

Authors: Khan AO

Abstract
PURPOSE: Early-onset retinal dystrophy is usually isolated but can also be the presenting manifestation of an undiagnosed systemic disease. The purpose of this report is to highlight the initial presentation of a girl with early-onset retinal dystrophy and chronic dermatitis who was found to have an undiagnosed congenital disorder of glycosylation (SRD5A3-CDG).
METHODS: Retrospective case report.
RESULTS: A 13-year-old Baluchi girl was referred for evaluation of low vision since soon after birth. Clinical exam confirmed retinal dystrophy. She also had developmental disability and chronic dermatitis. Brain MRI was normal. Whole exome and confirmatory Sanger sequencing uncovered homozygosity for a SRDA3 deletion (p.Gln96delinsX) that was previously reported in two other Baluchi SRDA3-CDG families with ocular coloboma, optic atrophy, atopic dermatitis, cerebellar hypoplasia, and developmental disability. Early-onset retinal dystrophy was not mentioned in those two families but has since been documented in other SRDA3-CDG families harboring different biallelic variants in the gene.
DISCUSSION: Early-onset retinal dystrophy with chronic dermatitis should raise suspicion for biallelic SRDA3 mutations, particularly in the context of developmental disability. Exome sequencing can be a useful analysis in retinal dystrophy patients with multisystem disease. Homozygosity for the SRDA3 deletion p.Gln96delinsX is not always associated with ocular coloboma.

PMID: 30019980 [PubMed - as supplied by publisher]

Paternal lineage early onset hereditary ovarian cancers: A Familial Ovarian Cancer Registry study.

PLoS Genet. 2018 02;14(2):e1007194

Authors: Eng KH, Szender JB, Etter JL, Kaur J, Poblete S, Huang RY, Zhu Q, Grzesik KA, Battaglia S, Cannioto R, Krolewski JJ, Zsiros E, Frederick PJ, Lele SB, Moysich KB, Odunsi KO

Abstract
Given prior evidence that an affected woman conveys a higher risk of ovarian cancer to her sister than to her mother, we hypothesized that there exists an X-linked variant evidenced by transmission to a woman from her paternal grandmother via her father. We ascertained 3,499 grandmother/granddaughter pairs from the Familial Ovarian Cancer Registry at the Roswell Park Cancer Institute observing 892 informative pairs with 157 affected granddaughters. We performed germline X-chromosome exome sequencing on 186 women with ovarian cancer from the registry. The rate of cancers was 28.4% in paternal grandmother/granddaughter pairs and 13.9% in maternal pairs consistent with an X-linked dominant model (Chi-square test X2 = 0.02, p = 0.89) and inconsistent with an autosomal dominant model (X2 = 20.4, p<0.001). Paternal grandmother cases had an earlier age-of-onset versus maternal cases (hazard ratio HR = 1.59, 95%CI: 1.12-2.25) independent of BRCA1/2 status. Reinforcing the X-linked hypothesis, we observed an association between prostate cancer in men and ovarian cancer in his mother and daughters (odds ratio, OR = 2.34, p = 0.034). Unaffected mothers with affected daughters produced significantly more daughters than sons (ratio = 1.96, p<0.005). We performed exome sequencing in reported BRCA negative cases from the registry. Considering age-of-onset, one missense variant (rs176026 in MAGEC3) reached chromosome-wide significance (Hazard ratio HR = 2.85, 95%CI: 1.75-4.65) advancing the age of onset by 6.7 years. In addition to the well-known contribution of BRCA, we demonstrate that a genetic locus on the X-chromosome contributes to ovarian cancer risk. An X-linked pattern of inheritance has implications for genetic risk stratification. Women with an affected paternal grandmother and sisters of affected women are at increased risk for ovarian cancer. Further work is required to validate this variant and to characterize carrier families.

PMID: 29447163 [PubMed - indexed for MEDLINE]

Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk.

PLoS Genet. 2018 02;14(2):e1007111

Authors: Waller RG, Darlington TM, Wei X, Madsen MJ, Thomas A, Curtin K, Coon H, Rajamanickam V, Musinsky J, Jayabalan D, Atanackovic D, Rajkumar SV, Kumar S, Slager S, Middha M, Galia P, Demangel D, Salama M, Joseph V, McKay J, Offit K, Klein RJ, Lipkin SM, Dumontet C, Vachon CM, Camp NJ

Abstract
The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.

PMID: 29389935 [PubMed - indexed for MEDLINE]

Longitudinal exome-wide association study to identify genetic susceptibility loci for hypertension in a Japanese population.

Exp Mol Med. 2017 Dec 08;49(12):e409;

Authors: Yasukochi Y, Sakuma J, Takeuchi I, Kato K, Oguri M, Fujimaki T, Horibe H, Yamada Y

Abstract
Genome-wide association studies have identified various genetic variants associated with complex disorders. However, these studies have commonly been conducted in a cross-sectional manner. Therefore, we performed a longitudinal exome-wide association study (EWAS) in a Japanese cohort. We aimed to identify genetic variants that confer susceptibility to hypertension using ~244 000 single-nucleotide variants (SNVs) and physiological data from 6026 Japanese individuals who underwent annual health check-ups for several years. After quality control, the association of hypertension with SNVs was tested using a generalized estimating equation model. Finally, our longitudinal EWAS detected seven hypertension-related SNVs that passed strict criteria. Among these variants, six SNVs were densely located at 12q24.1, and an East Asian-specific motif (haplotype) 'CAAAA' comprising five derived alleles was identified. Statistical analyses showed that the prevalence of hypertension in individuals with the East Asian-specific haplotype was significantly lower than that in individuals with the common haplotype 'TGGGT'. Furthermore, individuals with the East Asian haplotype may be less susceptible to the adverse effects of smoking on hypertension. The longitudinal EWAS for the recessive model showed that a novel SNV, rs11917356 of COL6A5, was significantly associated with systolic blood pressure, and the derived allele at the SNV may have spread throughout East Asia in recent evolutionary time.

PMID: 29217820 [PubMed - indexed for MEDLINE]

Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism.

Hum Genomics. 2017 Nov 14;11(1):28

Authors: Alsemari A, Al-Younes B, Goljan E, Jaroudi D, BinHumaid F, Meyer BF, Arold ST, Monies D

Abstract
BACKGROUND: Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic heterogeneity. We expand aaRSs-related phenotypes through characterization of the clinical and molecular basis of a novel autosomal-recessive syndrome manifesting severe mental retardation, ataxia, speech impairment, epilepsy, short stature, microcephaly, hypogonadism, and growth hormone deficiency.
RESULTS: A G>A variant in exon 29 of VARS2 (c.3650G>A) (NM_006295) was identified in the index case. This homozygous variant was confirmed by Sanger sequencing and segregated with disease in the family studied. The c.3650G>A change results in alteration of arginine to histidine at residue 1217 (R1217H) of the mature protein and is predicted to be pathogenic.
CONCLUSIONS: These findings contribute to a growing list of aaRSs disorders, broadens the spectrum of phenotypes attributable to VARS2 mutations, and provides new insight into genotype-phenotype correlations among the mitochondrial synthetase genes.

PMID: 29137650 [PubMed - indexed for MEDLINE]

De novo Mutation in CACNA1S Gene in a 20-Year-Old Man Diagnosed with Metabolic Myopathy.

Arch Iran Med. 2017 Sep;20(9):617-620

Authors: Edizadeh M, Vazehan R, Javadi F, Dehdahsi S, Fadaee M, Faraji Zonooz M, Parsimehr E, Ahangari F, Abolhassani A, Kalhor Z, Fattahi Z, Beheshtian M, Kariminejad A, Akbari MR, Najmabadi H, Nafissi S

Abstract
The calcium channel, voltage-dependent, L-type, alpha 1S subunit (CACNA1S) gene encodes a skeletal Ca2+ channel which is involved in calcium-dependent processes such as muscle contraction and neurotransmitter release. Mutations in this gene have been accompanied by hypo- and normokalemic periodic paralysis, thyrotoxic periodic paralysis, and susceptibility to malignant hyperthermia. We report the clinical and genetic findings in a patient diagnosed with metabolic myopathy who had episodic attacks of muscle pain and weakness but with no family background of the disease. Next-generation sequencing (NGS) using a panel targeting metabolic myopathy and myotonia genes identified a de novo heterozygous pathogenic variant c.3724A>G, p.Arg1242Gly, in exon 30 of CACNA1S. As the second report of this variant, this case may broaden the CACNA1S-related disease spectrum to include normokalemic periodic paralysis.

PMID: 29048924 [PubMed - indexed for MEDLINE]

Multi-genic pattern found in rare type of hypopituitarism: a whole-exome sequencing study of Han Chinese with pituitary stalk interruption syndrome.

J Cell Mol Med. 2017 Dec;21(12):3626-3632

Authors: Guo QH, Wang CZ, Wu ZQ, Qin Y, Han BY, Wang AP, Wang BA, Dou JT, Wu XS, Mu YM

Abstract
Pituitary stalk interruption syndrome (PSIS) is a rare type of hypopituitarism manifesting various degrees of pituitary hormone deficiency. Although mutations have been identified in some familial cases, the underpinning mechanisms of sporadic patients with PSIS who are in a vast majority remain elusive, necessitating a comprehensive study using systemic approaches. We postulate that other genetic mechanisms may be responsible for the sporadic PSIS. To test this hypothesis, we conducted a study in 24 patients with PSIS of Han Chinese with no family history using whole-exome sequencing (WES) and bioinformatic analysis. We identified a group of heterozygous mutations in 92% (22 of 24) of the patients, and these genes are mostly associated with Notch, Shh, Wnt signalling pathways. Importantly, 83% (20 of 24) of the patients had more than one mutation in those pathways suggesting synergy of compound mutations underpin the pathogenesis of sporadic PSIS.

PMID: 28707430 [PubMed - indexed for MEDLINE]

Novel Mutations in EPCAM Cause Congenital Tufting Enteropathy.

J Clin Gastroenterol. 2018 Jan;52(1):e1-e6

Authors: Tang W, Huang T, Xu Z, Huang Y

Abstract
BACKGROUND AND AIMS: Congenital tufting enteropathy (CTE) is a rare autosomal recessive form of intractable diarrhea of infancy. Patients develop chronic diarrhea within days after birth, leading to severe malabsorption and significant mortality. CTE is characterized by subtotal villous atrophy with crypt hyperplasia. Typical features include abnormal villi in the intestinal epithelium and disorganization of surface enterocytes with focal crowding, resembling tufts. The pathogenesis of CTE remains poorly understood. CTE has been reported in Western populations, but until now had not been reported in China. The objective of this study was to identify the gene responsible for CTE in a Chinese individual.
METHODS: A 13-year-old girl with suspected CTE, whose parents were both healthy, was evaluated in our clinic. Tissues were obtained by endoscopy and examined by electron microscopy. Genomic DNA, extracted from the peripheral blood of the child and parents, was subjected to whole-exome sequencing. After mutations in the gene encoding epithelial cell adhesion molecule (EPCAM) were identified, expression of EPCAM was examined by immunohistochemistry staining.
RESULTS: Whole-exome sequencing revealed compound heterozygous mutations in EPCAM in the patient, with immunohistochemical analysis showing complete loss of EPCAM expression in the intestinal villi and crypts.
CONCLUSIONS: We identified compound heterozygous mutations in EPCAM, with loss of EPCAM expression in duodenal enterocytes, in a patient with intractable diarrhea since infancy who was subsequently diagnosed with CTE. This is the first case of CTE to be reported in a Chinese patient.

PMID: 27875355 [PubMed - indexed for MEDLINE]

Comparison of Preoperative Administration of Pregabalin and Duloxetine on Cognitive Functions and Pain Management after Spinal Surgery: A Randomized Double-blind Placebo-controlled Study.

Clin J Pain. 2018 Jul 16;:

Authors: Altıparmak B, Güzel Ç, Gümüş Demirbilek S

Abstract
STUDY OBJECTIVE: The surgical trauma is known to induce hyperalgesia and if pain management is insufficient, it contributes to persistent pain in the postoperative period.In this study, our primary aims are to compare the effect of pregabalin and duloxetine on postoperative pain scores and cognitive functions. Our secondary aim is to determine drug-related side-effects.
DESIGN: Prospective, randomized, double-blind, placebo-controlled.
SETTINGS: Operating room, surgical ward.
PATIENTS: Nintyfour patients,18-65 years of age, ASA status I-II, scheduled for elective repair of lumbar disc herniation.
INTERVENTIONS: The patients were randomly divided into three groups; the first group orally received pregabalin 75▒mg one hour prior to the surgery and at the postoperative 12 and 24 hours. The second group orally received duloxetine 60▒mg one hour prior to the surgery. At the postoperative 12 hour, they received a placebo capsule and at the 24 hour, they received duloxetine 60▒mg again. The third group orally received placebo capsules at all timepoints.
MEASUREMENTS: Postoperative pain evaluation was conducted using visual analogue scale (VAS) at postoperative first minute, 30 minute, first hour, 12, 24 and 48 hour. The preoperative and postoperative 6 hour cognitive functions were evaluated with Montreal Cognitive Assessment (MOCA) test.
MAIN RESULTS: There was a significant reduction in mean MOCA scores postoperatively in all groups (P<0.01). The highest MOCA score reduction was in pregabalin group (1,83±1,31 point), then in duloxetine group (1,16±0,82) and least decrease was in control group (0,49±0,61). At all timepoints mean VAS scores of pregabalin and duloxetine groups were similar to each other and they were lower than control groups (P<0.05).
CONCLUSIONS: Preoperative use of duloxetine 60▒mg can be an useful alternative to pregabalin 75▒mg as it has similar analgesic effect on postoperative pain with fewer drug-related cognitive function deterioration.

PMID: 30020088 [PubMed - as supplied by publisher]

A Randomized Clinical Trial of the Efficacy and Safety of Sitagliptin Compared with Dapagliflozin in Patients with Type 2 Diabetes Mellitus and Mild Renal Insufficiency: The CompoSIT-R Study.

Diabetes Obes Metab. 2018 Jul 18;:

Authors: Scott R, Morgan J, Zimmer Z, Lam RLH, O'Neill EA, Kaufman KD, Engel SS, Raji A

Abstract
AIMS: To compare the efficacy and safety of the DPP-4 inhibitor sitagliptin with the SGLT-2 inhibitor dapagliflozin in patients with type 2 diabetes and mild renal insufficiency.
MATERIALS AND METHODS: Patients with HbA1c 7.0 to 9.5% (53 to ≤80 mmol/mol) and eGFR 60 to <90 mL/min/1.73m2 on metformin (≥1500 mg/day) ± sulfonylurea were randomized to sitagliptin 100 mg (N=307) or dapagliflozin 5 mg titrated to 10 mg (N=306) once-daily for 24 weeks. A longitudinal data analysis model was used to test the primary hypothesis that sitagliptin is non-inferior to dapagliflozin in reducing HbA1c at Week 24, with superiority to be tested if non-inferiority is met.
RESULTS: Baseline mean HbA1c (% [mmol/mol]) was 7.7 (60.9) and 7.8 (61.2), and mean eGFR (mL/min/1.73m2 ) was 79.4 and 76.9 for the sitagliptin and dapagliflozin groups, respectively. After 24 weeks, the between-group difference in LS mean (95% CI) changes from baseline in HbA1c was -0.15% (-0.26,-0.04) (-1.67 mmol/mol [-2.86,-0.48]), p=0.006, meeting the prespecified criteria for declaring both non-inferiority and superiority of sitagliptin vs. dapagliflozin. HbA1c goal of <7% (<53 mmol/mol) was met by 43% (sitagliptin) and 27% (dapagliflozin) of patients. No meaningful between-group difference was observed in a pre-specified analysis of 2-hour incremental post-prandial glucose excursion. Review of adverse events (AEs) was notable for a lower incidence of drug-related AEs with sitagliptin compared with dapagliflozin.
CONCLUSIONS: In patients with type 2 diabetes, mild renal insufficiency and inadequate glycemic control on metformin ± sulfonylurea, sitagliptin treatment resulted in greater improvement in glycemic control compared with dapagliflozin and was generally well-tolerated. This article is protected by copyright. All rights reserved.

PMID: 30019498 [PubMed - as supplied by publisher]

Effect of Fluconazole on the Pharmacokinetics Properties of Imrecoxib, a Novel NSAID: A Single-center, Open-label, Self-controlled Study in Healthy Chinese Male Volunteers.

Clin Ther. 2018 Jul 13;:

Authors: Zuo CZ, Gong Y, Hou XY, Zhang YF, Peng WX, Zhu RH, Zhong DF, Chen XY

Abstract
PURPOSE: Imrecoxib is one type of cyclooxygenase-2 inhibitor with the capability of reducing the potential cardiovascular risk caused by other NSAIDs. Co-administration with other medications can affect the cytochrome P450 (CYP) 2C9 enzyme function; thus, imrecoxib metabolism can be affected. The purpose of this research was to evaluate the effects of fluconazole, which is known to inhibit CYP2C9, on imrecoxib's pharmacokinetic (PK) parameters.
METHODS: In this single-center, single-arm, open-label, self-controlled study, 12 healthy Chinese male volunteers (mean [SD] age, 22.6 [2.43] years) received the following 2 treatments separated by a washout period of 8days under a fasting state: (1) a single oral dose of imrecoxib 100 mg; and (2) fluconazole 200mg/d over 6days followed by concurrent dosing of imrecoxib 100mg and fluconazole 200mg. Plasma concentrations of imrecoxib (M0) and its metabolites (4'-hydroxymethyl metabolite [M1] and 4'-carboxylic acid metabolite [M2]) for PK analysis were obtained at 0 (baseline) and 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, and 72hours after imrecoxib dosing. Safety and tolerability assessments were performed throughout the study.
FINDINGS: All subjects completed the study. There was 1 adverse event; drug-induced liver damage in 1 subject occurred after he received imrecoxib plus fluconazole, and the subject recovered without any sequelae. Coadministration with fluconazole resulted in much higher plasma imrecoxib concentrations, with an increase of 88% in Cmax and 72% in AUC0-t compared with only imrecoxib treatment, which showed that fluconazole may increase plasma exposure to imrecoxib. Fluconazole also caused a small, but not clinically relevant, decrease in M1 and M2 mean Cmax (13% and 14%, respectively), but there was minimal change in M1 and M2 mean AUC0-t (3% and 2%). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or adverse events between treatments.
IMPLICATIONS: Concurrent administration of imrecoxib and fluconazole did not seem to change imrecoxib's safety profile. The ratio (imrecoxib + fluconazole/imrecoxib) for AUC0-t was 1.72 (90% CI, 1.41-2.11) and for Cmax it was 1.88 (90% CI, 1.59-2.21). Hence, it is necessary to adjust the imrecoxib dose when it is concurrently used with other CYP2C9 inhibitors.

PMID: 30017171 [PubMed - as supplied by publisher]

Treatment of inherited bone marrow failure syndromes beyond transplantation.

Hematology Am Soc Hematol Educ Program. 2017 12 08;2017(1):96-101

Authors: Calado RT, Clé DV

Abstract
Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.

PMID: 29222242 [PubMed - indexed for MEDLINE]

Dispensability of Annual Laboratory Follow-Up After More than 2 Years of Valproic Acid Use: A Systematic Review.

CNS Drugs. 2017 Nov;31(11):939-957

Authors: Meijboom RW, Grootens KP

Abstract
BACKGROUND: The necessity of annual laboratory follow-up in patients treated with valproic acid (VPA) is controversial.
OBJECTIVE: We investigated the need for annual laboratory follow-up of liver enzymes, electrolytes, and full blood count (FBC) in patients treated with VPA.
PATIENTS AND METHODS: A systematic search in Evidence-Based Medicine Reviews (EBMR), MEDLINE, and EMBASE was undertaken in December 2016 to identify all published articles investigating or citing valproic acid, liver function disorders, electrolyte disorders, and FBC deviations.
RESULTS: This review included 108 articles. As the number of participants and duration of the study was not adequate in most studies to detect rare adverse events, studies did not demonstrate a clear prevalence of hepatotoxicity. While a transient increase of transaminases is common and seldom harmful, severe hepatotoxicity is a rare phenomenon and is not prevented by routine laboratory monitoring. VPA had no relevant effect on serum calcium, sodium, potassium, and albumin. The prevalence of FBC varied from 0.6 to 27.8%, occurred mostly in the first 2 years of therapy, and was usually asymptomatic.
CONCLUSIONS: Long-term monitoring in VPA treatment is only necessary when there have been dose adjustments, co-medication switches, or co-morbidity. In uncomplicated cases, annual laboratory follow-up may be discontinued after 2 years of VPA treatment. Encouraging patients to be vigilant is more effective in the detection of hepatotoxicity than laboratory testing. Follow-up of FBC at 3-6 months, 1 year, and 2 years after start or after a dose increase of VPA or interacting medication is sufficient.

PMID: 29214384 [PubMed - indexed for MEDLINE]

Comparing Safety and Efficacy of "Third-Generation" Antiepileptic Drugs: Long-Term Extension and Post-marketing Treatment.

CNS Drugs. 2017 Nov;31(11):959-974

Authors: Kwok CS, Johnson EL, Krauss GL

Abstract
Four "third-generation" antiepileptic drugs (AEDs) were approved for adjunctive treatment of refractory focal onset seizures during the past 10 years. Long-term efficacy and safety of the drugs were demonstrated in large extension studies and in reports of subgroups of patients not studied in pivotal trials. Reviewing extension study and post-marketing outcome series for the four newer AEDs-lacosamide, perampanel, eslicarbazepine acetate and brivaracetam-can guide clinicians in treating and monitoring patients. AED extension studies evaluate treatment retention, drug tolerability, and drug safety during individualized treatment with flexible dosing and thus provide information not available in rigid pivotal trials. Patient retention in the studies ranged from 75 to 80% at 1 year and from 36 to 68% at 2-year treatment intervals. Safety findings were generally similar to those of pivotal trials, with no major safety risks identified and with several specific adverse drug effects, such as hyponatremia, reported. The third-generation AEDs, some through new mechanisms and others with improved tolerability compared to related AEDs, provide new options in efficacy and tolerability.

PMID: 29204953 [PubMed - indexed for MEDLINE]

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