bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetic and exposure simulation analysis for cediranib (AZD2171) in pooled Phase I/II studies in patients with cancer
Authors: Li Jianguo , Al‐Huniti Nidal , Henningsson Anja , Tang Weifeng , Masson Eric 
Published: February 2017

AimsA population pharmacokinetic (PK) model was developed for cediranib to simulate cediranib exposure for different doses, including comedication with strong uridine glucuronosyl transferase/P‐glycoprotein inducers such as rifampicin, in cancer patients.MethodsPlasma concentrations and covariates from 625 cancer patients after single or multiple oral cediranib administrations ranging from 0.5 to 90 mg in 19 Phase I and II studies were included in the analysis. Stepwise covariate modelling was used to develop the population PK model. The final model was used to simulate cediranib exposure in cancer patients to evaluate cediranib target coverage and the need for dose adjustment for covariates or coadministration with rifampicin.ResultsA two‐compartment model with sequential zero‐ and first‐order absorption and first‐order elimination adequately described the cediranib concentration–time courses. Body weight and age were identified as having statistically significant impact on cediranib PK, but only <21% impact on AUC and maximum concentrations. Simulated lower bounds of 90% prediction interval or median of unbound cediranib concentrations after cediranib 15 or 20 mg exceeded the IC50 for vascular endothelial growth factor receptors‐1, ‐2 and ‐3. Exposures of cediranib 20 or 30 mg with coadministration of rifampicin were comparable to those of 15 or 20 mg, respectively, without coadministration.ConclusionsNo covariate was identified to require dose adjustment for cediranib. Cediranib exposure following 15 or 20 mg daily dose administration is adequate overall for inhibition of in vitro estimated vascular endothelial growth factor receptor‐1, ‐2 and ‐3 activities. An increase in cediranib dose may be needed for cediranib coadministered with strong uridine glucuronosyl transferase/P‐glycoprotein inducers such as rifampicin.
A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE‐3
Authors: Berger Rolf M. F. , Gehin Martine , Beghetti Maurice , Ivy Dunbar , Kusic‐Pajic Andjela , Cornelisse Peter , Grill Simon , Bonnet Damien ,   the FUTURE‐3 investigators
Published: February 2017

AimThe aim of the present study was to investigate whether increasing the bosentan dosing frequency from 2 mg kg–1 twice daily (b.i.d.) to 2 mg kg–1 three times daily (t.i.d.) in children with pulmonary arterial hypertension (PAH) (from ≥3 months to <12 years of age) would increase exposure.MethodsAn open‐label, prospective, randomized, multicentre, multiple‐dose, phase III study was conducted. Patients (n = 64) were randomized 1:1 to receive oral doses of bosentan of 2 mg kg–1 b.i.d. or t.i.d. The main pharmacokinetic endpoint was the daily exposure to bosentan over 24 h corrected to the 2 mg kg–1 dose (AUC0–24C). The maximum plasma concentration corrected to the 2 mg kg–1 dose (CmaxC), the time to reach the maximum plasma concentration (tmax) and safety endpoints were also assessed.ResultsThe geometric mean [95% confidence interval (CI)] for AUC0–24C was 8535 h.ng ml–1 (6936, 10 504) and 7275 h.ng ml–1 (5468, 9679) for 2 mg kg–1 b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.85 (0.61, 1.20)]. The geometric mean (95% CI) for CmaxC was 743 ng ml–1 (573, 963) and 528 ng ml–1 (386, 722) for 2 mg kg–1 b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.71 (0.48, 1.05)]. The median (range) for tmax was 3.0 h (0.0–7.5) and 3.0 h (1.0–8.0) for 2 mg kg–1 b.i.d. and t.i.d., respectively. The proportions of patients who experienced ≥1 adverse event were similar in the b.i.d. (66.7%) and t.i.d. (67.7%) groups.ConclusionsThere appeared to be no clinically relevant difference in exposure to bosentan, or in safety, when increasing the frequency of bosentan dosing from b.i.d. to t.i.d. Therefore, the present study provides no indication that the dosing recommendation should be changed, and 2 mg kg–1 b.i.d. remains the recommended dosing regimen for bosentan in paediatric PAH patients.
Patients with learning disabilities who lack capacity detained under the Mental Health Act in the UK: A case study
Authors: Sawhney Indermeet , Zia Asif , Gates Bob 
Published: February 2017

Accessible Summary

In England and Wales, some people with learning disabilities may have to be detained under the Mental Health Act 2007 as patients in a hospital for a period of assessment and or treatment if they are suffering from a mental disorder, and it is for the interests of their own health and safety, or to protect others.

Patients who are detained under Section 2 of the Mental Health Act 2007 can apply to the Mental Health Tribunal to decide whether they should be detained in a psychiatric hospital or be discharged.

The Mental Health Tribunal has the power to discharge these patients after a hearing.

Patients who lack capacity to apply to the tribunal are unable to have a tribunal hearing.

The European Court has ruled that this is unfair to these patients.

There needs to be a system in place to ensure that these patients get a tribunal hearing.

AbstractBackgroundIn the UK, the Mental Health Tribunal is a long‐established safeguard for patients detained under the Mental Health Act. This gives such patients an effective appeal mechanism to ensure legal protection of their liberty. This act contains sections that allow for civil detention in the case of mental disorder. The right to apply to the tribunal against such detention is underpinned by the right to liberty under Article 5 of the European Convention of Human Rights (ECHR). Some patients with learning disabilities may lack capacity and the ability to challenge their detention.MethodThis article presents a case study of a woman with Down's syndrome and severe learning disabilities. Whilst this woman was detained under the Mental Health Act, she could have applied for a review of her detention to the Mental Health Tribunal within 14 days. She did not do so because she lacked capacity to instruct solicitors. Subsequently, as a result of appeal, the case proceeded through English and European judicial review.ResultsThe European Court of Human Rights, in the case of MH v UK (2013), has ruled that the appeals procedure for patients without capacity detained under Section 2 of the Mental Health Act is not compatible with Article 5(4) of the European Convention of Human Rights. The European Court has ruled that special procedural safeguards are required to enable this cohort of patients to exercise their rights guaranteed by Article 5(4).ConclusionsResponsible clinicians [treating consultant psychiatrists] need to ensure that all patients detained under section 2 of the Mental Health Act have an assessment of their capacity to apply to the tribunal. There need to be systems in place to alert hospital managers when a patient lacks capacity to apply for a tribunal. Hospital managers should request the Secretary of State to apply for a tribunal in these instances. Knowledge of this ruling is relevant to informing the practice of other interdisciplinary healthcare professionals working with such patients.
Diagnostic red flags: steroid‐treated malignant CNS lymphoma mimicking autoimmune inflammatory demyelination
Authors: Barrantes‐Freer Alonso , Engel Aylin Sophie , Rodríguez‐Villagra Odir Antonio , Winkler Anne , Bergmann Markus , Mawrin Christian , Kuempfel Tania , Pellkofer Hannah , Metz Imke , Bleckmann Annalen , Hernández‐Durán Silvia , Schippling Sven , Rushing Elisabeth J. , Frank Stephan , Glatzel Markus , Matschke Jakob , Hartmann Christian , Reifenberger Guido , Müller Wolf , Schildhaus Hans‐Ulrich , Brück Wolfgang , Stadelmann Christine 
Published: February 2017

AbstractThe presence of inflammation and demyelination in a central nervous system (CNS) biopsy points towards a limited, yet heterogeneous group of pathologies, of which multiple sclerosis (MS) represents one of the principal considerations. Inflammatory demyelination has also been reported in patients with clinically suspected primary central nervous system lymphoma (PCNSL), especially when steroids had been administered prior to biopsy acquisition. The histopathological changes induced by corticosteroid treatment can range from mild reduction to complete disappearance of lymphoma cells. It has been proposed that in the absence of neoplastic B cells, these biopsies are indistinguishable from MS, yet despite the clinical relevance, no histological studies have specifically compared the two entities. In this work, we analyzed CNS biopsies from eight patients with inflammatory demyelination in whom PCNSL was later histologically confirmed, and compared them with nine well defined early active multiple sclerosis lesions. In the patients with steroid‐treated PCNSL (ST‐PCNSL) the interval between first and second biopsy ranged from 3 to 32 weeks; all of the patients had received corticosteroids before the first, but not the second biopsy. ST‐PCNSL patients were older than MS patients (mean age: ST‐PCNSL: 62 ± 4 years, MS: 30 ± 2 years), and histological analysis revealed numerous apoptoses, patchy and incomplete rather than confluent and complete demyelination and a fuzzy lesion edge. The loss of Luxol fast blue histochemistry was more profound than that of myelin proteins in immunohistochemistry, and T cell infiltration in ST‐PCNSL exceeded that in MS by around fivefold (P = 0.005). Our data indicate that in the presence of extensive inflammation and incomplete, inhomogeneous demyelination, the neuropathologist should refrain from primarily considering autoimmune inflammatory demyelination and, even in the absence of lymphoma cells, instigate close clinical follow‐up of the patient to detect recurrent lymphoma.
Calcium signalling through L‐type calcium channels: role in pathophysiology of spinal nociceptive transmission
Authors: Roca‐Lapirot Olivier , Radwani Houda , Aby Franck , Nagy Frédéric , Landry Marc , Fossat Pascal 
Published: February 2017

L‐type voltage‐gated calcium channels are ubiquitous channels in the CNS. L‐type calcium channels (LTCs) are mostly post‐synaptic channels regulating neuronal firing and gene expression. They play a role in important physio‐pathological processes such as learning and memory, Parkinson's disease, autism and, as recognized more recently, in the pathophysiology of pain processes. Classically, the fundamental role of these channels in cardiovascular functions has limited the use of classical molecules to treat LTC‐dependent disorders. However, when applied locally in the dorsal horn of the spinal cord, the three families of LTC pharmacological blockers – dihydropyridines (nifedipine), phenylalkylamines (verapamil) and benzothiazepines (diltiazem) – proved effective in altering short‐term sensitization to pain, inflammation‐induced hyperexcitability and neuropathy‐induced allodynia. Two subtypes of LTCs, Cav1.2 and Cav1.3, are expressed in the dorsal horn of the spinal cord, where Cav1.2 channels are localized mostly in the soma and proximal dendritic shafts, and Cav1.3 channels are more distally located in the somato‐dendritic compartment. Together with their different kinetics and pharmacological properties, this spatial distribution contributes to their separate roles in shaping short‐ and long‐term sensitization to pain. Cav1.3 channels sustain the expression of plateau potentials, an input/output amplification phenomenon that contributes to short‐term sensitization to pain such as prolonged after‐discharges, dynamic receptive fields and windup. The Cav1.2 channels support calcium influx that is crucial for the excitation‐transcription coupling underlying nerve injury‐induced dorsal horn hyperexcitability. These subtype‐specific cellular mechanisms may have different consequences in the development and/or the maintenance of pathological pain. Recent progress in developing more specific compounds for each subunit will offer new opportunities to modulate LTCs for the treatment of pathological pain with reduced side‐effects.Linked ArticlesThis article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc
Opioids and the immune system – friend or foe
Authors: Plein Lisanne Mirja , Rittner Heike L 
Published: February 2017

Systemically administered opioids are among the most powerful analgesics for treating severe pain. Several negative side effects (respiratory depression, addiction, nausea and confusion) and the risk of opioid‐induced hyperalgesia accompany opioid administration. One other side effect is the potential of opioids to suppress the immune response and thereby to increase the vulnerability to infections. The link between opioids and immunosuppression has been investigated both in vitro and in vivo as well as in patients. However, the results are inconsistent: Exogenous opioids such as morphine and fentanyl have been found to impair the function of macrophages, natural killer cells and T‐cells and to weaken the gut barrier in vitro and in animal studies. In epidemiological studies, high doses and the initiation of opioid therapy for non‐malignant pain have been correlated with a higher risk of infectious diseases such as pneumonia. However clear randomized controlled studies are missing. Furthermore, immune cells including neutrophils, macrophages and T‐cells have been shown to secrete endogenous opioid peptides, which then bind to peripheral opioid receptors to relieve inflammatory and neuropathic pain. In addition to cytokines, hormones and bacterial products, the release of opioid peptides is stimulated by the application of exogenous opioids. In summary, there is a reciprocal interaction between the immune system and endogenous as well as exogenous opioids. Further to the existing epidemiological studies, controlled clinical studies are needed in the future to elucidate the role of the opioid–immune system interaction in patients and to determine its clinical relevance.Linked ArticlesThis article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc
PGE2/EP4 receptor attenuated mucosal injury via β‐arrestin1/Src/EGFR‐mediated proliferation in portal hypertensive gastropathy
Authors: Tan Siwei , Chen Xiaoliang , Xu Minyi , Huang Xiaoli , Liu Huiling , Jiang Jie , Lu Yu , Peng Xiaojie , Wu Bin 
Published: February 2017

Background and PurposePortal hypertensive gastropathy (PHG) is a serious complication of liver cirrhosis and a potential cause of bleeding in patients with cirrhosis. Suppressed mucosal epithelial proliferation is a crucial pathological characteristic of PHG. Our studies demonstrated an important role for PGE2 and its EP4 receptor in the promotion of mucosal proliferation. However, whether β‐arrestin1 (β‐arr1), a well‐established mediator of GPCRs, is involved in the PGE2/EP4 receptor‐mediated mucosal proliferation complex in PHG remains unclear. The aim of the study was to investigate whether β‐arr1 participated in PGE2/EP4 receptor‐mediated mucosal proliferation by recruiting the Src/EGF receptor (EGFR) complex to activate Akt/proliferating cell nuclear antigen (PCNA) signalling in PHG.Experimental ApproachGastric mucosal proliferation was examined in patients with PHG and the PHG model of β‐arr1‐knockout (β‐arr1‐KO) and β‐arr1‐wild type (β‐arr1‐WT) mice. The induction of β‐arr1 and EP4 receptor expression and the Src/EGFR signalling elements was investigated, and the mechanisms underlying PGE2‐regulated gastric mucosal proliferation were analysed.Key ResultsPortal hypertension suppressed COX‐1 but not COX‐2, which was accompanied by a down‐regulation of PGE2 generation and EP4 receptor levels in the mucosa of patients with PHG. PGE2 administration markedly promoted mucosal proliferation in a mouse model of PHG. Targeted deletion of β‐arr1 abolished PGE2/EP4 receptor‐mediated gastric proliferation in PHG by repressing the Src/EGFR/Akt/PCNA signalling network.Conclusions and ImplicationsThese results indicate that β‐arr1 regulates PGE2/EP4 receptor‐mediated mucosal proliferation by promoting activation of the Src/EGFR/Akt/PCNA signalling pathway, and thus, this network is a potential therapeutic target for PHG.
Protective antibodies against Clostridium difficile are present in intravenous immunoglobulin and are retained in humans following its administration
Authors: Negm O H , MacKenzie B , Hamed M R , Ahmad O A J , Shone C C , Humphreys D P , Ravi Acharya K , Loscher C E , Marszalowska I , Lynch M , Wilcox M H , Monaghan T M 
Published: February 2017

Summary
The prevalence of serum antibodies against Clostridium difficile (CD) toxins A and B in healthy populations have prompted interest in evaluating the therapeutic activity of intravenous immunoglobulin (IVIg) in individuals experiencing severe or recurrent C. difficile infection (CDI). Despite some promising case reports, a definitive clinical role for IVIg in CDI remains unclear. Contradictory results may be attributed to a lack of consensus regarding optimal dose, timing of administration and patient selection as well as variability in specific antibody content between commercial preparations. The purpose of this study was to investigate retrospectively the efficacy of three commercial preparations of IVIg for treating severe or recurrent CDI. In subsequent mechanistic studies using protein microarray and toxin neutralization assays, all IVIg preparations were analysed for specific binding and neutralizing antibodies (NAb) to CD antigens in vitro and the presence of anti-toxin NAbs in vivo following IVIg infusion. A therapeutic response to IVIg was observed in 41% (10 of 17) of the CDI patients. Significant variability in multi-isotype specific antibodies to a 7-plex panel of CD antigens and toxin neutralization efficacies were observed between IVIg preparations and also in patient sera before and after IVIg administration. These results extend our current understanding of population immunity to CD and support the inclusion of surface layer proteins and binary toxin antigens in CD vaccines. Future strategies could enhance IVIg treatment response rates by using protein microarray to preselect donor plasma/serum with the highest levels of anti-CD antibodies and/or anti-toxin neutralizing capacities prior to fractionation.
A systematic review of known interventions for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia and a meta‐analysis of the vaptans
Authors: Bhandari Sunil , Peri Alessandro , Cranston Iain , McCool Rachael , Shaw Alison , Glanville Julie , Petrakova Larisa , O'Reilly Karl 
Published: February 2017

AbstractInternational and national guidelines on the treatment of chronic nonhypovolaemic hypotonic hyponatraemia differ; therefore, we have undertaken this systematic review and meta‐analysis to investigate the efficacy and safety of interventions for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia. Following registration of the review protocol with PROSPERO, systematic literature searches were conducted to identify randomized and quasi‐randomized controlled trials assessing any degree of fluid restriction or any drug treatment with the aim of increasing serum sodium concentration in patients with chronic nonhypovolaemic hypotonic hyponatraemia. Where appropriate, outcome data were synthesized in a meta‐analysis. A total of 45 716 bibliographic records were identified from the searches and 18 trials (assessing conivaptan, lixivaptan, tolvaptan and satavaptan) met the eligibility criteria. Results suggest that all four vasopressin receptor agonists (“vaptans”) significantly improve serum sodium concentration. Lixivaptan, satavaptan and tolvaptan were associated with greater rates of response versus placebo. There was no evidence of a difference between each of the vaptans compared with placebo for mortality, discontinuation and rates of hypernatraemia. No RCT evidence of treatments other than the vaptans for hyponatraemia such as oral urea, salt tablets, mannitol, loop diuretics demeclocycline or lithium was identified. Vaptans demonstrated superiority over placebo for outcomes relating to serum sodium correction. Few trials documented the potential benefit of vaptans on change in health‐related quality of life as a result of treatment. There was also a lack of high‐quality RCT evidence on the comparative efficacy of the vaptans and other treatment strategies for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia.
Peripheral blood leucocytes show differential expression of tumour progression‐related genes in colorectal cancer patients who have a postoperative intra‐abdominal infection: a prospective matched cohort study
Authors: Alonso S. , Mayol X. , Nonell L. , Salvans S. , Pascual M. , Pera M. ,   the Colorectal Cancer Research Group (Hospital del Mar Medical Research Institute)
Published: February 2017

AbstractAimAnastomotic leak is associated with higher rates of recurrence after surgery for colorectal cancer. However, the mechanisms responsible are unknown. We hypothesized that the infection‐induced inflammatory response may induce overexpression of tumour progression‐related genes in immune cells. The aim was to investigate the effect of postoperative intra‐abdominal infection on the gene expression patterns of peripheral blood leucocytes (PBL) after surgery for colorectal cancer.MethodProspective matched cohort study. Patients undergoing surgery for colorectal cancer were included. Patients who had anastomotic leak or intra‐abdominal abscess were included in the infection group (n = 23) and matched with patients without complications for the control group (n = 23). PBL were isolated from postoperative blood samples. Total RNA was extracted and hybridized to the Affymetrix Human Gene 1.0 ST microarray.ResultsPatients in the infection group displayed 162 upregulated genes and 146 downregulated genes with respect to the control group. Upregulated genes included examples coding for secreted cytokines involved in tumour growth and invasion (S100P, HGF, MMP8, MMP9, PDGFC, IL1R2). Infection also upregulated some proangiogenic genes (CEP55, TRPS1) and downregulated some inhibitors of angiogenesis (MME, ALOX15, CXCL10). Finally, some inhibitors (HP, ORM1, OLFM4, IRAK3) and activators (GNLY, PRF1, FGFBP2) of antitumour immunity were upregulated and downregulated, respectively, suggesting that the inflammatory environment caused by a postoperative infection favours immune evasion mechanisms of the tumour.ConclusionAnalysis of PBL shows differential expression of certain tumour progression‐related genes in colorectal cancer patients who have a postoperative intra‐abdominal infection, which in turn may promote the growth of residual cancer cells to become recurrent tumours.