Stability of monoclonal antibodies after simulated subcutaneous administration

Changes in the environment from the drug product to the human physiology might lead to physical and/or chemical modifications of the protein drug, such as in vivo aggregation and fragmentation. Although subcutaneous (SC) injection is a common route of administration for therapeutic proteins, knowledge on in vivo stability in the SC tissue is limited. In this study, we developed a physiologic in vitro model simulating the SC environment in patients. We assessed the stability of two monoclonal antibodies (mAbs) in four different protein-free fluids under physiologic conditions. We monitored protein stability over two weeks using a range of analytical methods, in analogy to testing purposes of a drug product. Both mAbs showed an increase of protein aggregates, fragments, and acidic species. mAb1 was consistently more stable in this in vitro model than mAb2, highlighting the importance of comparing the stability of different mAbs under physiologic conditions. Throughout the study, both mAbs were substantially less stable in bicarbonate buffers as compared to phosphate-buffered saline. In summary, our developed model was able to differentiate stability between molecules. Bicarbonate buffers were more suitable compared to phosphate-buffered saline in regards to simulating the in vivo conditions and evaluating protein liabilities.     

Treating Fragile X syndrome with the diuretic bumetanide: a case report

We report that daily administration of the diuretic NKCC1 chloride co‐transporter, bumetanide, reduces the severity of autism in a 10‐year‐old Fragile X boy using CARS, ADOS, ABC, RDEG and RRB before and after treatment. In keeping with extensive clinical use of this diuretic, the only side effect was a small hypokalaemia. A double‐blind clinical trial is warranted to test the efficacy of bumetanide in FRX. Conclusion: This single case report showed an improvement of the scores of each test used after 3 months of treatment. Double‐blind clinical trials are warranted to test the efficacy of bumetanide in FRX.     

Les médecins traitants devant le défi du dépistage et de la prise en charge de l’endométriose : résultats d’une enquête

ObjectiveTo evaluate the knowledge of general practitioners concerning the endometriosis diagnostic and care.Population and methodsSurvey enrolling 100 general practitioners of the 76th Seine Maritime French department (region of Upper Normandy) who usually perform gynaecological follow up, asked to answer an irreversible 36 item step-by-step questionnaire.ResultsAmong them, 44% perform more than one gynaecological consultation each week. They were 63% to feel ill at ease in the diagnosis and follow up of women presenting with endometriosis. One half of physicians could not cite three main symptoms of the disease out of dysmenorrhea, dyspareunia, chronic pelvic pain and infertility. Only 38% of general practitioners perform a clinical gynaecological examination when they suspect the endometriosis, and 28% of them recommended MRI to confirm the diagnosis. They are 24% to refer the patient without delay, but only 52% to the universitary hospital, which is the tertiary regional referral center, while 68% of them refer to a fellow practicing in a private facility. They were 64% to believe that therapeutic amenorrhea is on the bottom of the medical therapy. General practitioners were more likely to accurately answer the questionnaire when they attended gynaecological advanced courses during previous 5 years and when they followed up more than three patients previously managed for endometriosis.Discussion and conclusionGeneral practitioners’ knowledge about endometriosis is limited, with possible direct consequences on the delay of the diagnosis. The attendance of gynaecological advanced courses and the exchange of information between gynaecologic surgeons and general practitioners who follow up the patients appear to be two-way to improve the accuracy of the answers to the questionnaire.     

The Effectiveness of Lifestyle Interventions to Reduce Cardiovascular Risk in Patients with Severe Mental Disorders: Meta-Analysis of Intervention Studies

Patients with severe mental illness have higher prevalences of cardiovascular risk factors (CRF). The objective is to determine whether interventions to modify lifestyles in these patients reduce anthropometric and analytical parameters related to CRF in comparison to routine clinical practice. Systematic review of controlled clinical trials with lifestyle intervention in Medline, Cochrane Library, Embase, PsycINFO and CINALH. Change in body mass index, waist circumference, cholesterol, triglycerides and blood sugar. Meta-analyses were performed using random effects models to estimate the weighted mean difference. Heterogeneity was determined using i² statistical and subgroups analyses. 26 studies were selected. Lifestyle interventions decrease anthropometric and analytical parameters at 3 months follow up. At 6 and 12 months, the differences between the intervention and control groups were maintained, although with less precision. More studies with larger samples and long-term follow-up are needed.     

TGF-beta -- an excellent servant but a bad master

ABSTRACT: The transforming growth factor (TGF-beta) family of growth factors controls an immense number of cellular responses and figures prominently in development and homeostasis of most human tissues. Work over the past decades has revealed significant insight into the TGF-beta signal transduction network, such as activation of serine/threonine receptors through ligand binding, activation of SMAD proteins through phosphorylation, regulation of target genes expression in association with DNA-binding partners and regulation of SMAD activity and degradation. Disruption of the TGF-beta pathway has been implicated in many human diseases, including solid and hematopoietic tumors. As a potent inhibitor of cell proliferation, TGF-beta acts as a tumor suppressor; however in tumor cells, TGF-beta looses anti-proliferative response and become an oncogenic factor. This article reviews current understanding of TGF-beta signaling and different mechanisms that lead to its impairment in various solid tumors and hematological malignancies.     

Hématome infecté du cul-de-sac de Douglas : une complication spécifique de la chirurgie de l’endométriose profonde postérieure du fond vaginal

ObjectiveSurgical management of deep pelvic endometriosis may be responsible for various complications, such as infected pelvic haematic collection of the Douglas pouch. The aim of this study is to describe this unfavourable outcome and to estimate its frequency in the series of women managed by our team.Patients and methodsRetrospective study enrolling 163 women undergoing surgical removal of deep posterior endometriosis involving the vagina, from January 2008 to September 2011. We indentified women presenting with postoperative fever associated with computed tomographic findings suggesting an abscess of the Douglas pouch. Women characteristics, complication's management and outcomes were analysed in each case.ResultsTen patients presented an inflammatory syndrome associated to hypothetical Douglas pouch abscess, revealed 6 days postoperatively on average. All women reported increasing pelvic pain, fever higher than 38.5 °C, increased level of leucocytes and C reactive protein, and liquid collection of the Douglas pouch. Surgical management was carried out in nine women, revealing a pelvic collection of cloudy haematic liquid. Various bacteria were identified in six cases out of nine, suggesting liquid contamination through vagina opening. Postoperative outcome were immediately favourable.Discussion and conclusionInflammatory syndrome associated with infected haematic collection of the Douglas pouch is a postoperative complication of the surgical removal of deep endometriosis involving the posterior vagina. Surgical removal of the haematic collection allows rapid and definitive favourable outcomes.