Pharmaceutical compounding of orphan active ingredients in Belgium : how community and hospital pharmacists can address the needs of patients with rare diseases

Background: Pharmaceutical compounding of orphan active ingredients can offer cost-effective treatment to patients when no other drug product is available for a rare disease or during periods of drug product shortages. Additionally, it allows customized therapy for patients with rare diseases. However, standardized compounding formulas and procedures, and monographs are required to ensure the patients' safety. Results: Standardized formulas and compounding procedures were developed for seven orphan active ingredients (L-arginine, sodium benzoate, sodium phenylbutyrate, L-carnitine, chenodesoxycholic acid, primaquine phosphate, pyridoxal phosphate) and one non-orphan molecule (sodium perchlorate) regularly compounded by hospital pharmacists for extemporaneous use. The stability of these formulations was evaluated over 3months at refrigerated (5 degrees C) and standard storage conditions (25 degrees C/60%RH) using HPLC-based assays and a suitable shelf life was assigned to the formulations. Additionally, suitable analytical methods for quality control of formulations of pyridoxal phosphate and sodium perchlorate were developed as monographs for these components were not available in the European Pharmacopeia or United States Pharmacopeia. Conclusions: Availability of compounding formulas and protocols, as well as stability information, for orphan active ingredients can improve patients' access to treatment for rare diseases. Such data were collected for seven orphan active ingredients to treat patients with rare diseases when no other treatment is available. More efforts are needed to develop standardized formulas and compounding procedures for additional orphan active ingredients whose clinical efficacy is well-known but which are not available as products with a marketing authorization. Additionally, a legal framework at EU level is required to enable the full potential of pharmaceutical compounding for orphan active ingredients

Cancer and renal insufficiency results of the BIRMA study

Background: Half of anticancer drugs are predominantly excreted in urine. Dosage adjustment in renal insufficiency (RI) is, therefore, a crucial issue. Moreover, patients with abnormal renal function are at high risk for drug-induced nephrotoxicity. The Belgian Renal Insufficiency and Anticancer Medications (BIRMA) study investigated the prevalence of RI in cancer patients, and the profile/dosing of anticancer drugs prescribed. Methods:Primary end point: to estimate the prevalence of abnormal glomerular filtration rate (GFR; estimated with the abbreviated Modification of Diet in Renal Disease formula) and RI in cancer patient. Secondary end point: to describe the profile of anticancer drugs prescribed (dose reduction/nephrotoxicity). Data were collected for patients presenting at one of the seven Belgian BIRMA centres in March 2006. Results: A total of 1218 patients were included. The prevalence of elevated SCR (1.2 mg per 100 ml) was 14.9%, but 64.0% had a GFR90 ml min 1 per 1.73 m 2. In all, 78.6% of treated patients (n1087) were receiving at least one drug needing dosage adjustment and 78.1% received at least one nephrotoxic drug. In all, 56.5% of RI patients receiving chemotherapy requiring dose reduction in case of RI did not receive dose adjustment. Conclusions: The RI is highly frequent in cancer patients. In all, 80% of the patients receive potentially nephrotoxic drugs and/or for which dosage must be adjusted in RI. Oncologists should check the appropriate dose of chemotherapeutic drugs in relation to renal function before prescribing. © 2010 Cancer Research UK.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

The Saliva and Muscle Study (SaMu): Rationale and Protocol for Associations between Salivary Microbiome and Accelerated Muscle Ageing

Background The gut microbiome is recognized as a pivotal factor in the pathophysiology of sarcopenia—a condition marked by the accelerated loss of muscle strength, mass and function with ageing. Despite this well-known gut-muscle axis, the potential links between other microbial ecosystems and sarcopenia remain largely unexplored. The oral microbiome has been linked to various age-related health conditions such as rheumatoid arthritis and colorectal cancer. However, its potential association with sarcopenia is unknown. The Saliva and Muscle (SaMu) study seeks to address this knowledge gap. Methods The SaMu study comprises three sequential phases. In phase 1, a cross-sectional analysis will be conducted on a cohort of 200 individuals aged 70 years or older to examine the relationship between salivary microbiome and sarcopenia status. Participants will be recruited in the three main places of living: general community, assisted living facilities and nursing homes. The salivary microbiome composition will be evaluated utilizing shotgun metagenomics sequencing, while sarcopenia status will be determined through muscle mass (determined by whole-body bioelectrical impedance analysis and calf circumference), muscle strength (grip strength and the 5-times-sit-to-stand test) and physical performance (usual walking speed). In addition to investigating the microbiome composition, the study aims to elucidate microbiome functions by exploring potential omic associations with sarcopenia. To achieve this, salivary proteomics, metabolomics and quorum sensing peptidomics will be performed. Covariates that will be measured include clinical variables (sociodemographic factors, health status, health-related behaviours, oral health and quality of life) as well as blood variables (immune profiling, hormones, kidney and liver function, electrolytes and haematocrit). In phase 2, an in-depth mechanistic analysis will be performed on an envisaged subcohort of 50 participants. This analysis will explore pathways in muscle tissue using histology, genomics and transcriptomics, focusing on (maximal) 25 healthy older adults and (maximal) 25 with severe sarcopenia. Phase 3 involves a two-year clinical follow-up of the initial participants from the cross-sectional analysis, along with a resampling of blood and saliva. Additionally, secondary outcomes like falls, hospitalization and mortality will be examined. Discussion Using a salivary multi-omics approach, SaMu primarily aims to clarify the associations between the oral microbiome and sarcopenia. SaMu is expected to contribute to the discovery of predictive biomarkers of sarcopenia as well as to the identification of potential novel targets to prevent/tackle sarcopenia. This study-protocol is submitted for registration at the ISRCTN registry.publishedVersio

Partner notification for sexually transmitted infections in developing countries: a systematic review

<p>Abstract</p> <p>Background</p> <p>The feasibility and acceptability of partner notification (PN) for sexually transmitted infections (STIs) in developing countries was assessed through a comprehensive literature review, to help identify future intervention needs.</p> <p>Methods</p> <p>The Medline, Embase, and Google Scholar databases were searched to identify studies published between January 1995 and December 2007 on STI PN in developing countries. A systematic review of the research extracted information on: (1) willingness of index patients to notify partners; (2) the proportion of partners notified or referred; (3) client-reported barriers in notifying partners; (4) infrastructure barriers in notifying partners; and (5) PN approaches that were evaluated in developing countries.</p> <p>Results</p> <p>Out of 609 screened articles, 39 met our criteria. PN outcome varied widely and was implemented more often for spousal partners than for casual or commercial partners. Reported barriers included sociocultural factors such as stigma, fear of abuse for having an STI, and infrastructural factors related to the limited number of STD clinics, and trained providers and reliable diagnostic methods. Client-oriented counselling was found to be effective in improving partner referral outcomes.</p> <p>Conclusions</p> <p>STD clinics can improve PN with client-oriented counselling, which should help clients to overcome perceived barriers. The authors speculate that well-designed PN interventions to evaluate the impact on STI prevalence and incidence along with cost-effectiveness components will motivate policy makers in developing countries to allocate more resources towards STI management.</p

Estrogen mediated-activation of miR-191/425 cluster modulates tumorigenicity of breast cancer cells depending on estrogen receptor status.

MicroRNAs (miRNAs), single-stranded non-coding RNAs, influence myriad biological processes that can contribute to cancer. Although tumor-suppressive and oncogenic functions have been characterized for some miRNAs, the majority of microRNAs have not been investigated for their ability to promote and modulate tumorigenesis. Here, we established that the miR-191/425 cluster is transcriptionally dependent on the host gene, DALRD3, and that the hormone 17β-estradiol (estrogen or E2) controls expression of both miR-191/425 and DALRD3. MiR-191/425 locus characterization revealed that the recruitment of estrogen receptor α (ERα) to the regulatory region of the miR-191/425-DALRD3 unit resulted in the accumulation of miR-191 and miR-425 and subsequent decrease in DALRD3 expression levels. We demonstrated that miR-191 protects ERα positive breast cancer cells from hormone starvation-induced apoptosis through the suppression of tumor-suppressor EGR1. Furthermore, enforced expression of the miR-191/425 cluster in aggressive breast cancer cells altered global gene expression profiles and enabled us to identify important tumor promoting genes, including SATB1, CCND2, and FSCN1, as targets of miR-191 and miR-425. Finally, in vitro and in vivo experiments demonstrated that miR-191 and miR-425 reduced proliferation, impaired tumorigenesis and metastasis, and increased expression of epithelial markers in aggressive breast cancer cells. Our data provide compelling evidence for the transcriptional regulation of the miR-191/425 cluster and for its context-specific biological determinants in breast cancers. Importantly, we demonstrated that the miR-191/425 cluster, by reducing the expression of an extensive network of genes, has a fundamental impact on cancer initiation and progression of breast cancer cells

Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We present the final prespecified overall survival (OS) analysis of the open-label, phase III CLEAR study in treatment-naïve patients with advanced renal cell carcinoma (aRCC). With an additional follow-up of 23 months from the primary analysis, we report results from the lenvatinib plus pembrolizumab versus sunitinib comparison of CLEAR. Treatment-naïve patients with aRCC were randomly assigned to receive lenvatinib (20 mg orally once daily in 21-day cycles) plus pembrolizumab (200 mg intravenously once every 3 weeks) or sunitinib (50 mg orally once daily [4 weeks on/2 weeks off]). At this data cutoff date (July 31, 2022), the OS hazard ratio (HR) was 0.79 (95% CI, 0.63 to 0.99). The median OS (95% CI) was 53.7 months (95% CI, 48.7 to not estimable [NE]) with lenvatinib plus pembrolizumab versus 54.3 months (95% CI, 40.9 to NE) with sunitinib; 36-month OS rates (95% CI) were 66.4% (95% CI, 61.1 to 71.2) and 60.2% (95% CI, 54.6 to 65.2), respectively. The median progression-free survival (95% CI) was 23.9 months (95% CI, 20.8 to 27.7) with lenvatinib plus pembrolizumab and 9.2 months (95% CI, 6.0 to 11.0) with sunitinib (HR, 0.47 [95% CI, 0.38 to 0.57]). Objective response rate also favored the combination over sunitinib (71.3% v 36.7%; relative risk 1.94 [95% CI, 1.67 to 2.26]). Treatment-emergent adverse events occurred in >90% of patients who received either treatment. In conclusion, lenvatinib plus pembrolizumab achieved consistent, durable benefit with a manageable safety profile in treatment-naïve patients with aRCC

Wireless Neuromodulation for Chronic Back Pain: Delivery of High-Frequency Dorsal Root Ganglion Stimulation by a Minimally Invasive Technique

Objective. To evaluate the analgesic effect of a dorsal root ganglion (DRG) stimulation technology utilizing high-frequency pulse rates to treat intractable chronic back and leg pain. Methods. This case study presents the outcomes, with a novel, wireless, minimally invasive miniature neurostimulator system in a case of chronic back pain. The subject was implanted bilaterally with a Freedom 4A quadripolar electrode array at the L2 dorsal root ganglion. Stimulation was applied using 10 kHz pulse rate and 30 μs pulse width. A VAS pain-rating scale, Oswestry Disability Index (ODI), EQ-5D-5L Quality of Life Questionnaire 5 dimensions, and Patients’ Global Impression of Change (PGIC) scale were evaluated at 12 weeks and 6 months post implantation. Results. VAS pain scores for back pain reduced from 91 to 31 mms and 80 to 35 mms for leg pain. Additionally, while stimulation remained paresthesia-free, there were a marked decrease in pain medications and an increase in quality of life. Also, an increase in functionality from crippled to moderate was reported. There were no adverse reactions related to the procedure or device. Conclusion. The minimally invasive, wireless approach to deliver high-frequency, paresthesia-free DRG stimulation for treatment of chronic back and leg pain associated with FBSS was effective and encouraging.</jats:p

P-297 Regulation and functions of PGRMC1 in the human endometrium and in endometriosis

Abstract Study question What is the role of PGRMC1 in the human endometrium (especially in tissue remodeling) and its potential contribution to the development of endometrial diseases? Summary answer In primary endometrial stromal cell culture, PGRMC1 downregulation modifies expression of genes implicated in extracellular matrix remodeling as well as in cell migration and invasion. What is known already It has been suggested that Progesterone Receptor Membrane Component-1 (PGRMC1) is involved in gynecological pathologies. In particular, Pgrmc1 conditional KO in the mouse female reproductive tract induced subfertility and spontaneous development of endometrial cysts. Moreover, siRNA-mediated downregulation of PGRMC1 expression influenced TNF-α-induced activity of matrix metalloproteinase-9 (MMP-9) in cytotrophoblast cells, suggesting that PGRMC1 is a regulator of MMPs. In addition to playing a major role in the physiological breakdown of the human endometrium at menstruation, MMPs are strongly suspected to favor the pathogenesis of endometriosis lesions. Study design, size, duration Not applicable Participants/materials, setting, methods We compared transcriptomes obtained by RNA-sequencing from distinct primary endometrial stromal cell (ESC) cultures transfected with one of two specific siRNA targeting PGRMC1 mRNA or with a control siRNA. Expression changes for selected genes were confirmed by RT-qPCR. Migration and invasion capacities of the cells were also studied using Transwell assay. Finally, immunocytochemistry was performed on these primary cultures to localize the presence of PGRMC1 as well as the canonical progesterone receptor (PR). Main results and the role of chance RNA-sequencing data converged to show that the reduction of PGRMC1 expression by the specific siRNA significantly increased (up to 3-fold) the expression of several genes involved in the extracellular matrix (ECM) remodeling, as well as in the processes of migration and invasion. These changes were reproduced by RT-qPCR on other distinct primary endometrial stromal cultures isolated from other patients. In parallel, Transwell assays showed no significant changes in the migration and invasion capacities of the primary endometrial stromal cell cultures previously invalidated for PGRMC1 by transfection of the cells with a specific siRNA by comparison with a control siRNA. However, immunocytochemistry studies on these primary endometrial stromal cells showed that progesterone receptor (PR) labeling was restricted to cell nuclei, suggesting a constitutively activated PR in these cultures. Limitations, reasons for caution The absence of changes in migration and invasion properties of primary ESC cultures observed by Transwell assay could be due to the fact that the progesterone receptor seems to be constitutively activated in these cultures potentially causing a repressive effect on the migration and invasion capacity of the cells. Wider implications of the findings The modification of expression of genes implicated in ECM remodeling, and cell migration and invasion after PGRMC1 downregulation in primary ESC cultures is interesting in the context of endometriosis in which reduction of PGRMC1 expression could improve the migration and invasion capacities of lesions to implant into the host tissue. Trial registration number Not applicable </jats:sec