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Patients with rare diseases are often confronted with the fact that effective medicines are unavailable or simply not being developed. This situation jeopardizes the health of a large population of vulnerable patients with rare diseases. Pharmacy compounded formulations can provide a safe alternative when authorized treatments are unavailable or unsuitable. Practical guidelines on how to develop and implement pharmacy compounded formulations for patients with rare diseases are limited. The aim of this article is to provide guidance for when and how to apply pharmacy compounded formulations for patients with rare diseases. This is illustrated with two challenging examples: the development and implementation of pharmacy compounding of 1) chenodeoxycholic acid (CDCA) capsules for patients with cerebrotendinous xanthomatosis (CTX) and 2) cholic acid (CA) capsules for patients with rare bile acid synthesis defects (BASD). All critical steps of the development of CDCA and CA capsules are explained and summarized in a practical guideline.

Background Bile acid synthesis defects (BASDs) can be severely disabling involving the liver and nervous system, potentially due to elevated levels of toxic C 27 -bile acid intermediates. Cholic acid (CA) supplementation is hypothesized to decrease bile acid production, stimulate bile secretion and -flow, and slowing down disease progression. This systematic review assesses the clinical and biochemical effectiveness, and safety of CA in BASDs patients. Methods A systematic review of MEDLINE, Embase and clinical trial registries (ClinicalTrials.gov, ICTRP registry) using controlled MeSH- and Emtree terms. Results From 526 articles 70 publications were deemed eligible for inclusion based on title and abstract. 14 publications were included after full-text assessment comprising case reports and -series with 1–35 patients (162 patients in total) receiving 1 week to 16,5 years of CA treatment. All presented data on effectiveness, 8 studies also presented data on safety. The included population concerned patients with Zellweger spectrum disorders ( n  = 73), 3β-Hydroxy-Δ5-C 27 -steroid oxidoreductase deficiency ( n  = 62), cerebrotendinous xanthomatosis ( n  = 22), Δ4-3-oxosteroid 5β-reductase deficiency ( n  = 13), and α-methylacyl-CoA racemase deficiency ( n  = 3). Main outcomes concerned liver disease (12 studies), general physical examinations, biochemical outcomes, and safety (9 studies), and fat-soluble vitamin absorption (7 studies). The overall risk of bias score was considered to be critical (1 study), serious (4 studies), and moderate (9 studies). Major issues were missing data (10 studies), generalized data (8 studies), and no wash-out between treatments (4 studies). Conclusion More controlled studies are required as the available data is insufficient to draw definite conclusions on the effectiveness and safety of CA treatment in BASD patients. Establishing an independent international disease registry could better utilize existing real-world data.

Bile acid synthesis defects (BASDs) comprise a group of rare diseases that can be severely disabling. Bile acid supplementation with 5 to 15 mg/kg cholic acid (CA) has been hypothesized to decrease endogenous bile acid production, stimulate bile secretion, and improve bile flow and micellar solubilization, thereby improving the biochemical profile and potentially slowing down disease progression. Currently, CA treatment is unavailable in the Netherlands, and CA capsules were compounded by the Amsterdam UMC Pharmacy from CA raw material. This study aims to determine the pharmaceutical quality and stability of the pharmacy compounded CA capsules. Pharmaceutical quality tests were performed on 25 mg and 250 mg CA capsules according to general monographs of the European Pharmacopoeia 10th ed. For the stability study, the capsules were stored under long-term conditions (25 °C ± 2 °C/60% ± 5% RH) and accelerated conditions (40 °C ± 2 °C/75% ± 5% RH). Samples were analyzed at 0, 3, 6, 9 and 12 months. The findings demonstrate that the pharmacy compounded CA capsules within a range of 25–250 mg that complied with the European regulations in regard to product quality and safety. The pharmacy compounded CA capsules are suitable for use in patients with BASD, as clinically indicated. With its simple formulation, pharmacies are provided a guidance on product validation and stability testing when commercial CA capsules are unavailable.

Allografts are the most common bone grafts for repairing osseous defects. However, their use is associated with an increased risk for infections, donor disease transmission and osteointegration deficiency. Resolvin D1 (RvD1) is an endogenous lipid with a scientifically proven pivotal role in inflammation resolution and osteoclastogenesis inhibition. Yet, its biological relevance as a potential bone regenerative drug has been scarcely studied. Here, we aim to investigate the RvD1 effect on allograft osteointegration in the alveolar bone regeneration (ABR) murine model. ABR model consisted of osseous defects that were generated by the extraction of the maxillary first molar in C57BL/6 mice. The sockets were filled with allograft and analyzed RNA sequencing. Then they were locally injected with either RvD1 or saline single or repeated administrations. The mice were sacrificed 2W after the procedure, and regenerated sites were analyzed using CT and histology. First, MC3T3-E1 preosteoblasts were plated with IL-17 pro-inflammatory medium, and RANKL/OPG ratio was measured. Secondly, the MC3T3-E1 were cultured w/o RvD1, for 3W. Osteoblasts' markers were evaluated in different days, using qRT-PCR and Alizarin Red staining for calcified matrix. , neither allograft alone nor single RvD1 administration promote bone regeneration in comparison to the control of spontaneous healing and even triggered an elevation in NR1D1 and IL1RL1 expression, markers associated with inflammation and inhibition of bone cell differentiation. However, repeated RvD1 treatment increased bone content by 135.92% ± 45.98% compared to its specific control, repeated sham, and by 39.12% ± 26.3% when compared to the spontaneous healing control group (n=7/group). Histologically, repeated RvD1 reduced the number of TRAP-positive cells, and enhanced allograft osteointegration with new bone formation. , RvD1 rescued OPG expression and decreased RANKL/OPG ratio in IL-17 pro-inflammatory conditions. Furthermore, RvD1 increased the expression of RUNX2, OSX, BSP and OC/BGLAP2 and the mineralized extracellular matrix during MC3T3-E1 osteoblasts differentiation. Repeated administrations of RvD1 promote bone regeneration a dual mechanism: directly, enhancement of osteoblasts' differentiation and indirectly, through reduction of osteoclastogenesis and RANKL/OPG ratio. This suggests that RvD1 may be a potential therapeutic bioagent for osseous regeneration following allograft implantation.