Loss-of-function (LoF) mutations in GRIN2B result in neurologic abnormalities due to N-methyl-D-aspartate receptor (NMDAR) dysfunction. Affected persons present with various symptoms, including intellectual developmental disability (IDD), hypotonia, communication deficits, motor impairment, complex behavior, seizures, sleep disorders and gastrointestinal disturbance. Recently, in vitro experiments showed that D-serine mitigates function to GluN2B (mutation)-containing NMDARs. 11 previous case reports are published on (experimental) L-serine treatment of patients between 1.5 and 12 years old with GRIN2B missense or null mutations, some of whom showed notable improvement in motor and cognitive performance, communication, behavior and abnormalities on electro encephalography (EEG). Our objective is to further evaluate the effectiveness of L-serine for GRIN2B-related neurodevelopmental disorder (GRIN2B-NDD), using an n-of-1 trial design, increasing the level of evidence. These n-of-1 trials, consisting of 2 cycles of 6 months, will be performed to evaluate the effect of L-serine compared to placebo in 4 patients with a GRIN2B LoF mutation. The aggregation of multiple n-of-1 trials will provide an estimate of the average treatment effects. The primary outcome is the Perceive-Recall-Plan-Perform of Task Analysis, assessing developmental skills. Secondary outcomes include Goal Attainment Scaling, seizure log books, EEGs, sleep log books, the irritability subscale of the Aberrant Behavior Checklist, the Bristol Stool Scale and the Pediatric Quality of Life Inventory. This study employs an innovative methodological approach to evaluate the effectiveness of L-serine for patients with a GRIN2B LoF mutation. The results will establish a foundation for implementing L-serine as a disease-modifying treatment in GRIN2B-NDD.

Objectives Several studies have investigated the effectiveness of high-dose ambroxol in treating patients with Gaucher disease type 3. Since there are no registered high-dose ambroxol preparations available, information on the development of this preparation can be important to improve access. The pharmacy and clinical pharmacology department of Amsterdam University Medical Center has developed a simple 75 mg ambroxol hydrochloride (HCl) capsule formulation for this purpose. The aim of this study was to investigate the stability of 75 mg ambroxol capsules. Methods Three batches (n=1000) of 75 mg ambroxol HCl capsules were produced and stored in climate chambers for 6 months under accelerated (40±2°C and 75% relative humidity (RH)±5% RH) and long-term (25±2°C and 60% RH±5% RH) conditions. At 0, 3 and 6 months, appearance, identity, related substances, assay, uniformity of dosage units (content uniformity (CU)), dissolution and microbiology were evaluated. The specifications and acceptance criteria were derived from the European Pharmacopoeia and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Results All parameters met the predefined specifications from t=0 to t=6 months for both the accelerated and long-term stability studies. There were no visible changes in appearance of the capsule content, no degradation products above 0.05%, and no decrease in ambroxol content. Furthermore, the capsules met the criteria for CU with an acceptance value ≤15.0. The dissolution was rapid, with ≥80% of ambroxol released from the capsules within 30 min, and no microbiological growth was observed. Conclusions The 75 mg ambroxol HCl capsules are stable for at least 6 months at room temperature. This paper provides guidance to pharmacies for compounding of high-dose ambroxol HCl capsules to ensure the availability of ambroxol for patients in need.

Background/Objectives: Ambroxol hydrochloride (AMB) is a promising chaperone for treating neurological manifestations in Gaucher disease type 3 (GD3). The Amsterdam University Medical Center planned to conduct an n-of-1 clinical trial using high-dose AMB (25 mg/kg/day). As an adequate commercial AMB formulation is unavailable for this high target dosage, we aimed to develop high-dose AMB capsules and assess the formulated capsule’s quality. Methods: AMB API was sourced and tested according to the requirements of the European Pharmacopoeia. Capsule formulations of 75 mg and 200 mg AMB were developed. Drug product specifications were set following international guidelines (ICH Q6A) and the European Pharmacopoeia. Analytical methods were developed and validated, and three validation batches of each capsule strength were produced and analyzed. Results: The contents and the Acceptance Values (AVs) of the initial AMB batches (both strengths) varied between 89.1% to 92.7% (specification: 90% to 110%) and 12.4 to 17.6 (specification ≤ 15.0), respectively, indicating non-uniform AMB distribution. Consequently, the production of 200 mg capsules was discontinued, and modifications were made to the 75 mg capsule formulation, followed by the production of three optimized 75 mg validation batches. These batches met the specified criteria, with an AMB content and AV values ranging from 93.9% to 96.5% and 12.4 to 14.9, respectively. Furthermore, rapid dissolution profiles were observed (>80% dissolution within 15 min). No degradation products or microbiological impurities were detected after production. Conclusions: The optimized formulation of 75 mg AMB capsules formulated within the hospital pharmacy setting resulted in qualitative and uniform capsules which can be used in clinical trials.

Background In renally impaired patients, guidelines recommend a 25–50% dalteparin dose reduction with anti-Xa monitoring to reduce bleeding risk. However, pharmacokinetic considerations and results from previous studies dispute the need for dose reduction. Therefore, in our hospitals an alternative dose reduction to 75% or a 100% is used. This study aimed to assess anti-Xa levels to confirm or refute the need for dose reduction and to investigate the association between dose, anti-Xa levels and bleeding events. Methods This multicentre retrospective observational study included patients aged ≥18 years during a 3-year period with an estimated glomerular filtration rate of <60 mL/min/1.73 m² or on renal replacement therapy, receiving ≥7500 IU dalteparin daily. Only correctly sampled plasma anti-Xa levels were included and stratified into intensive care unit (ICU) and non-ICU patients. Stratum-adjusted odds ratios were determined to compare the likelihood of achieving adequate anti-Xa levels between a 75% and 100% dose. Bleeding events were classified into minor and major events. Results A total of 167 anti-Xa levels were included, with 148 anti-Xa levels belonging to patients receiving a 75% or 100% dose. Anti-Xa levels were highly scattered: 55% below and 6% above the anti-Xa ranges. In all patients the probability that anti-Xa levels fell within the range was higher for patients receiving a 100% dose than for those receiving a 75% dose (OR 2.66, 95% CI 1.24 to 5.70, p=0.012). Eight bleeding events occurred, including one minor event in a patient with an anti-Xa level above range and five events in patients on renal replacement therapy with anti-Xa levels within or below range. Conclusions In renally impaired patients a 100% dalteparin dose increases the likelihood of achieving adequate anti-Xa levels compared with a 75% dose, without leading to over-exposure. The occurrence of bleeding events did not differ between the 75% and 100% dose groups and appeared unrelated to anti-Xa levels. Pre-emptive dose reduction of dalteparin in renally impaired patients is likely to be unnecessary.