Pharmacometric in silico studies used to facilitate a national dose standardisation process in neonatology - application to amikacin.

BACKGROUND AND AIMS: Pharmacometric in silico approaches are frequently applied to guide decisions concerning dosage regimes during the development of new medicines. We aimed to demonstrate how such pharmacometric modelling and simulation can provide a scientific rationale for optimising drug doses in the context of the Swiss national dose standardisation project in paediatrics using amikacin as a case study. METHODS: Amikacin neonatal dosage is stratified by post-menstrual age (PMA) and post-natal age (PNA) in Switzerland and many other countries. Clinical concerns have been raised for the subpopulation of neonates with a post-menstrual age of 30-35 weeks and a post-natal age of 0-14 days ("subpopulation of clinical concern"), as potentially oto-/nephrotoxic trough concentrations (Ctrough >5 mg/l) were observed with a once-daily dose of 15 mg/kg. We applied a two-compartmental population pharmacokinetic model (amikacin clearance depending on birth weight and post-natal age) to real-world demographic data from 1563 neonates receiving anti-infectives (median birth weight 2.3 kg, median post-natal age six days) and performed pharmacometric dose-exposure simulations to identify extended dosing intervals that would ensure non-toxic Ctrough (Ctrough <5 mg/l) dosages in most neonates. RESULTS: In the subpopulation of clinical concern, Ctrough <5 mg/l was predicted in 59% versus 79-99% of cases in all other subpopulations following the current recommendations. Elevated Ctrough values were associated with a post-natal age of less than seven days. Simulations showed that extending the dosing interval to ≥36 h in the subpopulation of clinical concern increased the frequency of a desirable Ctrough below 5 mg/l to >80%. CONCLUSION: Pharmacometric in silico studies using high-quality real-world demographic data can provide a scientific rationale for national paediatric dose optimisation. This may increase clinical acceptance of fine-tuned standardised dosing recommendations and support their implementation, including in vulnerable subpopulations.

Comment on Shaniv et al. Neonatal Drug Formularies-A Global Scope. Children 2023, 10, 848.

We read the article by Shaniv D. et al. entitled "Neonatal Drug Formularies-A Global Scope" [...].

Burden of Postinfectious Symptoms after Acute Dengue, Vietnam.

We assessed predominantly pediatric patients in Vietnam with dengue and other febrile illness 3 months after acute illness. Among dengue patients, 47% reported >1 postacute symptom. Most resolved by 3 months, but alopecia and vision problems often persisted. Our findings provide additional evidence on postacute dengue burden and confirm children are affected.

Biomedical applications of bisphosphonates.

Since their discovery over 100 years ago, bisphosphonates have been used industrially as corrosion inhibitors and complexing agents. With the discovery of their pharmacological activity in the late 1960s, implicating their high affinity for hydroxyapatite, bisphosphonates have been employed in the treatment of bone diseases and as targeting agents for colloids and drugs. They have notably been investigated for the treatment of Paget's disease, osteoporosis, bone metastases, malignancy-associated hypercalcemia, and pediatric bone diseases. Currently, they are first-line medications for several of these diseases and are taken by millions of patients worldwide, mostly postmenopausal women. A major problem associated with their use is their low oral bioavailability. Several delivery systems have been proposed to improve their absorption and to direct them to sites other than bone tissues. Beyond their important pharmacological role, the medical applications of bisphosphonates are numerous. In addition, their metal-chelating properties have been exploited to coat and stabilize implants, nanoparticulates, and contrast agents. In this contribution, we review the pharmacological and clinical uses of bisphosphonates and highlight their novel applications in the pharmaceutical and biomedical fields.

siRNA transfection with calcium phosphate nanoparticles stabilized with PEGylated chelators.

Despite the enormous therapeutic potential of siRNAs, their delivery is still problematic due to unfavorable biodistribution profiles and poor intracellular bioavailability. Calcium phosphate co-precipitate has been used for nearly 40 years for in vitro transfection due to its non-toxic nature and simplicity of preparation. However, rapid particle growth has largely prevented the translation of this method for in vivo purposes. It has recently been shown that bisphosphonate derivatives can physically stabilize calcium phosphate nanoparticles while still allowing for efficient cell transfection with plasmid DNA. Herein, two novel PEGylated chelating agents (PEG-alendronate and PEG-inositolpentakisphosphate) with enhanced stabilizing properties are introduced, and it is demonstrated that the bisphosphonate-stabilized nanoparticles can efficiently deliver siRNA in vitro. The nanoparticles are mainly taken up by clathrin-dependent endocytosis, and acidification of the endosomal compartment is required to release the entrapped siRNA into the cytosol. Furthermore, particle uptake enhances the inhibition of the mevalonate pathway by the bisphosphonate in macrophages.

Brain metabolite composition in relation to cognitive function and dystrophin mutations in boys with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a hereditary X-linked recessive disorder affecting the synthesis of dystrophin, a protein essential for structural stability in muscle. Dystrophin also occurs in the central nervous system, particularly in the neocortex, hippocampus and cerebellum. Quantitative metabolic analysis by localized (1) H MRS was performed in the cerebellum (12 patients and 15 controls) and a temporo-parietal location (eight patients and 15 controls) in patients with DMD and healthy controls to investigate possible metabolic differences. In addition, the site of individual mutations on the dystrophin gene was analyzed and neuropsychological cognitive functions were examined. Cognitive deficits in the patient group were found in line with earlier investigations, mainly concerning verbal short-term memory, visuo-spatial long-term memory and verbal fluency, but also the full-scale IQ. Causal mutations were identified in all patients with DMD. Quantitative MRS showed consistent choline deficits, in both cerebellar white matter and temporo-parietal cortex, as well as small, but significant, metabolic abnormalities for glutamate and total N-acetyl compounds in the temporo-parietal region. Compartment water analysis did not reveal any abnormalities. In healthy subjects, choline levels were age related in the cerebellum. The choline deficit contrasts with earlier findings in DMD, where a surplus of choline was postulated for the cerebellum. In patients, total N-acetyl compounds in the temporo-parietal region were related to verbal IQ and verbal short-term memory. However, choline, the putative main metabolic abnormality, was not found to be associated with cognitive deficits. Furthermore, in contrast with the cognitive performance, the metabolic brain composition did not depend significantly on whether or not gene mutations concerned the expression of the dystrophin isoform Dp140, leading to the conclusion that the effect of the missing Dp140 isoform on cognitive performance is not mediated through the observed metabolite composition, or is caused by local effects beyond the resolution accessible to MRS investigations.

Neuropsychological impairments and the impact of dystrophin mutations on general cognitive functioning of patients with Duchenne muscular dystrophy.

Mutations in the dystrophin gene have long been recognised as a cause of mental retardation. However, for reasons that are unclear, some boys with dystrophin mutations do not show general cognitive deficits. To investigate the relationship between dystrophin mutations and cognition, the general intellectual abilities of a group of 25 boys with genetically confirmed Duchenne muscular dystrophy were evaluated. Furthermore, a subgroup underwent additional detailed neuropsychological assessment. The results showed a mean full scale intelligence quotient (IQ) of 88 (standard deviation 24). Patients performed very poorly on various neuropsychological tests, including arithmetics, digit span tests and verbal fluency. No simple relationship between dystrophin mutations and cognitive functioning could be detected. However, our analysis revealed that patients who lack the dystrophin isoform Dp140 have significantly greater cognitive problems.

Gene delivery with bisphosphonate-stabilized calcium phosphate nanoparticles.

Nucleic acid drugs are promising new therapeutics, due to their possible applications in a wide variety of diseases and their strong targeting potential and associated lower off-target effects compared to conventional pharmaceuticals. However, their poor intracellular bioavailability and rapid degradation hinder their development as drugs. Therefore, efficient delivery is a major challenge. Various systems have been developed to overcome this problem. The entrapment of genetic material into nanoparticles constitutes a promising approach to increase the in vitro and in vivo transfection activity. Calcium phosphate-DNA co-precipitates have been used for gene delivery for more than 35 years and have the advantage of being nontoxic, easy to produce, and having the ability to complex nucleic acids leading to efficient transfection. Conventional synthetic methods yield particles that are only stable for a short period of time. Herein is proposed a versatile, surfactant-free method to stabilize calcium phosphate-DNA nanoparticles based on the use of poly(ethylene glycol)-functionalized bisphosphonate. The strength of the interaction between the bisphosphonate and the calcium phosphate enabled the formation of stable, but bioresorbable particles of around 200 nm, which exhibited physical stability over several days. Additionally, the nanoparticles revealed good and sustained ability to transfect cells while displaying low toxicity.

Aminated linear and star-shape poly(glycerol methacrylate)s: synthesis and self-assembling properties.

Over the past 10 years, polyglycerols and their structurally related analogs have received considerable attention in the biomedical field. Poly(glycidyl methacrylate) (PGMA) is a versatile polymer because its pendant epoxide groups can be opened with different functional groups to generate poly(glycerol methacrylate)s (PGOHMA) derivatives. In this work, linear and star-shape PGMAs were synthesized by atom transfer radical polymerization and then functionalized with four different amines by ring-opening addition. This resulted in the formation of polyglycerol-like polymers having both hydroxyl and amine moieties and different water-solubility. The water-insoluble polymers could form pH-sensitive nanoassemblies, while the soluble derivatives efficiently complexed a short strand polynucleotide. The aminated polyglycerol interacted more avidly with the oligonucleotide than the control poly(ethyleneimine), and high transfection efficacy could be obtained with the linear derivative. Such polymers could find practical applications for the delivery of drugs and nucleic acids.

The effect of hyaluronic acid on silk fibroin conformation.

The molecular conformation of silk fibroin drastically changes the physical properties of this biomaterial. Herein, we investigated the capacity of hyaluronic acid to modify the conformational transition of silk fibroin into its crystalline beta-sheet form. For this aim, matrices composed of these two polymers were prepared and studied. Instrumental analysis confirmed the presence of two intermixed phases: one of pure hyaluronic acid, and another consisting of a molecular dispersion of silk fibroin and hyaluronic acid. Studies performed with silk fibroin/hyaluronic acid matrices indicated that hyaluronic acid induces molecular transition of silk fibroin into a beta-sheet structure when incubated in water, and that it synergistically enhances beta-sheet formation together with methanol treatment. The enhancement of beta-sheet content observed for silk fibroin/hyaluronic acid matrices correlated with improved mechanical properties: blended matrices had higher compressive moduli and higher breaking strengths than pure silk fibroin matrices. These new properties, together with the capacity of silk fibroin/hyaluronic acid to form partially insoluble matrices without any treatment with organic solvents, make this blend composition an interesting material for biomedical applications.