Dispensing Oral Temozolomide in Children: Precision and Stability of a Novel and Ready to Use Liquid Formulation in Comparison with Capsule Derived Mixtures.

Temozolomide (TMZ) is part of the therapeutic armamentarium used in managing pediatric cancers; however, available oral forms (capsules) are not adapted for use in children. Our aim was to assess the dose accuracy and stability of TMZ using capsule contents mixed with food compared with a novel, ready-to-use liquid formulation specifically developed for children (Ped-TMZ, brand name KIZFIZO). Dose accuracy and TMZ stability testing were performed with TMZ capsule contents (90 mg) mixed with food vehicles (apple juice, apple sauce, cream, milk, and mashed potatoes) and compared to an equivalent dose of Ped-TMZ.

A Multicenter Randomized Bioequivalence Study of a Novel Ready-to-Use Temozolomide Oral Suspension vs. Temozolomide Capsules.

Background: Temozolomide (TMZ) oral suspension (Ped-TMZ, KIZFIZO) is being developed for the treatment of relapsed or refractory neuroblastoma, a rare cancer affecting infants and young children. The study assessed the safety and the bioequivalence of this novel pediatric formulation with existing TMZ oral capsules.

Methods: In vitro dissolution profiles and the bioequivalence were evaluated following the European Medicines Agency "Guidelines on the investigation of Bioequivalence".

Development of a Hospital Compounded, Taste-Masked, Temozolomide Oral Suspension and 5-Year Real-Life Experience in Treating Paediatric Patients.

The development of oral pediatric forms by pharmaceutical companies is still insufficient. In fact, many drugs used in paediatric oncology, such as temozolomide, are not labeled and adapted for paediatric use. Temozolomide (TMZ) is an alkylating agent used as the standard of care for many adult and pediatric brain tumours, such as neuroblastoma, glioblastoma and medulloblastoma.

Proposition of a Minimal Effective Dose of Vigabatrin for the Treatment of Infantile Spasms Using Pediatric and Adult Pharmacokinetic Data.

Vigabatrin is an antiepileptic drug indicated as monotherapy in infantile spasms. However, the pharmacokinetic profile of this compound in infants and young children is still poorly understood, as is the minimal effective dose, critical information given the risk of exposure-related retinal toxicity with vigabatrin. A reasonable approach to determining this minimal dose would be to identify the lowest dose providing a low risk of exposure overlap with the 36-mg/kg dose, which is the highest dose associated with an increased risk for treatment failure, based on randomized dose-ranging data.

Determination of the R(-) and S(+)-enantiomers of vigabatrin in human plasma by ultra-high-performance liquid chromatography and tandem mass-spectrometry.

An analytical method was developed for the quantification in plasma of the R and S enantiomers of vigabatrin (VGB), a drug used for the treatment of some refractory pediatric epileptic syndromes. After adding 50μL of the internal standard, which consisted of a 15mg/L solution of deuterated racemic VGB, and 100μL of water to 100μL of plasma samples, a protein precipitation was performed by adding 600μL of methanol. The supernatant was evaporated to dryness under a stream of nitrogen and the dry residue was reconstituted with 500μL of water.

A convergent approach to (-)-callystatin A based on local symmetry.

The key is symmetry! A convergent synthetic approach of the highly cytotoxic natural product (-)-callystatin A was developed assembling three fragments through Julia-Kocienski olefination and Stille cross-coupling. The new strategy relies on a pivotal local symmetry of the target molecule. In this preliminary study, particular attention was devoted to facilitate the catalytic enantiocontrol of strategic stereogenic centers present in each of the fragments (see scheme).

Halothane-anesthetized rabbit: a new experimental model to test the effects of besipirdine and duloxetine on lower urinary tract function.

Introduction: The effects of besipirdine and its main metabolite, HP-748, as well as duloxetine and tomoxetine in the lower urinary tract (LUT) were studied using in vitro and in vivo techniques.

Materials And Methods: For in vivo studies, besipirdine or duloxetine effects on cystometric parameters and striated sphincter electromyographic (SS-EMG) activity were investigated. On the isolated urethra, norepinephrine (NE) concentration-response curves (CRC) were performed in the presence of besipirdine, duloxetine or tomoxetine.

Total synthesis of (+)-crocacin C using hidden symmetry.

A highly convergent and protecting-group-free synthesis of (+)-crocacin C, featuring an enzymatic enantioselective desymmetrization of a meso-diol, a base-induced ring opening of a THP ring, and a one-pot hydrostannylation/Stille coupling as the key steps, is reported. The natural product was obtained in 11 steps and 22.3% overall yield starting from readily available oxabicycle 1.

Enantioselective enzymatic desymmetrization of highly functionalized meso tetrahydropyranyl diols.

The enantioselective enzymatic desymmetrization of several highly substituted meso-tetrahydropyranyl diols is described. This transformation leads to valuable building blocks containing up to five stereogenic centers, which are revealed in a single step with both high yields and excellent enantiomeric excesses. Moreover, it was shown that this kind of building blocks could provide an easy access to both enantiomers of highly functionalized stereotetrads.

New spiro-piperidines as 5-HT2B receptor antagonists.

A functional screening highlighted a series of spiro-piperidines as 5-HT2B receptor antagonists. Preliminary structure-activity relationship has been explored driving to potent antagonists (IC50 = 1 nM) and indicating directions for further explorations.

Discovery of protein-protein binding disruptors using multi-component condensations small molecules.

A series of small molecule compounds interfering with the binding process of VEGF and NRP1 has been identified and further optimized. Full synthetic details as well as SAR are reported which demonstrate that expeditious MCC-based syntheses may lead to valuable molecules addressing challenging targets such as protein-protein interactions. Preliminary functional assay data confirm that these compounds may be further developed toward drug candidates.

5-Aminooxazole as an internal traceless activator of C-terminal carboxylic acid: rapid access to diversely functionalized cyclodepsipeptides.

A conceptually novel macrolactonization protocol has been developed. It is a domino process involving a sequence of: 1) protonation of 5-aminooxazole leading to the electrophilic iminium salt; 2) trapping of the iminium species by the neighboring C-terminal carboxylic acid leading to a putative spirolactone; and 3) intramolecular nucleophilic addition of the tethered alcohol to the spirolactone followed by fragmentation. The strategically incorporated 5-aminooxazole serves as an internal traceless activator of the neighboring C-terminal carboxylic acid, since it became an integral part of the peptide backbone after cyclization.

Ammonium chloride-promoted four-component synthesis of pyrrolo[3,4-b]pyridin-5-one.

A novel multicomponent synthesis of 5-aminooxazole starting from simple and readily available inputs is described. Thus, simply heating a methanol solution of an aldehyde 3, an amine 4, and an alpha-isocyanoacetamide 5 provided the 5-aminooxazole (1) in good to excellent yield. The reaction of 1 with alpha,beta-unsaturated acyl chloride 13 lead to the formation of pyrrolo[3,4-b]pyridin-5-one (2) in a single operation.

A New Heterocyclic Multicomponent Reaction For the Combinatorial Synthesis of Fused 3-Aminoimidazoles.

When general and reliable, multicomponent reactions are among the most powerful tools in modern drug discovery. The principle of chemical ligation of reactive partners (see reaction scheme) has been employed to find a new, highly efficient synthesis of fused 3-aminoimidazoles.