Evaluation of parenteral diluent contamination by caprolactam.

Purpose: A leachable cyclic amide (caprolactam) can be found in normal saline (NS) and 5% dextrose in water (D5W) plastic bags widely used in clinical practice if they contain polyamide in a multilayer sheeting. This contamination and the parameters that could influence its content have never been studied in a public work such as a scientific publication.

Methods: Two independent laboratories validated a caprolactam dosing method and studied contamination levels in several containers.

DprE1 and Ddn as promising therapeutic targets in the development of novel anti-tuberculosis nitroaromatic drugs.

Tuberculosis remains the second deadliest infectious disease in humans and a public health threat due to the emergence of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. Therefore, it is urgent to identify new anti-tuberculosis treatments and novel therapeutic targets to prevent the emergence of resistance. In recent years, the study of anti-tuberculosis properties of nitroaromatic compounds has led to the identification of two novel biological targets, the deazaflavin (F)-dependent nitroreductase Ddn and the decaprenylphosphoryl-β-d-ribose 2'-epimerase DprE1.

Target fishing reveals PfPYK-1 and PfRab6 as potential targets of an antiplasmodial 4-anilino-2-trichloromethylquinazoline hit compound.

We present investigations about the mechanism of action of a previously reported 4-anilino-2-trichloromethylquinazoline antiplasmodial hit-compound (Hit A), which did not share a common mechanism of action with established commercial antimalarials and presented a stage-specific effect on the erythrocytic cycle of P. falciparum at 8 < t < 16 h. The target of Hit A was searched by immobilising the molecule on a solid support via a linker and performing affinity chromatography on a plasmodial lysate.

Novel thienopyrimidones targeting hepatic and erythrocytic stages of Plasmodium parasites with increased microsomal stability.

Based on the structure of a previously identified hit, Gamhepathiopine 1, which showed promising antiplasmodial activity, but poor microsomal stability, several strategies were investigated to improve the metabolic stability of the compounds. This included the introduction of fluorine or deuterium atoms, as well as carbocyclic groups. Among the new compounds, the 2-aminocyclobutyl derivative 5g demonstrated enhanced microsomal stability compared to compound 1, while retaining antiplasmodial activity against erythrocytic and hepatic stages of Plasmodium, without significant cytotoxicity against primary hepatocytes.

Low-dose erythromycin in pediatrics: Formulation and stability of 20 mg hard gelatin capsules.

Objective: Erythromycin is a macrolide antibiotic that is also prescribed off-label in premature neonates as a prokinetic agent. There is no oral formulation with dosage and/or excipients adapted for these high-risk patients.

Methods: Clinical studies of erythromycin as a prokinetic agent were reviewed.

New antiplasmodial 4-amino-thieno[3,2-d]pyrimidines with improved intestinal permeability and microsomal stability.

The increasing number of Plasmodium falciparum strains resistant to current treatments justifies the urgent need to discover new compounds active on several stages of the parasite development. Based on the structure of Gamhepathiopine, a 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one previously identified for its dual activity against the sexual and asexual stages of P. falciparum, 25 new 4-amino-substituted analogues were synthesized and evaluated on the erythrocytic and hepatic stages of Plasmodium.

Stability Study of Parenteral N-Acetylcysteine, and Chemical Inhibition of Its Dimerization.

Parenteral N-acetylcysteine has a wide variety of clinical applications, but its use can be limited by a poor chemical stability. We managed to control parenteral N-acetylcysteine stability, and to study the influence of additives on the decrease of N-acetylcysteine degradation. First, an HPLC-UV dosing method of N-acetylcysteine and its main degradation product, a dimer, was validated and the stability without additive was studied.

Nitro-Containing Self-Immolative Systems for Biological Applications.

Since its introduction in 1981, the chemistry of self-immolative systems has received increasing attention in different application areas, such as analytical chemistry, medicinal chemistry, and materials science. This strategy is based on a stimulation that triggers a cascade of disassembling reactions leading to the release of smaller molecules. The particular reactivity of the nitro group, due to its powerful electron-withdrawing nature, has been exploited in the field of self-immolative chemistry.

Pre-formulation and Stability Study of 20-mcg Clonidine Hydrochloride Pediatric Capsules.

Objective: Clonidine hydrochloride is an antihypertensive, centrally acting α2 adrenergic agonist with various pediatric indications. For pediatric patients, 20-mcg clonidine hydrochloride capsules can be compounded from commercial tablets or from a pre-compounded titrated powder. These methods should be compared to ensure the best quality for the high-risk patients, and a beyond-use date should be established.

Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-]pyridine Antileishmanial Pharmacophore.

An antileishmanial structure−activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-a]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of Leishmania donovani and L. infantum, the best compounds were tested against the intracellular amastigote stage of L.

4-Substituted Thieno[3,2-]pyrimidines as Dual-Stage Antiplasmodial Derivatives.

Malaria remains one of the major health problems worldwide. The increasing resistance of to approved antimalarial drugs requires the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Based on the structure of Gamhepathiopine, a 2--butylaminothieno[3,2-]pyrimidin-4(3)-one hit, active on the sexual and asexual stages of the parasite and thanked for the introduction of various substituents at position 4 of the thienopyrimidine core by nucleophilic aromatic substitution and pallado-catalyzed coupling reactions, a series of 4-substituted thieno[3,2-]pyrimidines were identified as displaying in vitro activities against both the erythrocytic stage of and the hepatic stage of Among the 28 compounds evaluated, the chloro analogue of Gamhepathiopine showed good activity against the erythrocytic stage of moderate toxicity on HepG2, and better activity against hepatic parasites, compared to Gamhepathiopine.

Synthesis of antiplasmodial 2-aminothieno[3,2-d]pyrimidin-4(3H)-one analogues using the scaffold hopping strategy.

Gamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series.

Pd-catalyzed C-C and C-N cross-coupling reactions in 2-aminothieno[3,2-]pyrimidin-4(3)-one series for antiplasmodial pharmacomodulation.

In 2015, we identified gamhepathiopine (M1), a 2--butylaminothieno[3,2-]pyrimidin-4(3)-one antiplasmodial hit targeting all development stages of the human malarial parasite . However, this hit compound suffers from sensitivity to hepatic oxidative metabolism. Herein, we describe the synthesis of 33 new compounds in the 2-aminothieno[3,2-]pyrimidin-4(3)-one series modulated at position 6 of this scaffold.

Stability Studies of Fludrocortisone Acetate Capsules and Fludrocortisone Acetate Titrated Powders (Powder Triturates).

Fludrocortisone acetate is a drug used to treat adrenal insufficiencies which can be prescribed to hospitalized or ambulatory pediatric patients at dosages not commercially available. For these patients, 10-µg fludrocortisone capsules are currently compounded from a pre-compounded titrated powder (powder triturate). Fludrocortisone stability studies were carried out to ensure a valid beyond-use date.

Synthesis and Anti- Biological Evaluation of Novel 2-Nitropyrrole Derivatives.

Human American trypanosomiasis, called Chagas disease, caused by protozoan infection, represents a major public health problem, with about 7000 annual deaths in Latin America. As part of the search for new and safe anti- derivatives involving nitroheterocycles, we report herein the synthesis of ten 1-substituted 2-nitropyrrole compounds and their biological evaluation. After an optimization phase, a convergent synthesis methodology was used to obtain these new final compounds in two steps from the 2-nitropyrrole starting product.

Paediatric capsule compounding in hospital practices: by weight or by volume?

Objective: Capsule compounding is common for paediatric patients. In Europe, pharmacists often use a volume-based method whereas, in the USA, the weight-based method prevails. These two methods should be compared in order to help hospital pharmacists to make their choice.

A New Thienopyrimidinone Chemotype Shows Multistage Activity against Plasmodium falciparum, Including Artemisinin-Resistant Parasites.

Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. For decades, the research for novel antimalarials focused on the high-throughput screening of molecules that only targeted the asexual blood stages. In a search for new effective compounds presenting a triple action against erythrocytic and liver stages in addition to the ability to block the transmission of the disease the mosquito vector, 2-amino-thienopyrimidinone derivatives were synthesized and tested for their antimalarial activity.

2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of .

The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism of action. Based on the previous antiplasmodial hit-molecules identified in the 2-trichloromethylquinoxaline series, we report herein a structure-activity relationship (SAR) study at position two of the quinoxaline ring by synthesizing 20 new compounds.

Antiplasmodial 2-thiophenoxy-3-trichloromethyl quinoxalines target the apicoplast of Plasmodium falciparum.

The identification of a plant-like Achille's Heel relict, i.e. the apicoplast, that is essential for Plasmodium spp.

Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments.

Recent progress in reducing malaria cases and ensuing deaths is threatened by factors like mutations that induce resistance to artemisinin derivatives. Multiple drugs are currently in clinical trials for malaria treatment, including some with novel mechanisms of action. One of these, MMV390048, is a plasmodial kinase inhibitor.

Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines.

From three previously identified antiplasmodial hit compounds (-) and inactive series (), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives bearing either a carboxamido- or an alkoxy-group, to identify antiplasmodial compounds and to enrich the knowledge about the 2-trichloromethylquinazoline antiplasmodial pharmacophore. All compounds were evaluated in vitro for their cytotoxicity towards the HepG2 cell line and their activity against the multiresistant K1 strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC K1 ≤ 2 µM and SI ≥ 20) were identified among 4-carboxamido derivatives (, , and ) and two among 4-alkoxy derivatives ( and ).

Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties.

To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series.

8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi.

An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs.

Stability Studies of Antipyocyanic Beta-Lactam Antibiotics Used in Continuous Infusion.

In intensive care, beta-lactams can be reconstituted in 50 mL polypropylene syringes with NaCl 0.9 % and administered for 8 to 12 h at various concentrations with motor-operated syringe pumps. The feasibility and/or the stability of these antibiotic therapies are often poorly known by clinicians.