[Overview of hospital city repay for paediatric preparations initiated within the Marseille Public University Hospital system]. / État des lieux des modalités de poursuite en ville des préparations pharmaceutiques à usage pédiatrique initiées au sein de l'Assistance publique des Hôpitaux de Marseille.

OBJECTIVES: Hospital internal-use pharmacies are required to make pharmaceutical preparations in order to obtain a medication in a dosage and/or Galenic form (FG) suitable for pediatric use. The aim of this study is to assess the procedures for continuing pharmaceutical preparations initiated within the Assistance Publique des Hôpitaux de Marseille in an outpatient setting. METHODS: Hospital discharge prescriptions and/or consultation prescriptions involving paediatric magistral preparations and issued by our Hospital Centre were collected from two pharmacies with significant preparation activity at national level. An analysis of regulatory compliance was carried out, as well as a comparison of the formulation of preparations made in the outpatient setting and in the hospital. RESULTS: Au total, 45 prescriptions were collected, representing 52 preparation lines. The regulatory analysis revealed that all the prescriptions contained at least one non-conformity, 60.8% of which related to drug treatments. The prepared FG differed in the outpatient setting compared to the hospital in 46.2% of cases, and in 56% of cases, the vehicle and concentration of the active ingredient used differed when the FG was a liquid oral form. CONCLUSIONS: The lack of clear and complete hospital prescriptions makes it difficult to carry out treatment initiated in hospital in the outpatient setting. The multiplicity of information systems between hospitals and outpatient settings are obstacles to the interoperability needed to coordinate patient treatment, particularly in paediatrics. The quality of discharge prescriptions needs to be improved to optimise the patient care pathway.

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. Capsules of 20 milligrams of erythromycin were compounded with microcrystalline cellulose. Erythromycin capsules were analyzed using the chromatographic method described in the United States Pharmacopoeia which was found to be stability-indicating. The stability of 20 mg erythromycin capsules stored protected from light at room temperature was studied for one year. RESULTS: 20 mg erythromycin capsules have a beyond use date not lower than one year. CONCLUSION: 20 milligrams erythromycin capsules can be compounded in batches of 300 unities in hospital pharmacy with a beyond-use-date of one year at ambient temperature protected from light.

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. Then, the influence of several additives (ascorbic acid, sodium edetate, tocopherol and zinc) and of temperature on N-acetylcysteine dimerization was evaluated. Finally, the influence of zinc gluconate at different concentrations (administrable to patients) was investigated. Zinc gluconate at 62.5 µg·mL-1 allows the stabilization of 25 mg·mL-1 N-acetylcysteine solution for at least 8 days when stored at 5 ± 3 °C.

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. METHODS: We evaluated the difference between the volume-based method and the weight-based method with 10 mg spironolactone capsules. Six independent batches were made with each technique and their conformity was evaluated with a high-performance liquid chromatography assay. RESULTS: The weight-based method showed superiority over the volume-based method for the following parameters: spironolactone content homogeneity, total weight content homogeneity, batch reproducibility and batch conformity. No differences were seen in spironolactone content between the two methods, but an overall trend towards underweighing the excipient was found with the volume-based method. CONCLUSIONS: Capsule compounding with the weight-based method increases the quality of the resulting formulation. The weight-based method requires knowledge of the galenic parameters of the active pharmaceutical ingredient and excipients, but should be preferred to the volume-based method.

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. METHODS: Eight experimental batches were made from commercial tablets and 8 were made from microcrystalline cellulose (MCC)-based titrated powders. Quality controls were performed to determine the best compounding protocol. Stability study was conducted on capsules compounded with the best method. RESULTS: Of 8 batches manufactured from commercial tablets, 7 were compliant for both clonidine mean content and content uniformity, whereas 7 of 8 batches manufactured from titrated powders were not. A clonidine loss during compounding was evidenced by surface sampling analyses. Clonidine hydrochloride 20-mcg capsules' mean content remained higher than 90% of initial content for 1 year when stored at 25°C with 60% relative humidity and protected from light. CONCLUSIONS: Commercial tablets should be preferred to 1% clonidine hydrochloride and MCC titrated powder made from the active pharmaceutical ingredient. Twenty-microgram clonidine hydrochloride capsules made from commercial tablets are stable for 1 year when stored under managed ambient storage condition.

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. First, a stability-indicating fludrocortisone acetate dosing method was validated. Then fludrocortisone acetate 10-µg capsules and 1% fludrocortisone acetate titrated powders (powder triturates) were realized. Finally, stability studies were performed. The fludrocortisone acetate titrated powders (powder triturates) were stable for one year at controlled ambient temperature and protected from light, whereas 10-µg fludrocortisone acetate capsules were stable for six months. One year after, even if the fludrocortisone content remained conformed, an increase in product degradation was noted. Our work allowed us to determine a six-month beyond-use date for fludrocortisone acetate titrated powder (powder triturate) with the three most commonly used excipients for capsule compounding. We also confirmed the sixmonth theoretical stability for capsules.

Beyond-Use Dates Assignment for Pharmaceutical Preparations: Example of Low-Dose Amiodarone Capsules.

Background: Beyond-use dates (BUDs) in compounding practice are assigned from stability studies. The United States Pharmacopoeia (USP 42 NF 37) suggested to assign a 6 months BUD for dry oral forms. A new pediatric formula of amiodarone capsules was implemented in our hospital, with 3 dosages (5 mg, 20 mg, and 50 mg). Objective: BUD of these new formulas had to be determined by stability study. Methods: The method for the determination of amiodarone content was validated to be stability indicating, and a stability study was performed. Different excipients commonly used for capsule compounding were compared. Results: We found that, with microcrystalline cellulose as excipient, 50 mg amiodarone capsules were stable for 1 year, whereas 5 mg and 20 mg capsules were not. This difference was studied, and lactose or mannitol were found to be better excipients for 5 mg amiodarone capsules, despite their potential side effects. A potential drug-excipient interaction between microcrystalline cellulose and amiodarone hydrochloride is described. Conclusion: Amiodarone hydrochloride/microcrystalline cellulose capsules have a BUD of 1 month for 5 mg capsules, 6 months for 20 mg, and 1 year for 50 mg.

Impact of insulin adsorption in various containers during hyperkalaemia treatment.

BACKGROUND: Insulin-glucose therapy in hyperkalaemia treatment has a narrow therapeutic index for a safe and efficient use. We assess the variability of the effective delivered insulin under conditions used in the setting of hyperkalaemia treatment. METHODS: A range of simulated insulin infusions was studied using different containers (bag or syringes) according to the different hyperkalaemia treatment procedures of our institution. Insulin concentration was assayed using a chromatographic method on an automatic high-performance liquid chromatography. We calculated the effective delivered insulin and compared the time average of percentage delivered insulin (TAdi) between all the procedures. RESULTS: The TAdi was significantly decreased to 63.3% of the expected insulin delivery in the polyurethane (PE) bag compared with allover container. The procedure duration and the insulin concentration influenced the variability of the insulin delivery in the PE and glass bag. The polyvinyl chloride bag had the highest TAdi at 93.8%, without significant variation during the time. TAdi reaches ∼90% of the expected insulin with all the syringe procedure without variation according to the solute used to dilute insulin. CONCLUSIONS: Clinically significant variations in intravenous insulin delivery occur in the setting of hyperkalaemia treatment according to the container. The use of propylene syringe limits the insulin delivery variation. In the future, clinical studies on hyperkalaemia treatment by insulin-glucose therapy should detail the procedure precisely.

Ricin poisoning: A review on contamination source, diagnosis, treatment, prevention and reporting of ricin poisoning.

INTRODUCTION: Ricin, a toxic glycoprotein derived from the castor bean plant, is one of the most potent poisons known in the world. Ricin intoxication is a fatal and uncommon medical condition and recently its use as a potential bioterrorism agent has also been reported. This study aims to identify the main characteristics of diagnosed ricin poisoning cases worldwide in order to raise awareness of this toxin among the population and clinicians. METHODS: A collection of human case studies of ricin intoxication in the world was produced. The databases Pubmed, Sciencedirect and Google Scholar were used to extract articles from January 1980 to June 2020. RESULTS: Fifty ricin-intoxicated patients worldwide described in the literature have been identified. Most cases were found in Asia (19 cases), Europe (12 cases) and America (15 cases). Intoxication was mostly accidental (37 cases). Intoxication by castor bean is characterized by acute gastroenteritis-like disease as primary manifestations leading to severe fluid and electrolyte imbalance. The mechanism of death was peripheral vascular collapse and progressing multiple organ failure occurring 10h-72h after intoxication. The questioning of patients and family made it possible to retrieve an history of castor seeds or castor oil ingestion Patients received symptomatic treatment consisting mostly to rehydration with intravenous fluids and digestive decontamination performed with activated charcoal and/or gastric lavage within one day after the ingestion, to reduce gastrointestinal absorption of ricin. This decontamination treatment administered early has been very effective. Only six deaths were observed. DISCUSSION: Currently, no antidote, vaccine, or other specific effective treatment is available for ricin poisoning or prevention. Prompt treatment with supportive care was necessary to limit morbidity and mortality. To date, patient education is essential to prevent this accidental poisoning. CONCLUSION: Clinicians and health care professionals should have a high level of suspicion when faced with an outbreak of serious respiratory or gastrointestinal illness.

A Survey of Synthetic Routes and Antitumor Activities for Benzo[g]quinoxaline-5,10-diones.

Anthracycline antibiotics play an important role in cancer chemotherapy. The need to improve their therapeutic index has stimulated an ongoing search for anthracycline analogs with enhanced properties. This review aims to summarize the common synthetic approaches to benzo[g]quinoxaline-5,10-diones and their uses in heterocyclic chemistry. Because of the valuable biological activities of the 1,4-diazaanthraquinone compounds, a summary of the most promising heterocyclic quinones is provided together with their antitumor properties.

Antibody-Drug Conjugates in Thoracic Malignancies: Clinical Trials Reveal Both Promise and Challenges.

Thoracic malignancies are the main cause of cancer-related deaths worldwide. The need to develop new therapies is therefore urgent. The recognition of new potential therapeutic targets in thoracic malignancies has prompted the development of a number of antibody-drug conjugates. This new class of potent anticancer agents is supposed to more specifically and directly target the tumor while limiting toxicity for healthy tissues by delivering a toxic payload to tumor cells that are recognized by the presence of specific cell surface antigens. Progress in the development of antibody-drug conjugates over the last decade has been significant, with several promising advances. Unfortunately, many failures have also been encountered, often because of unexpectedly severe toxicities that contradicted the assumed mechanism of action, and major challenges remain. Various techniques to reduce the toxicities associated with antibody-drug conjugates are being studied, and the panorama of antibody-drug conjugates in clinical stages continues to increase and evolve. Current efforts in the conjugation and linker chemistries could result in the successful construction of clinically effective compounds. The future clinical development of antibody-drug conjugates could benefit from the identification of such payloads that can provide more safe and effective derivatives. Highly potent compounds with reasonable aqueous solubility, non-immunogenic profile, and stability in storage and the bloodstream should be important aspects of research into cytotoxic payloads.

A review of melioidosis cases imported into Europe.

Melioidosis is a tropical bacterial infection, rarely encountered, and poorly known by clinicians. In non-endemic areas, a misdiagnosis can lead to a fatal outcome. This study aims to identify the main characteristics of imported and diagnosed melioidosis cases in Europe to increase clinician's awareness of this diagnosis. A literature review of imported and diagnosed human melioidosis cases in Europe was performed. PubMed and Web of Science search engines were used for retrieving articles from 2000 to November 2018. Seventy-seven cases of imported melioidosis into Europe described in the literature were identified. More than half of the cases were acquired in Thailand (53%) by men (73%). Patients were usually exposed to Burkholderia pseudomallei during a holiday stay (58%) of less than 1 month (23%) and were hospitalized during the month following their return to Europe (58%). Among travelers, melioidosis is less often associated with risk factor (16%), diabetes being the most frequently comorbidity related (19%). The clinical presentation was multifaceted, pneumonia being the most common symptom (52%), followed by cardiovascular form (45%) and skin and soft tissues damages (35%). The diagnosis was obtained by culture (92%), often supplemented by morphological, biochemical, and molecular identification (23%). Misdiagnoses were common (21%). Over half of the patients received a complete and adapted treatment (56%). Mortality is lower for returning traveler (6%). Imported melioidosis cases into Europe have their own characteristics. This possibility should be considered in patients with pneumonia, fever, and/or abscess returning from endemic areas even years after.

Chickenpox: An update.

Despite its benign characteristics, chickenpox is a childhood disease responsible for complications and deaths, particularly in the high-risk population. VariZIG®, not commercialized in France, is a good alternative for seronegative individuals exposed to the virus and not eligible for vaccination. The efficacy of routine vaccination has been demonstrated with a decrease in chickenpox incidence and with the development of herd immunity. Over time, the protective antibody titer of vaccinated people decreases and can be maintained by two doses of the vaccine. A tetravalent measles-mumps-rubella-chickenpox vaccine, used in the United States, has a good tolerability in spite of the occurrence of fever and febrile seizures. Routine vaccination would contribute to make savings in France, by reducing direct and indirect costs of chickenpox.

Management of adult Clostridium difficile digestive contaminations: a literature review.

Clostridium difficile infections (CDI) dramatically increased during the last decade and cause a major public health problem. Current treatments are limited by the high disease recurrence rate, severity of clinical forms, disruption of the gut microbiota, and colonization by vancomycin-resistant enterococci (VRE). In this review, we resumed current treatment options from official recommendation to promising alternatives available in the management of adult CDI, with regard to severity and recurring or non-recurring character of the infection. Vancomycin remains the first-line antibiotic in the management of mild to severe CDI. The use of metronidazole is discussed following the latest US recommendations that replaced it by fidaxomicin as first-line treatment of an initial episode of non-severe CDI. Fidaxomicin, the most recent antibiotic approved for CDI in adults, has several advantages compared to vancomycin and metronidazole, but its efficacy seems limited in cases of multiple recurrences. Innovative therapies such as fecal microbiota transplantation (FMT) and antitoxin antibodies were developed to limit the occurrence of recurrence of CDI. Research is therefore very active, and new antibiotics are being studied as surotomycin, cadazolid, and rinidazole.

Dihydropyrimidinone/1,2,3-triazole hybrid molecules: Synthesis and anti-varicella-zoster virus (VZV) evaluation.

By combining the structural features of dihydropyrimidinone and 1,2,3-triazole heterocycles, novel hybrid compounds were synthesized using a simple and convenient method. A series of novel mono and bis 1,2,3-triazole was synthesized via copper-catalyzed Huisgen azide-alkyne cycloadditions (CuAAC) under microwave irradiation. The newly synthesized compounds were evaluated for their antiviral activity against varicella-zoster virus (VZV). Compounds 6aa, 7ab, 6ba and 6da showed valuable antiviral activities, with EC50 values ranging from 3.6 to 11.3 µM against TK+ and TK- VZV and without measurable cell-growth inhibition.

Original antileishmanial hits: Variations around amidoximes.

In continuation to our previous findings on amidoximes' antiparasitic activities, a new series of 23 original derivatives was designed and obtained by convergent synthesis. First, new terminal alkenes were synthesized by cross-coupling reaction. Then, cyclization was performed between terminal alkenes and ß-ketosulfones using manganese(III) acetate reactivity. Twenty-three amidoximes were tested for their in vitro activity against Leishmania amazonensis promastigotes and their toxicity on murine macrophages. Seven of the tested compounds exhibited an antileishmanial activity at lower than 10 µM with moderate to low toxicity. Six of these molecules showed activity at lower than 10 µM against promastigotes and toxicity at higher than 50 µM were selected and evaluated for their activity against intracellular Leishmania amazonensis amastigotes. Modulating chemical substituents in position 2 of dihydrofuran highly influenced their antileishmanial activities. The introduction of a methyl or trifluoromethyl group on the benzene ring of the benzyl group had a positive influence on activity without significantly increasing toxicity (52, 59, 60).

News on therapeutic management of MDR-tuberculosis: a literature review.

In 2015, the World Health Organization registered 10.4 million people who developed tuberculosis worldwide and 480,000 new cases of multidrug-resistant tuberculosis were identified. The care of multi and extensively drug-resistant tuberculosis is based on a combination of pyrazinamide and second-line drugs. These regimens are lengthy, partially effective and poorly tolerated. The challenge is to re-evaluate the use of existing molecules and to develop new agents more effective against resistant strains with shorter treatment duration. This literature review gives an overview of the latest research addressing these therapeutic objectives. Some molecules are in late stage clinical development among which pretomanid is showing promising results. Bedaquiline and delamanid have been recently approved by the Food and Drug Administration. The efficacy of drug regimens combining these molecules is under evaluation.

Cross-Coupling Synthesis of Methylallyl Alkenes: Scope Extension and Mechanistic Study.

Cross-coupling reactions between 2-methyl-2-propen-1-ol and various boronic acids are used to obtain aromatic-(2-methylallyl) derivatives. However, deboronation or isomerization side reactions may occur for several boronic acids. We describe herein the synthesis of original alkenes with good yields under mild reaction conditions that decrease these side reactions. The scope of this environmentally benign reaction is thereby extended to a wide variety of boronic acids. A mechanistic study was conducted and suggested a plausible catalytic cycle mechanism, pointing to the importance of the Lewis acidity of the boronic acid used.

New series of monoamidoxime derivatives displaying versatile antiparasitic activity.

Following the promising antileishmanial results previously obtained in monoamidoxime series, a new series of derivatives was synthesized using manganese(III) acetate, Wittig reactions and Suzuki-Miyaura cross coupling reactions. Pharmacomodulation in R(1), R(2) or R(3) substituents on the amidoxime structure is shown to influence antiprotozoan activity in vitro: a monosubstituted phenyl group in R1 (32-35) led to an activity against Leishmania donovani promastigotes (32, IC50 = 9.16 µM), whereas a polysubstituted group (36-37) led to an activity against Plasmodium falciparum (36, IC50 = 2.76 µM). Modulating chemical substituents in R(2) and R(3) only influenced the antiplasmodial activity in vitro. This suggests that the amidoxime scaffold has properties that could make it a promising new antiparasitic pharmacophore.