La découverte de l'insuline.

The first therapeutic benefits of insulin were recorded after the injection of pancreatic extract, given on January 23, 1922 in Toronto to a 14-year-old teenager. Until then, type I diabetes was always fatal, within weeks or months; the fatal outcome being delayed only at the cost of a drastic low-calorie diet. In previous decades, the importance of the pancreas in the development of diabetes had been pointed out, but all attempts to use a pancreatic extract had failed. It is with the objective of "neutralizing" the destructive effects of pancreatic juice (proteolytic) that the isolation of insulin was carried out by a research team which was totally improbable since it was headed by an orthopedic surgeon, Frederick Banting and a 22-year-old stagiaire, Charles Best. Their work was carried out in the university physiology laboratory of John Macleod and their outcome was made possible thanks to the skills of James Collip who purified the insulin preparation. Scientific reality invites us to emphasize that, Banting works, based on a wrong hypothesis, drew towards an historical discovery. Very quickly recognized as of major importance for medicine, the discovery was greeted by the attribution of the Nobel Prize in 1923. For a hundred years, insulin has not ceased to be an essential drug for tens of millions of patients in the world, but it has been a motor for scientific research: innovation in galenic pharmacy and biopharmacy, in fundamental chemistry as a subject for the study of the structure, analysis and synthesis of proteins, and finally, as a motor for the development of biotechnologies, since insulin was the first drug prepared by DNA-recombinant technology, and marketed in 1982.

[Clinical pharmacist influence at hospital to prevent overdosed prescription of acetaminophen]. / Impact du pharmacien clinicien à l'hôpital pour prévenir les posologies supra-thérapeutiques du paracétamol.

OBJECTIVES: The recommended daily dose of acetaminophen is limited to 60mg/kg/day with a maximum of 3g daily dose in adults weighing less than 50kg or in patients undergoing certain risk factors. This study aimed at assessing the fulfillment of those recommendations and the possible impact on the liver dysfunction at supra-therapeutic doses of acetaminophen. METHODS: This study was performed one day in 9 services. Patients characteristics, acetaminophen dose, daily dose administered, physiopathological aspects, markers of liver damage were collected. RESULTS: Among 542 prescriptions analyzed, 343 of them contained acetaminophen. The median age of patients studied was 81 years and one third weighed less than 50kg. The main risk factor of supra-therapeutic prescriptions was the lack of dose acetaminophen based on weight with 14% patients concerned and this risk raised at 17% when the pathophysiological conditions were included. The presence of pharmacists in medicals departments was more effective than the use of informatics programs limiting the dose systematically to 3g/day, or a distant pharmaceutical validation from care services to reduce the risk of acetaminophen overdose. According to the statement of administrations, only 4 of 49 patients received doses above 60mg/kg/day with a low impact on liver function tests. CONCLUSION: The continuous presence in pharmaceutical care services was the most effective measure to ensure effective implementation of acetaminophen recommendations.

[Fecal microbiota transplantation in recurrent Clostridium difficile infections. Framework and pharmaceutical preparation aspects]. / Le transfert de microbiote fécal lors d'infections récidivantes à Clostridium difficile. Cadre et aspects pharmacotechniques.

The fecal microbiota transplantation consists in introducing a preparation constituted by a dilution of stools of a healthy donor in the digestive tract of a patient recipient, to restore his intestinal physiological balance. This therapeutic approach was the subject of numerous studies showing its efficiency in the treatment of the recurrent infections with Clostridium difficile. The fecal microbiota transplantation has now a high level of clinical evidence, which explains that it appears in various international recommendations. In France, the fecal microbiota transplantation responds to the definition of a medication and can be executed as a pharmaceutical preparation or as an experimental drug for clinical trials under the responsibility of a hospital pharmacy. The objective of this paper is to propose a definition of a framework and to describe the methods of preparation of the fecal microbiota transplantation in the treatment of the recurrent infections with C. difficile and the interactions to consider for hospital pharmacies that do not have technical means to operate this technique.

[The story of Annales pharmaceutiques françaises. 1809-2009]. / L'histoire des Annales pharmaceutiques françaises. 1809-2009.

The Annales pharmaceutiques françaises is 200 years old. Initially, in 1809, the Bulletin de pharmacie was the organ of the Société de pharmacie de Paris. The journal was one of the dynamic events stimulated by the law of Germinal in year XI of the French revolution (1803). Its readership increased tremendously, rapidly making it the first regular journal in the pharmaceutical world. In 1984 it became the Journal de pharmacie et chimie published for a century. It was in 1943 that the journal took on its current name of the Annales pharmaceutiques françaises. The journal is now the official organ of the French National Academy of Pharmacy. The six annual issues are supplemented by an internet diffusion allowing readers access in all French-speaking countries.

Clearance of carbapenem-resistant Enterobacteriaceae vs vancomycin-resistant enterococci carriage after faecal microbiota transplant: a prospective comparative study.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) and vancomycin-resistant enterococci (VRE) carriage are increasing worldwide. Faecal microbiota transplantation (FMT) appears to be an attractive option for decolonization. This study aimed to evaluate CRE vs VRE clearance by FMT among carriers. METHODS: A multi-centre trial was undertaken on patients with CRE or VRE digestive tract colonization who received FMT between January 2015 and April 2017. Adult patients with CRE or VRE colonization, confirmed by three consecutive rectal swabs at weekly intervals, including one in the week prior to FMT, were included in the study. Patients with immunosuppression or concomitant antibiotic prescription at the time of FMT were excluded. Successful decolonization was determined by at least two consecutive negative rectal swabs [polymerase chain reaction (PCR) and culture] on Days 7, 14, 21 and 28, and monthly for three months following FMT. RESULTS: Seventeen patients were included, with a median age of 73 years [interquartile range (IQR) 64.3-79.0]. Median duration of carriage of CRE or VRE before FMT was 62.5 days (IQR 57.0-77.5). One week after FMT, three of eight patients were free of CRE colonization and three of nine patients were free of VRE colonization. After three months, four of eight patients were free of CRE colonization and seven of eight patients were free of VRE colonization. Qualitative PCR results were concordant with culture. Six patients received antibiotics during follow-up, three in each group. No adverse events were reported. CONCLUSION: CRE and VRE clearance rates were not significantly different in this study, possibly due to the small sample size, but a trend was observed. These data should be confirmed by larger cohorts and randomized trials.

Liposomal amphotericin B eye drops to treat fungal keratitis: physico-chemical and formulation stability.

Local fungal infections with Candida, Fusarium, Curvularia and Aspergillus can lead to serious ulceration of the cornea and must be treated rapidly. The current treatment consists of 0.15% (w/v) amphotericin B eye drops prepared from Fungizone, containing deoxycholate, irritant for the cornea, which reduces patient compliance. Eye drops based on liposomal amphotericin B (AmBisome would be a convenient alternative; however, according to the manufacturer's instructions, AmBisome can only be kept refrigerated for 1 week after reconstitution. A longer shelf-life at ambient temperature would be preferable for a preparation made in a hospital pharmacy and delivered to patients. Thus, the possibility of storing an ophthalmic preparation of 0.5% (w/v) liposomal amphotericin B after reconstitution was investigated. After 6 months at room temperature or at +2-8 degrees C, the hydrodynamic diameter measured by quasi-elastic light scattering remained constant at 108 +/- 30 nm with a polydispersity index lower than 0.15. Amphotericin B content, checked by a validated HPLC method, was maintained between 94 and 107%. Amphotericin B and soy phosphatidylcholine proportions remained constant, indicating that the liposomes remained intact and retained the drug. These results show the feasibility of an ophthalmic preparation based on liposomal amphotericin B developed in hospital pharmacies.

Is faecal microbiota transplantation an option to eradicate highly drug-resistant enteric bacteria carriage?

Carbapenem-resistant Enterobacteriaceae (CRE) or vancomycin-resistant enterococci (VRE) carriage present a major public health challenge. Decolonization strategies are lacking. We aimed to evaluate the impact of faecal microbiota transplantation (FMT) on a cohort of patients with digestive tract colonization by CRE or VRE. Eight patients were included: six carrying CRE and two colonized by VRE. One month after FMT, two patients were free from CRE carriage, and another patient was free from VRE after three months. In our experience, this strategy is safe.

[John Vane, 1927-2004, the pharmacologist of the vascular endothelium [corrected]]. / John R. Vane, "pharmacologue de l'endothélium vasculaire", 1927-2004.

The work of John Vane greatly contributed to the use of aspirin in cardiology. The impact of aspirin administration at low dose for the prevention of stroke or coronary attack results from its effect on enzymes regulating the production of prostaglandins. After understanding the mechanism of interaction between aspirin and the vascular endothelium, Vane proposed assigning a major physiological function to the vascular endothelium which then became a pharmacological target for new drugs. Using an ingenious "real time" biological assay of bloodstream hormones irrigating an isolated organ called the "blood-bathed organ cascade", John Vane developed a system for highly sensitive monitoring of several mediators like angiotensin, bradykinin and prostaglandins and discovered prostacyclin, a potent platelet aggregation inhibitor. Vane explained anti-inflammatory drugs effects (among which aspirin remains the leader) through their activity on cyclo-oxygenase and inhibition of prostacyclin and thromboxane production. Another cyclooxygenase isoform, so-called type 2, has been discovered in 1991. Thus, besides the constitutive COX-1, participating to stomach protection and renal artery vasodilatation, a COX-2 enzyme is existing, induced by inflammatory phenomenons and cytokines stimulation, allowing to design specific inhibitors "coxibs", playing an increasing but controversial role in the struggle against inflammation. He won Albert Lasker Prize in 1977 and Nobel Prize in medicine and physiology (shared with Sune Bergström and Bengt I. Samuelson) in 1982.

[Cyclosporine eye drops: A 4-year retrospective study (2009-2013)]. / Collyres de ciclosporine : étude d'une cohorte de patients de 2009 à 2013.

INTRODUCTION: The University Hospitals Paris Centre Pharmacy compounds three concentrations of cyclosporine eye drops: 20mg/mL (=2%); 5mg/mL (=0.5%) and 0.5mg/mL (=0.05%). Cyclosporine A 2% drops were developed in 1995 to prevent the rejection of high-risk cornea transplants after failure of topical steroids. The other concentrations of eye drops were developed for the treatment of various immune or inflammatory diseases of the cornea, conjunctiva and uvea. These eye drops are dispensed with a physician's prescription to hospitalized or ambulatory patients. A retrospective study over 4 years (2009-2013) was conducted to analyze the details of prescription and possible adverse events. MATERIALS AND METHODS: Dispensations made from January 1st, 2009 through December 31st, 2013 were studied, including patient age, dose of cyclosporine and practice location of prescribing physician. We also recorded the indications for cyclosporine eye drops in a sample of ambulatory patients. The analysis of local tolerability and the effect on visual comfort was based on questionnaires sent to the patients on cyclosporine 2% over a period of 2 months. RESULTS: Cyclosporine eye drops prescription grew continuously from 2009 through 2013 for all concentrations. In 2013, 5,859 patients were treated, among which 3,616 patients with topical cyclosporine 2%, 1,681 patients with 0.5%, and 562 patients with 0.05%. In total, this represents 62,621 eye drops. Treated patients ranged from 1 week to 100 years old. Topical 2% cyclosporine is indicated in 61% of cases to prevent high-risk corneal graft rejection. Other indications are corneal ulcer (6%), atopic keratoconjunctivitis (5%), vernal keratoconjunctivitis (5%) and herpetic keratitis (4%). Topical 0.5% cyclosporine is prescribed primarily for dry eye syndrome (20%) and to prevent rejection of high-risk corneal transplantation (11%), to treat ocular rosacea (10%), vernal keratoconjunctivitis (10%), atopic keratoconjunctivitis (8%) and Sjögren's syndrome (7%). Topical 0.05% cyclosporine is prescribed primarily for dry eye syndrome resistant to conventional treatment (47%) and Sjögren's syndrome (21%). Local tolerability of topical cyclosporine was evaluated in 388 patients. The majority of patients (63%) did not experience any adverse effects. The main side effects are redness, burning sensation and itching. CONCLUSION: Prescription of various formulations of topical cyclosporine is current practice for surgical indications: rejection of high-risk corneal transplantation; or medical indications: vernal or atopic keratoconjunctivitis and dry eye syndrome. Further prospective randomized studies would be necessary to validate formulations, doses and indications of cyclosporine eye drops.

Monitoring plasma levels of ganciclovir in AIDS patients receiving oral ganciclovir as maintenance therapy for CMV retinitis.

OBJECTIVES: To investigate whether low ganciclovir serum levels in patients on maintenance oral ganciclovir therapy are associated with recurrence of CMV retinitis. METHODS: A prospective study of the plasma concentration of ganciclovir after initiation of maintenance oral ganciclovir therapy in 14 AIDS patients who had recovered from acute cytomegalovirus (CMV) retinitis. RESULTS: Five of the 14 patients exhibited a mean time to recurrence of 37 days. The mean trough plasma concentration of ganciclovir in these patients after 1 month of oral ganciclovir therapy, was 0.40 +/- 0.30 mg/L. Nine patients had a mean time of progression of 263 days. The mean trough plasma concentration of ganciclovir in the latter patients was 0.80 +/- 0.60 mg/L. CONCLUSIONS: Patients exhibiting trough plasma levels of ganciclovir below 0.6 mg/L may be at higher risk of progression than patients who exhibited levels above 0.6 mg/L.

Six month administration of gelified intranasal insulin in 16 type 1 diabetic patients under multiple injections: efficacy vs subcutaneous injections and local tolerance.

OBJECTIVE: Nasal insulin administration is a potential route for intensive insulin management, less invasive and more rapid than subcutaneous injections. Previous studies have shown poor bioavailability (less than 15%) with nasal insulin administration with various absorption enhancers. The aim of the study was to evaluate in type 1 diabetic patients, the metabolic efficacy and local tolerance of a new gelified sprayed nasal insulin containing glychocolate and methylcellulose as absorption promoters. MATERIAL AND METHODS: The study was conducted in 16 type 1 diabetic patients (HbA1c 8.6+/-0.2%) in a cross-over trial including 2 six month randomized periods: a) NPH twice daily + 3 pre-prandial nasal insulin doses + nasal supplementation in case of unexpected hyperglycaemia; b) NPH twice daily + 3 pre-prandial regular insulin injections. End points were HbA1c levels, hypoglycaemic episodes and tolerance evaluated at month 0, 2, 6 and 8 on clinical symptoms and objective nasal assessments. RESULTS: Four patients were withdrawn because of nasal burning (3 cases) and persistent sinusitis (1 case), and one patient had purulent sinusitis at the month 6 examination. At month 6, HbA1c levels were comparable (8.3 +/- 0.1 vs 8.6 +/- 0.1%, m +/- SEM, NS) for nasal and subcutaneous period respectively. The number of hypoglycaemic events was identical during the 2 periods (88 episodes). Nasal tolerance with the gelified form was better than with the already reported lyophilized form but, when present, symptoms were more marked, suggesting a potentiating additional role of methylcellulose excipient on nasal intolerance. CONCLUSIONS: 1) Gelified nasal insulin is as efficient as subcutaneous regular insulin in type 1 diabetic patients. 2) Other galenic forms should be investigated to improve nasal tolerance and bioavailability.

Extreme insulin resistance: clinical management by external subcutaneous insulin infusion.

Management of very high insulin requirements in rare extreme insulin resistance syndromes is difficult and poorly documented. We report a case of a type B insulin-resistant patient requiring approximately 10,000 units of insulin per day, i.e. beyond the possibilities of current insulin formulations and delivery devices. Only the Panomat C10 portable pump model (Disetronic) and U500 Humulin (Lilly) allowed the required rate of 400 units per hour to be attained only when the reservoir was changed twice daily and the site and catheter were changed once daily. Three months after discharge, the patient was in good general and local condition, but with only fair diabetes control (glycated haemoglobin 9.5%).

Systemic morphine pharmacokinetics after ocular administration.

Pharmacokinetics of a single dose of morphine ocularly applied is reported in rabbits before and after lacrimal canaliculi ligature. Our investigations are based on a sensitive reversed-phase ion-pair chromatographic determination of morphine. This study describes the various resorption sites of morphine when administered through the conjunctiva. After ocular administration, morphine rapidly reaches high blood levels compatible with pharmacological activity. Ocular bioavailability of morphine is higher than after non-parenteral routes. Canaliculi ligature modifies the morphine pharmacokinetic profile without significant modification of drug bioavailability. Our results suggest a great capacity of drug resorption for the conjunctiva, and indicate the major role of nasal mucosa in physiological conditions.