Implementation assessment of a patient personalized clinical pharmacy programme (5P project) into orthogeriatric care pathway.

WHAT IS KNOWN AND OBJECTIVE: The orthogeriatric path (hip-fractured elderly patients) is composed of several transition points (emergency surgery, orthopaedic, geriatric and rehabilitation units). The intervention of clinical pharmacists can ensure the continuity of patients' drug management during their hospital stay. The aim of the study was to assess the implementation of clinical pharmacy activities in an orthogeriatric pathway, regarding its impact on medication error prevention, the healthcare professionals' and patients' satisfaction, and the estimated associated pharmaceutical workload. METHODS: Participants were aged 75 or older and managed for proximal femoral fracture. Their admission prescription was reviewed. If they were evaluated at high risk of adverse event (AE), medication reconciliation (MedRec) and pharmaceutical interviews (admission, discharge, and targeted on oral anticoagulant) were added at different steps of their care pathway. The achievement and duration of each clinical pharmacy activity were recorded. The number of pharmaceutical interventions (PI) made during prescription review, and unintentional discrepancies (UID) identified during MedRec were collected. A satisfaction questionnaire was sent to patients and healthcare professionals. RESULTS AND DISCUSSION: Among 455 included patients, 284 patients were considered at high risk of AE. Clinical pharmacy activity achievement rates varied between 12% and 98%. A total of 622 PI and 333 UID were identified. The overall patients' and healthcare professionals' satisfaction was rated from 63% to 100%. The total workload was estimated at 376 h: on average 16 min per prescription review, 43 min per admission MedRec, 26 min per discharge MedRec and 17 to 25 minutes per interview. CONCLUSION: The implementation of the programme showed a high potential of drug management securing. To sustain it, additional pharmaceutical human resources and high-performance computing tools are needed.

Minoxidil versus placebo in the treatment of arterial wall hypertrophy in children with Williams Beuren Syndrome: a randomized controlled trial.

BACKGROUND: Insufficient elastin synthesis leads to vascular complications and arterial hypertension in children with Williams-Beuren syndrome. Restoring sufficient quantity of elastin should then result in prevention or inhibition of vascular malformations and improvement in arterial blood pressure. METHODS: The aim of this study was to assess the efficacy and safety of minoxidil on Intima Media Thickness (IMT) on the right common carotid artery after twelve-month treatment in patient with Williams-Beuren syndrome. We performed a randomized placebo controlled double blind trial. All participants were treated for 12 months and followed for 18 months. The principal outcome was assessed by an independent adjudication committee blinded to the allocated treatment groups. RESULTS: The principal outcome was available for 9 patients in the placebo group and 8 patients in the minoxidil group. After 12-month treatment, the IMT in the minoxidil group increased by 0.03 mm (95% CI -0.002, 0.06) compared with 0.01 mm (95%CI - 0.02, 0.04 mm) in the placebo group (p = 0.4). Two serious adverse events unrelated to the treatment occurred, one in the minoxidil and 1 in the placebo group. After 18 months, the IMT increased by 0.07 mm (95% CI 0.04, 0.10 mm) in the minoxidil compared with 0.01 mm (95% CI -0.02, 0.04 mm) in the placebo group (p = 0.008). CONCLUSION: Our results suggest a slight increase after 12 and 18-month follow-up in IMT. More understanding of the biological changes induced by minoxidil should better explain its potential role on elastogenesis in Williams-Beuren syndrome. TRIALS REGISTRATION: US National Institutes of Health Clinical Trial Register (NCT00876200). Registered 3 April 2009 (retrospectively registered).

Prospective study of erythropoietin use on quality of life and cost effectiveness in acute myeloid leukemia and allogeneic hematopoietic stem cell transplantation patients.

BACKGROUND: Despite frequent anemia and multiple transfusions in patients undergoing chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia , recommendations for use of erythropoiesis-stimulating agents (ESAs) in these populations are still missing. The primary objective was the effect of ESA administration on patient's quality of life (QoL). Secondary objectives were hemoglobin (Hb) recovery, red blood cell (RBC) transfusions, overall survival, and event-free survival. METHODS: Adult patients with Hb ≤ 11 g/dL after consolidation chemotherapy for acute myeloid leukemia (group 1), or after allo-HSCT for any hematological diseases (group 2), were prospectively included. ESA was administered subcutaneously once per week during a maximum period of 6 months and was stopped when Hb level reached 12 g/dL. A paired-matched analysis using a historical control group was performed for secondary endpoints. Fifty-two patients were included in group 1, and 55 patients were in group 2. RESULTS: For the global population, a significant improvement of QoL was noticed with ESA use; 83% (group 1) and 71% (group 2) of patients achieved an Hb level ≥ 12 g/dL without transfusion requirement. The pair-matched analysis showed a reduction of 4 RBC units per patient in group 1 (P = .0002) and 3 RBC units per patient in group 2 (P = .04). No significant difference in terms of thromboembolic events, overall survival, and event-free survival was observed between ESA and control groups. A RBC transfusion median savings of €1712 per patient was estimated in each group. CONCLUSIONS: ESAs have a clinical and economic benefit on Hb recovery, could improve a patient's QoL, and lead to a significant reduction in number of RBC transfusions with no effect on survival.

A quantitative and qualitative method to control chemotherapeutic preparations by Fourier transform infrared-ultraviolet spectrophotometry.

Chemotherapy products in hospitals include a reconstitution step of manufactured drugs providing an adapted dosage to each patient. The administration of highly iatrogenic drugs raises the question of patients' safety and treatment efficiency. In order to reduce administration errors due to faulty preparations, we introduced a new qualitative and quantitative routine control based on Fourier Transform Infrared (FTIR) and UV-Visible spectrophotometry. This automated method enabled fast and specific control for 14 anticancer drugs. A 1.2 mL sample was used to assay and identify each preparation in less than 90 sec. Over a two-year period, 9370 controlled infusion bags showed a 1.49% nonconformity rate, under 15% tolerance from the theoretical concentration and 96% minimum identification matching factor. This study evaluated the reliability of the control process, as well as its accordance to chemotherapy deliverance requirements. Thus, corrective measures were defined to improve the control process.

Implementation and effectiveness of pharmacist-led interviews at patient hospital admission in a rheumatology department.

OBJECTIVES: Medication reconciliation is time-consuming and its complete deployment can be difficult. The implementation of a simplified process, such as patient interviews at admission without full reconciliation, may contribute to improve patient care. The objective of the present study was to describe the feasibility and assess the potential effectiveness of implementing pharmacist-led interviews at patient admission to a rheumatology department. METHODS: This is a prospective observational study of pharmacist-led interviews at patient admission conducted between April 2015 and May 2017 in the 34-bed rheumatology department of Edouard Herriot Hospital, a French university hospital. These interviews were structured to explore patient medication management at home. The main outcome was the number of medication errors at admission. Other outcomes were the total number of interviews, the number of interviews with at least one new item of information provided by the patient, the number of interviews with at least one medication error detected, and the number of interviews leading to a modification of the hospital medication order. RESULTS: A total of 247 interviews were carried out; there was an increase in the number of interviews over the study period (n=54 in 2015, n=98 in 2016, and n=95 for the first 5 months of 2017). Among the interviews conducted, 135 (55%) provided new information concerning patient medication management and 117 medication errors were identified in hospital orders (0.47/patient). There were 76 interviews (31%) with at least one medication error; all led to a medication order modification. CONCLUSIONS: The study found that pharmacist-led interviews at patient admission were effective in detecting medication errors. They could be an alternative to a full medication reconciliation process in targeted situations. When the patient interview does not provide sufficiently robust information, full medication reconciliation may be performed.

Development of clinical pharmacy programs integrated into patient care pathways using adverse event risks.

BACKGROUND: In the strained actual economic context, all clinical pharmacy activities cannot be achieved for all patients of all care pathways. So finding a way to prioritize moments and patients needing those activities is essential. This is the challenge of the "5P project" (Patient personalized clinical pharmacy program integrated into care pathway). OBJECTIVE: To present adverse event (AE) risk management approach applied to develop clinical pharmacy programs integrated into care pathway, using two methods. METHOD: Used as a priori AE risk management approach, the Delphi method and inductive approach analysis of semi-directed interviews were realized from April 1st to October 3rd, 2019, respectively in orthogeriatric (OG) and pediatric kidney transplantation (PKT) care pathways. Complementarily to bibliographic research, participants were medical and paramedical healthcare providers involved in the concerned care pathway. They have been interrogated regarding AE risks to identify the clinical pharmacy activities required, the patients who need them, and the appropriate steps of the care pathway. RESULTS: The Delphi method for OG care pathway has revealed: 1/. Patients were prioritized by the presence of at least 2 among the following 4 criteria: age ≥90 years old, cardiovascular diseases, prescribed potentially inappropriate medication for elderly patients, obesity or diabetes; priority steps were the post-operative and rehabilitation care steps. 2/. Prescription reviews, medication reconciliation and targeted pharmaceutical informative interview about oral anticoagulants were required. Nine semi-directed interviews used for PKT care pathway has revealed: 1/. Clinical pharmacy activities were carried out for all patients. Priority steps were pre-transplantation, immediate post-operative, and post-transplantation. 2/. Prescription reviews and educative interviews were required. CONCLUSIONS: The two presented methods can be used to both develop patient prioritization and targeting steps for clinical pharmacy activities, and integrate it into care pathway. Today, those two developed programs have been executed in our teaching hospital.

Safety and efficacy of prophylactic levetiracetam for prevention of epileptic seizures in the acute phase of intracerebral haemorrhage (PEACH): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The incidence of early seizures (occurring within 7 days of stroke onset) after intracerebral haemorrhage reaches 30% when subclinical seizures are diagnosed by continuous EEG. Early seizures might be associated with haematoma expansion and worse neurological outcomes. Current guidelines do not recommend prophylactic antiseizure treatment in this setting. We aimed to assess whether prophylactic levetiracetam would reduce the risk of acute seizures in patients with intracerebral haemorrhage. METHODS: The double-blind, randomised, placebo-controlled, phase 3 PEACH trial was conducted at three stroke units in France. Patients (aged 18 years or older) who presented with a non-traumatic intracerebral haemorrhage within 24 h after onset were randomly assigned (1:1) to levetiracetam (intravenous 500 mg every 12 h) or matching placebo. Randomisation was done with a web-based system and stratified by centre and National Institutes of Health Stroke Scale (NIHSS) score at baseline. Treatment was continued for 6 weeks. Continuous EEG was started within 24 h after inclusion and recorded over 48 h. The primary endpoint was the occurrence of at least one clinical seizure within 72 h of inclusion or at least one electrographic seizure recorded on continuous EEG, analysed in the modified intention-to-treat population, which comprised all patients who were randomly assigned to treatment and who had a continuous EEG performed. This trial was registered at ClinicalTrials.gov, NCT02631759, and is now closed. Recruitment was prematurely stopped after 48% of the recruitment target was reached due to a low recruitment rate and cessation of funding. FINDINGS: Between June 1, 2017, and April 14, 2020, 50 patients with mild-to-moderate severity intracerebral haemorrhage were included: 24 were assigned to levetiracetam and 26 to placebo. During the first 72 h, a clinical or electrographic seizure was observed in three (16%) of 19 patients in the levetiracetam group versus ten (43%) of 23 patients in the placebo group (odds ratio 0·16, 95% CI 0·03-0·94, p=0·043). All seizures in the first 72 h were electrographic seizures only. No difference in depression or anxiety reporting was observed between the groups at 1 month or 3 months. Depression was recorded in three (13%) patients who received levetiracetam versus four (15%) patients who received placebo, and anxiety was reported for two (8%) patients versus one (4%) patient. The most common treatment-emergent adverse events in the levetiracetam group versus the placebo group were headache (nine [39%] vs six [24%]), pain (three [13%] vs ten [40%]), and falls (seven [30%] vs four [16%]). The most frequent serious adverse events were neurological deterioration due to the intracerebral haemorrhage (one [4%] vs four [16%]) and severe pneumonia (two [9%] vs two [8%]). No treatment-related death was reported in either group. INTERPRETATION: Levetiracetam might be effective in preventing acute seizures in intracerebral haemorrhage. Larger studies are needed to determine whether seizure prophylaxis improves functional outcome in patients with intracerebral haemorrhage. FUNDING: French Ministry of Health.

How a Patient Personalised Clinical Pharmacy Programme Can Secure Therapeutic Care in an Orthogeriatric Care Pathway (5P Project)?

BACKGROUND: A new model was developed for integrating a personalised clinical pharmacy programme (5P project) into the orthogeriatric care pathway. OBJECTIVE: To secure the therapeutic care of orthogeriatric patients. DESIGN AND SETTING: Prospective descriptive study in a multisite teaching hospital from June 2019 to January 2020. SUBJECTS: Patients aged ≥75 years admitted for hip fracture. METHODS: A prescription review was performed for all patients at inclusion. Other clinical pharmacy activities (additional prescription review, pharmaceutical interviews, medication reconciliation) were dedicated to "high-risk" patients. Potential medication errors (ME), either pharmaceutical interventions (PI) or unintentional discrepancies (UID), were recorded. The potential clinical impact of PI was evaluated by a pluriprofessional expert panel using a validated tool. RESULTS: In the 455 patients included, 955 potential ME were detected, that is ≥1 potential ME for 324/455 (71%) patients. In acute care, 561 PI were formulated during prescription review for 440/455 (97%) patients and 348/561 (62%) were accepted by physicians. Medication reconciliation was performed for 213 patients, 316 UID were identified. In rehabilitation units, a second prescription review was performed for 112/122 (92%) "high-risk" patients, leading to 61 PI. The clinical impact was evaluated for 519/622 (83%) PI. A consensus was obtained for 310/519 (60%) PI: 147/310 (47%) were rated as having minor clinical impact, 138/310 (45%) moderate, 22/310 (7%) major, 2/310 (0.6%) vital, and 1/310 (0.3%) null. CONCLUSION: The 5P project secured the orthogeriatric care pathway by detecting a great number of potential ME, including PI mostly considered as having a significant clinical impact.

Dual 0.02% chlorhexidine digluconate - 0.1% disodium EDTA loaded thermosensitive ocular gel for Acanthamoeba keratitis treatment.

Poor bioavailability and low residence time limit the efficiency of conventional biguanide-based eye drops against Acanthamoeba keratitis. The aim of this work was to formulate an original anti-amoebic thermoreversible ocular gel combining biguanide and metalloproteases inhibitor - chelating agent. Chlorhexidine digluconate (CHX)-ethylenediaminetetraacetic acid disodium salt (Na2EDTA) were compounded in poloxamer 407 saline solution. 0.02% CHX - 0.1% Na2EDTA loaded thermosensitive ocular gel exhibited appropriate pH (5.73 ±â€¯0.06), iso-osmolality (314 ±â€¯5 mOsm/kg), viscosity (ranged between 15 and 25 mPa.s) and thermal gelation (26.5 °C and 33 °C) properties. Bioadhesion of gel was successfully tested onto isolated bovine eyes as well as the assessment of CHX penetration into the cornea. Intracorneal CHX concentration was found greater than trophozoite minimum amoebicidal concentration and minimal cysticidal concentration after 15-min and 2-h ocular exposure, respectively, while any CHX permeation through the cornea was detected (<51 ng/cm2/h). Improvement of CHX ocular bioavailability was attributed to probable solubilization of tear film lipid layer by poloxamer. In vitro efficiency of CHX-Na2EDTA ocular gel was confirmed from the drastic reduction of trophozoite and cyst survival (to 25% and 2%, respectively), confirming the potential of the multicomponent pharmaceutical material strategy for the treatment of Acanthamoeba keratitis.

Assessment of the clinical relevance of pharmacists' interventions performed during medication review in a rheumatology ward.

BACKGROUND: Pharmacists contribute to reduce the number of medication errors during medication review. Nevertheless, few French studies report the potential clinical impact of pharmacists' interventions performed after detecting drug-related problems. The objective was to evaluate the clinical relevance of pharmacists' interventions in a rheumatology ward from medical and pharmaceutical perspectives. METHOD: The analysis was conducted on pharmacists' interventions performed between January 1 and December 31, 2015 in a French teaching hospital. Similar pharmacists' interventions were grouped in one item and they were analysed according to 11 drug categories. The clinical significance of pharmacists' interventions was considered independently by a pharmacist and a rheumatologist using a validated French scale that categorises drug-related problems from minor to catastrophic. The agreement between the two professionals was analysed using the weighted kappa coefficient. RESULTS: Of 1313 prescriptions reviewed, 461 pharmacists' interventions (171 items) were formulated for drug-related problems with an acceptance rate of 67.2%. Of the 418 interventions selected for clinical significance analysis, 235 interventions (56.2%) for the physician and 400 interventions (95.7%) for the pharmacist were at least significant. The two professionals evaluated equally the clinical relevance of 90 items (50.6%). The categories with the most similarities were the analgesics/anti-inflammatory drugs (78.1%), the antidiabetics (75.0%) and the anticoagulants (71.4%). The agreement was estimated by a weighted kappa coefficient of 0.29. CONCLUSION: This work highlights the positive clinical relevance of pharmacists' interventions in rheumatology and the importance of medico-pharmaceutical collaboration to prevent medication errors.

Production and stability study of a hospital parenteral nutrition solution for neonates.

Standard parenteral nutrition solutions are mixtures comprising interacting components that may degrade themselves over time. The objective of this study was to investigate the physicochemical and microbiological stability of a hospital preparation for parenteral nutrition in neonatology. The analyses were performed throughout the storage of the preparations at 2-8 °C (up to 4 months). The extent of stability was based on the determination of amino acids dosage, visual and physicochemical properties (glucose and electrolytes concentrations, pH and osmolality measurements, particle counting) and microbiological analysis (sterility test). A thermal degradation of ascorbic acid was conducted to evaluate the antioxidant properties of the parenteral mixture. Physicochemical and microbiological controls were found to comply with the specifications. Amino acids showed a good stability throughout the 4months storage except for cysteine, which was progressively degraded to cystine, conferring a yellow coloration to parenteral solutions. Parenteral nutrition standards solutions remain stable for 4 months at 2-8 °C, ensuring safe administration in preterm infants.

Long-term stability of gentamicin sulfate-ethylenediaminetetraacetic acid disodium salt (EDTA-Na2) solution for catheter locks.

A lock solution composed of gentamicin sulfate (5 mg/mL) and ethylenediaminetetraacetic acid disodium salt (EDTA-Na2, 30 mg/mL) could fully eradicate in vivo bacterial biofilms in totally implantable venous access ports (TIVAP). In this study, fabrication, conditioning and sterilization processes of antimicrobial lock solution (ALS) were detailed and completed by a stability study. Stability of ALS was conducted for 12 months in vial (25 °C ± 2 °C, 60% ± 5% relative humidity (RH), and at 40 °C ± 2 °C, RH 75% ± 5%) and for 24 h and 72 h in TIVAP (40 °C ± 2 °C, RH 75% ± 5%). A stability indicating HPLC assay with UV detection for simultaneous quantification of gentamicin sulfate and EDTA-Na2 was developed. ALS was assayed by ion-pairing high performance liquid chromatography (HPLC) needing gentamicin derivatization, EDTA-Na2 metallocomplexation of samples and gradient mobile phase. HPLC methods to separate four gentamicin components and EDTA-Na2 were validated. Efficiency of sterility procedure and conditioning of ALS was confirmed by bacterial endotoxins and sterility tests. Physicochemical stability of ALS was determined by visual inspection, osmolality, pH, and sub-visible particle counting. Results confirmed that the stability of ALS in vials was maintained for 12 months and 24 h and 72 h in TIVAP.

Formulation, stability testing, and analytical characterization of melatonin-based preparation for clinical trial.

A new institutional clinical trial assessed the improvement of sleep disorders in 40 children with autism treated by immediate-release melatonin formulation in different regimens (0.5 mg, 2 mg, and 6 mg daily) for one month. The objectives of present study were to (i) prepare low-dose melatonin hard capsules for pediatric use controlled by two complementary methods and (ii) carry out a stability study in order to determine a use-by-date. Validation of preparation process was claimed as ascertained by mass uniformity of hard capsules. Multicomponent analysis by attenuated total reflectance Fourier transformed infrared (ATR-FTIR) of melatonin/microcrystalline cellulose mixture allowed to identify and quantify relative content of active pharmaceutical ingredients and excipients. Absolute melatonin content analysis by high performance liquid chromatography in 0.5 mg and 6 mg melatonin capsules was 93.6%±4.1% and 98.7%±6.9% of theoretical value, respectively. Forced degradation study showed a good separation of melatonin and its degradation products. The capability of the method was 15, confirming a risk of false negative <0.01%. Stability test and dissolution test were compliant over 18 months of storage with European Pharmacopoeia. Preparation of melatonin hard capsules was completed manually and melatonin in hard capsules was stable for 18 months, in spite of low doses of active ingredient. ATR-FTIR offers a real alternative to HPLC for quality control of high-dose melatonin hard capsules before the release of clinical batches.

Infraorbital and infratrochlear nerve blocks combined with general anaesthesia for outpatient rhinoseptoplasty: A prospective randomised, double-blind, placebo-controlled study.

INTRODUCTION: We conducted a study to determine the efficacy of bilateral extraoral infraorbital and infratrochlear nerve blocks during outpatient rhinoseptoplasty under general anaesthesia. PATIENTS AND METHODS: In this prospective, double-blind, randomised, controlled trial, 40 adult patients undergoing outpatient rhinoseptoplasty under general anaesthesia were assigned to receive bilateral infraorbital and infratrochlear nerve blocks with either 10mL of 0.25% levobupivacaine (Group LB) or isotonic saline (control group). Patients in Group LB received 0.1mL/kg of isotonic saline as a placebo and patients in the control group received 0.1mL/kg of morphine. The primary endpoint was total perioperative morphine consumption (intraoperative and in the post-anaesthesia care unit). The secondary endpoints were pain scores, time spent in the post-anaesthesia care unit and the outpatient ward, block-related complications and patient satisfaction. RESULTS: The total dose of perioperative morphine was lower in Group LB than in the control group (2.5±2.8mg versus 9.5±3.5mg, respectively, P<0.001). The mean±SD or median [IQR] times spent in the post-anaesthesia care unit (60±10min and 78±33min, respectively, P<0.03) and in the outpatient ward (210 [178-223] min versus 275 [250-300] min, respectively, P<0.001) were lower in Group LB than in the control group. There were no differences between groups for other endpoints. CONCLUSION: Bilateral extraoral infraorbital and infratrochlear nerve blocks performed with 0.25% levobupivacaine during general anaesthesia combining remifentanil and desflurane reduce the perioperative dose of morphine and the time spent in the post-anaesthesia care unit and the outpatient ward in adult patients undergoing outpatient rhinoseptoplasty.

Evaluation of Safe Infusion Devices for Antineoplastic Administration.

Nurses endure daily low-level exposure to cytotoxic drugs, which can lead to significant absorption with potential harmful consequences. New sterile medical devices called cytotoxic safe infusion systems (CSISs), intended by their manufacturers to improve safety and quality of cytotoxic drug infusions, have been made commercially available. CSISs from 3 manufacturers were tested in 2 cancer units and compared with standard infusion sets. The aim of this study is to evaluate the devices regarding occupational exposure, quality of the infusion, and economic aspects.

[Long-term benzodiazepine use among dialysis patient: A descriptive study]. / Prise de benzodiazépines au long cours chez les patients dialysés : une étude descriptive.

BACKGROUND: Dialysis patients frequently have anxiety and sleeping disorders and that explains a benzodiazepine treatment. A significant proportion of dialysis patients are long-term users even though it is not recommended to take benzodiazepine for more than 3 months. Risks of such a use are well identified. Nephrologists frequently have to prescribe benzodiazepines. This prescription is complex and there are few studies regarding the factors of benzodiazepine use among this population. OBJECTIVES: To determine the prevalence and the factors related to a long-term benzodiazepine use by dialysis patients. To determine the prevalence and the motivation of patients to stop taking medication among the long-term users who got information about the risk of such a use. METHOD: The study includes 91 dialysis chronic patients. Their characteristics were collected from medical records and interviews with the patients. RESULTS: The average age of patients is 65,8 years. In all, 50.5% take benzodiazepines. Among benzodiazepine users, the prevalence of long-term use is 78.3%. Long-term benzodiazepine users (a) are older, (b) less active, (c) frequently diabetic, (d) depressive, (e) unable to walk, (f) less often registered on the kidney transplant waiting list, and (g) had less kidney transplant previously. Benzodiazepine doses of long-term users were higher than the doses of short-term users. Moreover, 60% of patients who are chronic users want to take action and stop the treatment. Observation of side effects, impression of ineffectiveness and fear of addiction are the most identified motivation to stop treatment. CONCLUSION: The prevalence of benzodiazepine chronic use by dialysis patients is high. Giving information to the patient about the use of these molecules seems to have a positive impact on the decision to stop.

New easy handling and sampling device for bioavailability screening of topical formulations.

Biopharmaceutical assessment of topical drug formulations is widely carried out by using vertical diffusion cells (Franz type cell). Although Franz diffusion cell model is well designed for percutaneous absorption studies, the extent of drug penetration within the skin requires more adapted device. Recently, we have developed a new patented versatile, easy-to-use, and disposable diffusion cell called VitroPharma. In this study we have assessed the cutaneous bioavailability of caffeine as hydrophilic compound model using Franz diffusion cell and VitroPharma. The percutaneous absorption of caffeine assessed with Franz diffusion cell and VitroPharma was characterized by using (i) finite dose model and (ii) classical pharmacokinetic analysis. Furthermore, the follow-up of caffeine penetration within the skin was determined by sequential measurements of tissular drug concentration throughout the time of skin exposure with VitroPharma. However, classical experimental design using Franz diffusion cell involved unique determination of tissular concentration at the final point of skin exposure protocol. Finally, device equivalence between Franz diffusion cell and VitroPharma was claimed from percutaneous absorption data analysis. Concomitant assessment of dual penetration and permeation kinetics by using VitroPharma reinforced the understanding of skin drug delivery.

Nilotinib and peginterferon alfa-2a for newly diagnosed chronic-phase chronic myeloid leukaemia (NiloPeg): a multicentre, non-randomised, open-label phase 2 study.

BACKGROUND: Nilotinib is now recommended for patients with newly diagnosed chronic myeloid leukaemia in chronic phase and leads to important rates of molecular response 4·5 log (MR(4·5)), allowing the prospect of therapy cessation. However, most patients do not reach this criterion and nilotinib is taken for lengthy periods, resulting in chronic or late-onset adverse events. Nilotinib combined with interferon might further increase rates of MR(4·5), avoid late side-effects, and allow therapy cessation. In a phase 2 trial we aimed to assess the feasibility, safety, and deep molecular response of the combination of nilotinib (600 mg daily) and peginterferon alfa-2a in newly diagnosed patients with chronic-phase chronic myeloid leukaemia (CML). METHODS: In a non-randomised, open-label, phase 2 trial, we enrolled adult patients (age ≥18 years) without any organ failure who had BCR-ABL-positive, chronic-phase CML, at diagnosis. After a priming procedure with 90 µg per week of peginterferon alfa-2a alone for a month, we gave patients peginterferon alfa-2a 45 µg per week combined with nilotinib 600 mg daily until 24 months after interferon initiation. The primary endpoint was the cumulative incidence of MR(4·5) at 12 months after initiation of peginterferon alfa-2a. Data were analysed by a modified intention-to-treat principle. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-019786-28. FINDINGS: Between March 24, 2011, and Sept 27, 2011, we enrolled 42 patients. One patient withdrew consent before receiving any study treatment so was excluded from analysis; 41 patients received treatment with peginterferon alfa-2a and nilotinib. At 12 months, seven (17%) patients had achieved MR(4·5). Haematological and hepatic adverse events were frequent-with grade 3-4 neutropenias occurring in ten (24%) patients, grade 3-4 thrombocytopenias occurring in ten (24%) patients, grade 3-4 cholestatic events occurring in seven (17%) patients, and grade 3-4 elevations in aspartate aminotransferase or alanine aminotransferase occurring in three (7% patients-particularly during the first 3 months. However, 30 (73%) patients remained on interferon therapy at 1 year. Three grade 3-4 cardiac events (7% of patients, all coronary stenoses) occurred at later timepoints. INTERPRETATION: The combination of peginterferon alfa-2a resulted in good molecular responses in patients. Despite substantial toxic effects, most patients remained on the study drugs for more than a year. This combination should now be tested in a randomised controlled trial. FUNDING: Novartis Pharma.

Bladder tissue permeability and transport modelling of intravesical alum, lidocaine hydrochloride, methylprednisolone hemisuccinate and mitomycin C.

The aims of this study were to assess the tissue permeability of the bladder and to characterize the transport of four drugs displaying different physico-chemical properties and commonly used in intravesical delivery, through porcine bladder. The transport of aluminium through porcine bladder was assessed by using a vertical static diffusion cell. Lidocaine hydrochloride, methylprednisolone hemisuccinate and mitomycin C were tested by using three different experimental setups, including vertical static diffusion cell, microdialyseur and lab-patented device. Penetration results on different experimental setups were homogenous suggesting dependency on physico-chemical characteristics of drug and subsequent interaction with bladder wall structure. Oppositely, permeation varied consistently with experimental setup characteristics (i.e., permeation surface, receptor fluid volume and hydrodynamic). Mathematical modelling of drug transport through bladder wall is proposed considering scarce literature on this route of administration. Practical outcome of this study could drive compounding optimization towards improvement of safety and efficacy in patient undergoing intravesical administration.

Production and stability study of a hospital parenteral nutrition solution for neonates / 药物分析学报

Standard parenteral nutrition solutions are mixtures comprising interacting components that may de-grade themselves over time. The objective of this study was to investigate the physicochemical and microbiological stability of a hospital preparation for parenteral nutrition in neonatology. The analyses were performed throughout the storage of the preparations at 2–8 °C (up to 4 months). The extent of stability was based on the determination of amino acids dosage, visual and physicochemical properties (glucose and electrolytes concentrations, pH and osmolality measurements, particle counting) and mi-crobiological analysis (sterility test). A thermal degradation of ascorbic acid was conducted to evaluate the antioxidant properties of the parenteral mixture. Physicochemical and microbiological controls were found to comply with the specifications. Amino acids showed a good stability throughout the 4months storage except for cysteine, which was progressively degraded to cystine, conferring a yellow coloration to parenteral solutions. Parenteral nutrition standards solutions remain stable for 4 months at 2–8 °C, ensuring safe administration in preterm infants.