[Monitoring student skills during community pharmacy placements: Retrospective analysis of dashboards]. / Suivi des compétences des étudiants au cours du stage de pratique professionnelle en pharmacie officinale : analyse rétrospective des tableaux de bord.

OBJECTIVES: The aim of this work is to describe the skills considered to have been acquired by students during their professional practice placements, with particular emphasis on skills related to the new roles of pharmacists. METHODS: Skills are monitored during the professional practice placement using the dashboard included in the guide designed by the college of community pharmacy placement supervisors. Each skill is assessed at three points during the placement. The assessment is carried out jointly by the student and his or her placement supervisor using the dashboard, which is available online in the form of a form on the Moodle platform. We conducted a retrospective analysis of the professional practice placement dashboards for the 2018-2019 to 2022-2023 academic years. RESULTS: The response levels for the three phases of the dashboard are very high, always exceeding 90% of students completing their placement. All of the scorecards show a progression in the acquisition of skills throughout the placement and enable certain skills to be distinguished in terms of their level of acquisition at the end of the placement. The focus on pharmaceutical interviews shows that the rate of acquisition of this skill is over 85% in 2021 and 2023, the years in which the subject of the public health project was the performance and quality assurance of pharmaceutical interviews in pharmacies, whereas it is no higher than 38% in the other years. CONCLUSIONS: Our work shows the contribution of the professional practice placement dashboard in monitoring student progress. The analysis carried out reveals different levels of mastery at the start of the placement and different levels of progress depending on the skills. It also reveals the contribution made by the intervention on the content of the placement, particularly in terms of the acquisition of certain skills, especially those related to new tasks such as conducting pharmaceutical interviews.

Sleep Medication in Older Adults: Identifying the Need for Support by a Community Pharmacist.

Many older adults take benzodiazepines and sedative-hypnotics for the treatment of sleep disorders. With a view to considering the possible discontinuation of hypnotics, the objectives of the present study were to describe bedtime habits and sleep patterns in older adults and to identify the sleep medications taken. An expert group developed a structured interview guide for assessing the patients' bedtime habits, sleep patterns, and medications. During an internship in a community pharmacy, 103 sixth-year pharmacy students conducted around 10 interviews each with older adults (aged 65 or over) complaining of sleep disorders and taking at least one of the following medications: benzodiazepines, benzodiazepine derivatives ("Z-drugs"), antihistamines, and melatonin. A prospective, observational study was carried out from 4 January to 30 June 2016. The pharmacy students performed 960 interviews (with 330 men and 630 women; mean ± standard deviation age: 75.1 ± 8.8). The most commonly taken hypnotics were the Z-drugs zolpidem (n = 465, 48%) and zopiclone (n = 259, 27%). The vast majority of patients (n = 768, 80%) had only ever taken a single hypnotic medication. The median [interquartile range] prescription duration was 120 (48-180) months. About 75% (n = 696) of the patients had at least 1 poor sleep habit, and over 41% (n = 374) had 2 or more poor sleep habits. A total of 742 of the patients (77%) reported getting up at night-mainly due to nycturia (n = 481, 51%). Further, 330 of the patients (35%) stated that they were keen to discontinue their medication, of which 96 (29%) authorized the pharmacist to contact their family physician and discuss discontinuation. In France, pharmacy students and supervising community pharmacists can identify problems related to sleep disorders by asking simple questions about the patient's sleep patterns. Together with family physicians, community pharmacists can encourage patients to discuss their hypnotic medications.

In vitro and in silico approach to study the hormonal activities of the alternative plasticizer tri-(2-ethylhexyl) trimellitate TEHTM and its metabolites.

Tri-(2-ethylhexyl) trimellitate (TEHTM) is a plasticizer for polyvinyl chloride (PVC) material used in medical devices. It is an alternative to di-(2-ethylhexyl) phthalate (DEHP), a well-known reprotoxic and endocrine disruptor. As plasticizers are known to easily migrate when in contact with fatty biological fluids, patient exposure to TEHTM is highly probable. However, there is currently no data on the potential endocrine-disrupting effects of its human metabolites. To evaluate the effects of TEHTM metabolites on endocrine activity, they were first synthesized and their effects on estrogen, androgen and thyroid receptors, as well as steroid synthesis, were investigated by combining in vitro and in silico approaches. Among the primary metabolites, only 4-MEHTM (4-mono-(2-ethylhexyl) trimellitate) showed agonist activities on ERs and TRs, while three diesters were TR antagonists at non-cytotoxic concentrations. These results were completed by docking experiments which specified the ER and TR isoforms involved. A mixture of 2/1-MEHTM significantly increased the estradiol level and reduced the testosterone level in H295R cell culture supernatants. The oxidized secondary metabolites of TEHTM had no effect on ER, AR, TR receptors or on steroid hormone synthesis. Among the fourteen metabolites, these data showed that two of them (4-MEHTM and 2/1-MEHTM) induced effect on hormonal activities in vitro. However, by comparing the concentrations of the primary metabolites found in human urine with the active concentrations determined in bioassays, it can be suggested that the metabolites will not be active with regard to estrogen, androgen, thyroid receptors and steroidogenesis-mediated effects.

Comparative Effects of Di-(2-ethylhexyl)phthalate and Di-(2-ethylhexyl)terephthalate Metabolites on Thyroid Receptors: In Vitro and In Silico Studies.

Plasticizers added to polyvinylchloride (PVC) used in medical devices can be released into patients' biological fluids. Di-(2-ethylhexyl)phthalate (DEHP), a well-known reprotoxic and endocrine disruptor, must be replaced by alternative compounds. Di-(2-ethylhexyl) terephthalate (DEHT) is an interesting candidate due to its lower migration from PVC and its lack of reprotoxicity. However, there is still a lack of data to support the safety of its human metabolites with regard to their hormonal properties in the thyroid system. The effects of DEHT metabolites on thyroid/hormone receptors (TRs) were compared in vitro and in silico to those of DEHP. The oxidized metabolites of DEHT had no effect on T3 receptors whereas 5-hydroxy-mono-(ethylhexyl)phthalate (5-OH-MEHP) appeared to be primarily an agonist for TRs above 0.2 µg/mL with a synergistic effect on T3. Monoesters (MEHP and mono-(2-ethylhexyl)terephthalate, MEHT) were also active on T3 receptors. In vitro, MEHP was a partial agonist between 10 and 20 µg/mL. MEHT was an antagonist at non-cytotoxic concentrations (2-5 µg/mL) in a concentration-dependent manner. The results obtained with docking were consistent with those of the T-screen and provide additional information on the preferential affinity of monoesters and 5-OH-MEHP for TRs. This study highlights a lack of interactions between oxidized metabolites and TRs, confirming the interest of DEHT.

Polypharmacy in older patients: identifying the need for support by a community pharmacist.

BACKGROUND: The community pharmacist is a key player in medication reviews of older outpatients. However, it is not always clear which individuals require a medication review. The objective of the present study was to identify high-priority older patients for intervention by a community pharmacist. METHODS: As part of their final-year placement in a community pharmacy, pharmacy students conducted 10 interviews each with older adults (aged 65 or over) taking at least five medications daily. The student interviewer also offered to examine the patient's home medicine cabinet. An interview guide was developed by an expert group to assess the difficulties in managing and taking medications encountered by older patients. RESULTS: The 141 students interviewed a total of 1370 patients (mean age: 81.5; mean number of medications taken daily: 9.3). Of the 1370 interviews, 743 (54.2%) were performed in the patient's home, and thus also included an examination of the home medicine cabinet. Adverse events were reported by 566 (42.0%) patients. A total of 378 patients (27.6%) reported difficulties in preparing, administering and/or swallowing medications. The inspections of medicine cabinets identified a variety of shortcomings: poorly located cabinets (in 15.0% of inspections), medication storage problems (21.7%), expired medications (40.7%), potentially inappropriate medications (15.0%), several different generic versions of the same drug (19.9%), and redundant medications (20.4%). CONCLUSIONS: In a community pharmacy setting, high-priority older patients for intervention by a community pharmacist can be identified by asking simple questions about difficulties in managing, administering, taking or storing medications.

In vitro and in silico hormonal activity studies of di-(2-ethylhexyl)terephthalate, a di-(2-ethylhexyl)phthalate substitute used in medical devices, and its metabolites.

Plasticizers added to polyvinylchloride used in medical devices can be released into patients' biological fluids. The substitution of di-(2-ethylhexyl)phthalate (DEHP) by alternative plasticizers is essential but their safety must be demonstrated. DEHP, di-(2-ethylhexyl)terephthalate (DEHT) and their metabolites were investigated using level 2 Organization for Economic Co-operation and Development bioassays to screen for in vitro hormonal changes. Differences between the DEHP and DEHT metabolites were observed. Albeit weak, the hormonal activities of DEHT-derived metabolites, e.g., 5-OH metabolite of mono-(ethylhexyl)terephthalate (5-OH-MEHT), were detected and the results of docking experiments performed on estrogen receptor alpha and androgen receptor agreed with the biological results. A co-stimulation of human estrogen receptor alpha and human androgen receptor was also observed. With regard to steroidogenesis, a 16-fold increase in estrogen synthesis was measured with 5-OH-MEHT. Therefore, even if DEHT remains an interesting alternative to DEHP because of its low migration from medical devices, it seems important to verify that multi-exposed patients in neonatal intensive care units do not have urinary levels of oxidized metabolites, in particular 5-OH-MEHT, suggesting a potential endocrine-disrupting effect.

[Community pharmacists' interventions to prevent and screen chronic kidney disease patients]. / Implication du pharmacien d'officine dans le parcours de soins de la maladie rénale chronique.

Chronic kidney disease (CKD) is a major concern of public health. The pharmacist is known as a health practitioner involved in prevention and therapeutic education. Our study aimed at defining the impact of community pharmacists' interventions for preventing and screening CKD. In our observational prospective study of 5 months conducted in 109 community pharmacy, we included 2 groups of patients: A (therapeutic optimization): CKD patients and B (CKD screening): population at risk. In group A, we included 354 patients, mainly women (51.2%), in stage 3 of CKD, mean age 73 years old, with hypertension alone (40.6%) or associated with diabetes (44%). About 70% of the patients had a follow up by a nephrologist and 45% of them were good adherent according to the Morisky-Green self-report. However, approximately 20% of patients did not have nephroprotective treatments in their regimen although they were on stage 3 or 4 CKD patients, and about half of them were not aware of medical situations at risk. Concerning group B, 532 patients were included. The pharmaceutical interventions screened 10% of patients with a GFR<60mL/min/1.73m2. The community pharmacists' interventions helped to optimize the therapeutic management of CKD patients and in the early screening of patients at risk. More studies are needed to extrapolate our observations to a larger population.

Docking study: PPARs interaction with the selected alternative plasticizers to di(2-ethylhexyl) phthalate.

Phthalates, used in medical devices (MDs), have been identified as reproductive and developmental toxicants. Their toxicity varies somewhat depending on the specific phthalate and is in part linked to the activation of Peroxisome Proliferating-Activated Receptors (PPARs). So, the use of MDs containing targeted phthalates such as di(2-ethylhexyl) phthalate (DEHP) has been challenged by European directive 2007/47/EC. Therefore, MDs manufacturers were forced to quickly find replacement plasticizers. However, very little toxicological and epidemiological studies are available on human health. So, we proceeded to dock these chemicals in order to identify compounds that are likely to interact with PPARs binding sites. The results obtained are generally very mixed on the harmlessness of these alternatives. Moreover, no data exist on the biological effects of their possible metabolites. As DEHP toxicity resulted mainly from its major metabolites, generalizing the use of these plasticizers without conducting extensive studies on the possible effects on human health of their metabolites seems inconceivable.

Pharmacokinetic evaluation of a novel benzopyridooxathiazepine derivative as a potential anticancer agent.

BACKGROUND/AIMS: The in vivo metabolic profile of a benzopyridooxathiazepine (BPT) derivative, a potent tubulin polymerization inhibitor with a promising in vitro activity, was investigated. METHODS: The quantification of the BPT derivative and the identification of metabolites in the plasma of Wistar rats after i.p. and oral administration of 10 mg/kg were performed by the HPLC-mass spectrometry method. RESULTS: Following a single i.p. dose of the BPT derivative, the plasma concentrations showed a biexponential decay (with a rapid decline) followed by a slow decay with a terminal half-life of 77.90 min. The area under the concentration-time curve from time 0 to infinity (AUC0-∞) was 18.90 µg/ml·min. After oral administration, the plasmatic concentrations reached a peak of 0.06 µg/ml at 35 min and then decayed with a half-life of 108 min. The AUC0-∞ was 10.25 µg/ml·min, representing 54.2% of the relative bioavailability. The compound was well distributed in the body, and its elimination seemed to be fast, regardless of the administration route. The major metabolic pathways were demethylation and hydroxylation reactions, both followed by conjugation with glucuronic acid. CONCLUSION: In rats, the BPT derivative is well distributed and undergoes extensive metabolism, leading to several metabolites. With promising in vitro activity and very good oral bioavailability, this compound seems to be an attractive candidate for further development as an anticancer agent.

Plasma malondialdehyde levels in children on 12-hour cyclic parenteral nutrition: are there health risks?

In children undergoing total parenteral nutrition (PN), lipids provide a key source of calories preventing or correcting energy deficits and improving outcomes. However, some of these lipids may undergo oxidation leading to the formation of malondialdehyde (MDA), a cytotoxic byproduct found in these patients. This paper aims to describe a sensitive method for detecting MDA and discuss its role in certain diseases commonly found in children on regular PN. To quantify MDA levels in children benefitting from long-term cyclic PN, a reliable and sensitive high-performance liquid chromatographic method based on a 1-step derivatization/extraction procedure analysis with ultraviolet determination at 305 nm wavelength was achieved. In control children without PN, MDA levels were on average 3.30 ± 0.08 µM. However, in children nourished intravenously by fat emulsion for a long time, in which liver problems have been identified, the circulating concentrations of MDA ranged widely at both the start and the end of a session, 3- to 10-fold, respectively, in comparison with the levels measured in controls. This finding indicates that PN administrated long term raises plasma MDA levels, indicating chronic exposure and therefore a possible health risk, particularly liver damage. This preliminary study using a limited number of patients and controls showed that children undergoing long-term PN are strongly exposed to MDA, which must be considered as a potent toxic compound rather than a simple marker of lipid peroxidation.

In vitro pharmacokinetic profile of a benzopyridooxathiazepine derivative using rat microsomes and hepatocytes: identification of phases I and II metabolites.

In the present study, the in vitro metabolic behavior of a benzopyridooxathiazepine (BZN), a potent tubulin polymerization inhibitor, was investigated by liquid chromatography-UV detection (LC-UV). First, simple and fast LC-UV methods have been optimized and validated to evaluate the pharmacokinetic profile of BZN using rat liver microsomes or hepatocytes primary cultures suspensions. Whatever the medium investigated, baseline resolution between the internal standard and BZN was achieved in a run time less than 15min using a Symmetry ODS column (150mm×4.6mm i.d., 5µm) and a mobile phase consisting of acetonitrile/water/formic acid 60:40:0.1 (v/v/v). Linearity was assessed in the 0.1-50µM and in the 0.05-5µM concentration ranges, respectively, in microsomal and hepatocyte matrix. According to the novel strategy based on the build of the accuracy profile, total error of the developed methods was included within the ±10% limits of acceptance. Then, from incubation of BZN with both liver microsomes and or hepatocytes, structural informations on phase I and phase II metabolites were acquired using liquid chromatography coupled to electrospray orbitrap mass spectrometer (LC-MS). Mass spectrum, double bond equivalent and elemental composition were useful data to access to the chemical structure of each metabolite. In microsomal suspension, four main metabolites were observed including monohydroxylation and dihydroxylation of the benzopyridooxathiazepine core, demethylation of the methoxyphenyl moiety, as well as their combinations. The phase II metabolites detected in hepatocytes suspension were the glucuronide adducts of both demethylated BZN and mono-oxygenated BZN. Based on the structural elucidation of the metabolites detected, we proposed an in vitro metabolic pathway of BZN, a new tubulin polymerization inhibitor.

Strong variability of di(2-ethylhexyl)phthalate (DEHP) plasmatic rate in infants and children undergoing 12-hour cyclic parenteral nutrition.

BACKGROUND: Medical devices such as perfusion materials in polyvinyl chloride may contain di(2-ethylhexyl)phthalate (DEHP). Several studies have questioned the harmlessness of phthalates, which have been shown to have toxic effects on the reproductive system and general development. This study was designed to assess DEHP exposure in infants and children benefitting from cyclic parenteral nutrition (PN). The results are compared with those obtained from children used as controls and receiving no PN, to estimate the potential risk to this pediatric population, taking into account exposure levels and already published data. METHODS: Plasmatic concentrations of DEHP were assessed by high-performance liquid chromatography from blood samples taken from 22 children at the start and finish of a 12-hour cyclic PN period and compared with those obtained from 20 control children of comparable age and gender. RESULTS: After a 12-hour cyclic PN period, DEHP migration varied widely among the patients. The concentrations were not quantifiable in 4 children at the start of PN. In 1 child, they were quantifiable neither at the start nor at the end of PN. However, for 17 children, DEHP concentrations were quantifiable at the start of PN and were very variable from one child to another. At the end, DEHP concentrations had significantly but variably increased in these children. No trace of DEHP was found in the blood samples from 20 healthy controls. CONCLUSION: Considering published data on phthalate toxicity, it would appear advisable to encourage the use of medical devices that are either phthalate or DEHP free.

Correlation between exposure to phthalates and concentrations of malondialdehyde in infants and children undergoing cyclic parenteral nutrition.

BACKGROUND: Plasticizers such as di(2-ethylhexyl) phthalate (DEHP) are added to polyvinyl chloride (PVC) to confer flexibility. However, DEHP is associated with reproductive disorders in humans. Because of its noncovalent bond to the PVC matrix, this plasticizer tends to leach easily. Infants and children undergoing cyclic, long-term parenteral nutrition (PN) could be particularly at risk of potential toxicity from DEHP due to regular exposure. Malondialdehyde (MDA) is one of the most commonly used markers of free radical activity. The purpose of this study was to investigate how long-term exposure to phthalate affects the plasmatic rate of MDA. METHODS: Studies were performed on 7 randomized infants and children on regular cyclic, long-term PN, and the results were compared with those of 5 nontreated infants. The circulating concentrations of DEHP in children and infants during the PN therapy were measured by high-performance liquid chromatography. The concentrations were assessed before and after the PN session. In the same way, plasma MDA concentrations were measured. RESULTS: The circulating concentrations of DEHP before and after a 10- to 11-hour cyclic PN treatment in 7 infants and children under regular perfusion ranged widely, showing a significant increase after the treatment among all the patients. The same phenomenon observed with the rate of MDA showed that the 2 events are closely dependent. Therefore, long-term exposure to DEHP during cyclic PN raised plasma MDA levels, indicating increased oxidative stress. CONCLUSION: Long-term exposure to DEHP during PN increased free radical activity in vivo.

Experimental study on infusion devices containing polyvinyl chloride: to what extent are they di(2-ethylhexyl)phthalate-free?

The use of medical devices containing highly criticized phthalates including di(2-ethylhexyl) phthalate (DEHP) has been challenged by European directive 2007/47/CE, put into effect in March 2010. New plasticizers are now being used to soften PVC in medical devices: trioctyltrimellitate (TOTM), di-isononyl-cyclohexan-1,2-dicarboxilate (DINCH) and di(2-ethylhexyl) terephthalate (DEHT). To quantify DEHP in nine DEHP-free medical devices made of PVC softened by alternative plasticizers, high performance liquid chromatography analysis with ultraviolet detection at 220 nm wavelength was achieved. An NMR spectroscopy was performed to confirm DEHP presence. Only two medical devices out of the nine tested were truly without DEHP. One of them showed traces of DEHP exceeding the threshold contamination of 0.1% in plastic mass set by REACH regulations. TOTM plasticizer is still incriminated when polyvinyl-chloride (PVC) is contaminated with DEHP. Manufacturers must verify the purity of their raw material, not only on PVC, but also on other soft plastics entering into the composition of medical infusion devices. The clinical consequences of exposure to certain levels of DEHP have not been evaluated. A solution could be to use alternative PVC-free materials.

Molecular modelling of phthalates - PPARs interactions.

Di(2-ethylhexyl) phthalate (DEHP) is the most widely plasticizer for polyvinyl chloride (PVC) that is used in plastic tubes, in medical and paramedical devices as well as in food storage packaging. The toxicological profile of DEHP has been evaluated in a number of experimental animal models and has been extensively documented. Its toxicity is in part linked to the activation of the peroxisome proliferator-activated receptor alpha (PPAR(alpha)). As a response, an intensive research for a new, biologically inert plasticizer has been initiated. Among the alternative studied, tri(2-ethylhexyl) trimellitate (TEHTM) or trioctyl trimellitate (TOTM) has attracted increasing interest. However, very little information is available on their biological effects. We proceeded to dock TOTM, DEHP and its metabolites in order to identify compounds that are likely to interact with PPAR(alpha) and PPAR(gamma) binding sites. The results obtained hint that TOTM is not able to bind to PPARs and should therefore be safer than DEHP.

Pharmacokinetics and dialysability of naltrexone in patients undergoing hemodialysis.

The disposition of naltrexone (NLT) (REVIA), an opioid antagonist intended for patients with impaired renal function and with severe intractable itching refractory to regular antipruritic therapy, was characterized. Hemodialysis effects on both efficacy and elimination of NLT also were assessed. We developed a simple, sensitive and selective reverse-phase high-performance liquid chromatographic (HPLC) method for measuring NLT plasma concentration in hemodialysis patients treated to relieve pruritus. NLT and the internal standard, naloxone (NLX) were extracted from plasma using a solid-phase extraction method with sep-pack C18 cartridge. The method was employed to determine both naltrexone pharmacokinetics and dialysability parameters during 4-h in dialyzed patients with chronic renal impairment. Thus, seven patients (2 men, 5 women) with end-stage renal disease and pruritus on regular hemodialysis were included. They received one tablet of NLT (Revia, 50 mg) orally prior dialysis session. The Cmax at the inlet and at the outlet the dialyzer were higher (255+/-117 ng/mL and 206+/-137 ng/ml respectively) in comparison with healthy subjects (9 - 44 ng/mL). The decrease hepatic first-pass metabolism of NLT consecutive to end-stage renal disease and the renal impairment could explain the increased levels of the drug in plasma. Tmax before and after dialysis plates remain unchanged as healthy subjects (approximately 1h). With regard to dialysability, a high dialyzer extraction ratio averating 30 % was found with a low dialysis clearance of 58.70+/-17 mL/min. The amount removed by dialysis is only 1.27 mg. We concluded that hemodialysis has little effect on NLT blood levels, and consequently on drug pharmacokinetics, when the drug is delivered to dialyzed patients following oral route. Thus, dosage adjustement is not required in the presence of advanced dialysis-dependant renal failure. In patients with end-stage renal disease, hemodialysis does not result in clinically significant alterations in the disposition of NLT. Post-dialysis supplementation is not required. These data suggest that there is no pharmacokinetic basis for modification of the initial dosage, but in view of NLT plasma concentration levels in the patients, a clinician could determine whether dosage adjustment are necessary and, if so, make the required calculations accurately.