PurposeMedicine acceptability, which is of the utmost importance for vulnerable patients’ adherence, is driven by both user and product characteristics. Herein, a novel multivariate approach integrating the many aspects of acceptability is used to discriminate positively and negatively accepted medicines in the older population.MethodsAn observational study was carried out in eight hospitals and eight nursing homes to collect a large set of real-life data on medicines uses in older patients (≥65 years). Mapping and clustering explored these multiple observational measures and summarised the main information into an intelligible reference framework. Resampling statistics were used to validate the model’s reliability.ResultsA three-dimensional map and two clusters defining acceptability profiles, as positive or negative, emerged from the 1079 evaluations. Factors of interest (medicines, user features…) were positioned on the map at the barycentre of their evaluations and assigned to an acceptability profile. Focusing on patients’ ability to swallow, we have highlighted the tool’s efficacy in demonstrating the impact of user features on medicine acceptability.ConclusionsThis multivariate approach provides a relevant judgement criterion for this multi-dimensional concept. Facilitating the choice of the most appropriate dosage form to achieve optimal acceptability in a targeted population, this tool is of real potential to improve clinical decisions.
Introduction Medicine acceptability is a multi-faceted concept driven by both product and user characteristics. Although a key factor for treatment effectiveness, especially in vulnerable populations, knowledge of those medicine features that best promote individual user acceptability remains fragmented. Focusing on paracetamol, this study has explored the appropriateness of pharmaceutical products in different dosage forms to achieve adequate patient acceptability from infants to centenarians. Methods This observational, multicentre, prospective study was carried out in 10 hospitals, 8 nursing homes and over 150 community dispensaries. Observers reported several behaviours/events evaluating acceptability for 1016 different pharmaceutical product uses in paediatrics (<18y.) and 1288 in the elderly (≥65y.). Using mapping and clustering, a multivariate approach offered an intelligible reference framework for each population, providing comprehensive scores: positively or negatively accepted. Results Among all the evaluations supporting the acceptability reference frameworks, there were 502 reports on paracetamol products intake. Herein we focused on the 5 products with ≥30 evaluations. Although oral suspension and powder for oral solution were positively-accepted in the paediatric group, the powder had a higher rate of negative patient reaction (p<0.001). Of those that received this formulation, 72% were ≤8y., and therefore suitable to receive the better accepted oral suspension. In the elderly, patients with swallowing disorders were preferentially treated with such powders (p<0.001), which were less often fully taken than orally disintegrating tablets (p<0.001). Even in those patients ≥90y., capsule formulations appeared to be the best accepted product in patients without swallowing alterations, and thus could be a suitable alternative to the powder in this population. Conclusions By better integrating patient characteristics when choosing dosage forms, clinicians and caregivers may improve treatment acceptability and adherence. Moreover, hospitals and healthcare institutions could optimise purchasing to best suit their local population, disseminating information to help staff align specific dosage forms to targeted patients.
BackgroundIn institutional care, oral liquid pharmaceutical products are widely prescribed for older patients, especially for those with swallowing disorders. As medicines acceptability is a key factor for compliance in the older population, this study investigated the acceptability of oral liquid pharmaceutical products in this targeted population.MethodsAn observational, multicenter, prospective study was conducted in eight geriatric hospitals and eight nursing homes in France. Observers reported several behaviours/events describing the many aspects of acceptability for various pharmaceutical products’ uses in patients aged 65 and older. Acceptability scores of oral liquid pharmaceutical products were obtained using an acceptability reference framework (CAST - ClinSearch Acceptability Score Test®): a 3D-map summarizing the different users’ behaviors, with two clusters defining the positively and negatively accepted profiles materialized by the green and red zones, respectively.ResultsAmong 1288 patients included in the core study and supporting the acceptability reference framework, 340 assessments were related to the administration of an oral liquid pharmaceutical product. The mean age of these patients was 87 (Range [66-104y]; SD = 6.7), 68% were women and 16% had swallowing disorders. Globally, the oral liquid pharmaceutical products were classified as “positively accepted,” the barycenter of the 340 assessments, along with the entire confidence ellipses surrounding it, were positioned on the green zone of the map. Sub-populations presenting a different acceptability profile have also been identified. For patients with swallowing disorders, the oral liquid pharmaceutical products were classified as “negatively accepted,” the barycenter of the 53 assessments along with 87% of its confidence ellipses were associated with this profile. A gender difference was observed for unflavored oral liquids. In women, they were classified “negatively accepted,” the barycenter of the 68 assessments with 75% of its confidence ellipses were located in the red zone, while they were classified “positively accepted” in men.ConclusionThis study showed that oral liquid pharmaceutical products are a suboptimal alternative to solid oral dosage forms in patients with swallowing disorders. To ensure an optimal acceptability, prescribers should also consider the presence of a taste-masker in these oral liquids. As highlighted herein, palatability remains crucial in older populations, especially for women.
cPlacental transfer of the HIV protease inhibitor darunavir was investigated in 5 term human cotyledons perfused with darunavir (1,000 ng/ml) in the maternal to fetal direction. The mean (؎ the standard deviation [SD]) fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 30 to 90 min) was 15.0% ؎ 2.1%, and the mean (؎SD) clearance index (darunavir FTR/ antipyrine FTR) was 40.3% ؎ 5.8%. This shows that darunavir crosses the placenta at a relatively low rate, resulting in fetal exposure.T he use of antiretroviral drugs has allowed for a spectacular reduction in mother-to-child transmission (MTCT) of HIV in the industrialized countries, with a current rate of Յ0.5% in France (1, 2). Darunavir is an HIV protease inhibitor (PI) that is increasingly used in combination with other drugs to treat HIV infection. It is now considered a first-line option in pregnant women (3, 4), although few data are available to date on its effects during pregnancy. It is classified by the FDA in pregnancy category C (4), meaning that animal studies have failed to demonstrate a risk to the fetus, but there have been no adequate and well-controlled studies in pregnant women. Most of the adverse events described are related to nucleoside reverse transcriptase inhibitors, particularly mitochondrial disease (6) and hematologic or cardiac function toxicities (7), whereas few antiretroviral drugs have shown any relation to the risk of malformations (8). The HIV protease inhibitors are largely well tolerated in utero (9), although there are reports of elevated neonatal bilirubin levels following atazanavir exposure (10) and transient adrenal dysfunction following perinatal lopinavir-ritonavir treatment (11). Determining fetal exposure to a specific drug is important in estimating its potential for preexposure prophylaxis (12), as well as its risk for toxicities in the fetus. Since data from animal studies are difficult to extrapolate to humans due to the differences in placental physiology, human studies are required. There are some data on cord blood concentrations of darunavir at delivery, but these data reflect only a single time point, and larger series are required for population pharmacokinetic modeling (13,14). The ex vivo human cotyledon is an accepted model in which to study and interpret placental transfer (15).The purpose of this study was to investigate the placental transfer of darunavir in the ex vivo human perfused cotyledon.Placentas were collected after uneventful pregnancies and term deliveries (Ն37 weeks gestational age) in a single center (a university hospital maternity department in Colombes, France) and were rapidly perfused on site. Written informed consent was obtained from each woman who donated a placenta, according to French bioethics guidelines (article L1211-2 of the Public Health Code).The darunavir base was provided by the manufacturer (Janssen, Issy-les-Moulineaux, France) as antipyrine-phosphate-buffered saline (PBS). Bradford reagent was purchased from SigmaAldrich (Saint Quentin Fallav...
e Placental transfers of the HIV nonnucleoside reverse transcriptase inhibitor rilpivirine were investigated in 8 term human cotyledons perfused with rilpivirine (400 ng/ml) in the maternal-to-fetal direction. The mean fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 15 to 90 min) was 26% ؎ 8% (mean ؎ standard deviation), and the clearance index (rilpivirine FTR/antipyrine FTR) was 61% ؎ 20%. This shows that rilpivirine crosses the placenta at a relatively high rate, suggesting that the fetus is exposed to the compound during treatment of the mother.A ntiretroviral drugs are remarkably effective for preventing vertical transmission of HIV-1, resulting in a decline in the rate of transmission, which is now less than 0.5% in France (1, 2). Current guidelines recommend antiretroviral therapy for all HIVinfected pregnant women for their own health and to prevent transmission (3, 4)., a diarylpyrimidine analog, is a nonnucleoside reverse transcriptase inhibitor (NNRTI) which is increasingly used to treat HIV infection and in recent guidelines is considered a first-line treatment. It is available in a single-tablet formulation in combination with tenofovir and emtricitabine (Complera-Eviplera). Rilpivirine is classified as a pregnancy category B drug by the Food and Drug Administration (4), which means that animal studies have failed to demonstrate a risk to the fetus, but there have been no adequate and well-controlled studies in HIV-1-infected pregnant women. To date, only one report has been published on two cases of rilpivirine use in pregnant women (5), in which the plasma concentrations of rilpivirine were lower than would be expected in nonpregnant women. Placental transfer was studied in one of these two cases. Currently, there are no data on the safety of rilpivirine use during pregnancy.Determining fetal exposure is important for all new medications in order to estimate the potential for preexposure prophylaxis and the risk for toxicities to the fetus. A number of adverse events have been reported following perinatal exposure to antiretroviral medications, including mitochondrial diseases (6). Since data from animal studies are difficult to extrapolate to humans due to differences in placental physiology, other preclinical approaches are required.The ex vivo human cotyledon is an accepted model used to study and interpret placental transfer (7,8). The purpose of this study was to investigate the placental transfer of rilpivirine in an ex vivo perfused human cotyledon.Placentas were collected after uncomplicated pregnancy with full-term delivery (Ն37 weeks gestational age) in mothers who were seronegative for HIV and hepatitis B and C viruses and had taken no medication, except for vitamin supplements and perimedullar analgesia. They were collected in a single center, the maternity ward of the Hôpitaux Universitaires Paris-Nord Val de Seine (Colombes, France), and were rapidly perfused on site. Written informed consent was obtained from each of the women who donated a placenta, acc...
Hypothesis and Background: The clinical treatment of sudden sensorineural hearing loss currently relies on the administration of steroids, either systemically or via intratympanic injections. Intratympanic injections bypass the hemato-cochlear barrier, reducing its systemic side effects. The efficacy of the injections is limited through rapid drug clearance via the Eustachian tube, and through nonoptimal properties of slow-release drug carriers. A new slow-release drug delivery vehicle based on hexyl-substituted-poly-lactic-acid (HexPLA), with the highest possible safety profile and complete bio-degradability, has been evaluated for safety and efficacy in a standardized guinea pig model of intratympanic injection. Methods: A total of 83 animals received through retrobullar injection either empty Nile-red-colored HexPLA vehicle, 5%-dexamethasone-HexPLA, 5%-dexamethasone suspension, or a sham operation. Long-term residence time of vehicle, biocompatibility, click- and pure-tone hearing thresholds, and dexamethasone levels in the perilymph were prospectively assessed. Results: At 1 week after injection, HexPLA vehicle was morphologically present in the middle ear and perilymph levels in the 5%-dexamethasone-HexPLA were on average 2 to 3 μg/ml and one order of magnitude higher compared with those of the 5%-dexamethasone suspension group. No significant postoperative morphological or functional changes were observed up to 3 months postdelivery. Conclusions: HexPLA is safe, fully biocompatible, and efficient for sustained high-dose, intratympanic delivery of dexamethasone at least for 1 week and therefore of high interest for the treatment of sudden sensorineural hearing loss and other acute inner ear diseases. Due to the favorable chemical properties, a wide range of other drugs can be loaded into the vehicle further increasing its potential value for otological applications.
In Table 1, the placenta 6 CM and CF values were inadvertently repeated for placenta 7. The table should appear as shown below.
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