Potentially inappropriate medications and anticholinergic and sedative burden in older patients with haemophilia or von Willebrand disease: The M'HEMORRH-AGE study.

WHAT IS KNOWN AND OBJECTIVE: In older patients, multiple chronic conditions lead to the intake of multiple medications and a higher risk of adverse drug events. The exposure to inappropriate medications in older patients with bleeding disorders is poorly explored. The aim of this study was to describe the exposure to potentially inappropriate medications (PIMs) and medications with anticholinergic and sedative properties in older community-dwelling patients with haemophilia or von Willebrand Disease (VWD). METHODS: The M'HEMORRH-AGE study (Medication in AGEd patients with HAEMORRHagic disease) is a multicentre prospective observational study. Community-dwelling patients over 65 years with haemophilia or VWD were included in the study. PIMs were identified using the EU(7)-PIM list, and the anticholinergic and sedative drug exposure was measured using the Drug Burden Index. RESULTS AND DISCUSSION: 142 older community-dwelling patients with haemophilia (n = 89) or VWD (n = 53) were included (mean age: 72.8 ± 5.8 years). PIMs were used by 45.8% of older patients and were mainly represented by cardiovascular (34.9%), nervous systems (26.7%) and alimentary tract and metabolism PIMs (25.6%). Regarding anticholinergic and/or sedative medications, 37.3% of older patients were exposed mainly due to nervous system medications (68.3%), for example analgesics. WHAT IS NEW AND CONCLUSION: The M'HEMORRH-AGE study showed the exposure to PIMs and anticholinergic/sedative medications was high in older community-dwelling patients with haemophilia or VWD. Interventions focusing on deprescription of these inappropriate medications should be conducted in this specific population.

Intra-Articular Hyaluronic Acid and Chondroitin Sulfate: Pharmacokinetic Investigation in Osteoarthritic Rat Models.

BACKGROUND: Viscosupplementation of synovial fluid with intra-articular (IA) injections of hyaluronic acid (HA) is widely used for symptomatic treatment of osteoarthritis (OA). Herein we present HCS, a new combination of chemicals, associating HA and chondroitin sulfate (CS), both members of the glycosaminoglycan (GAGs) family, which are major components of the joint. HA provides viscosity to the synovial fluid and CS provides elasticity to the cartilage. Reduced levels of HA and CS are observed in OA joints and are associated with progressive cartilage damage and loss. OBJECTIVE: The objective of the study was to evaluate the pharmacokinetic (PK) properties of both HA and CS after IA administration in a validated OA animal model. METHODS: Motion impairment measurements and histological examinations were used to validate the ability of an IA injection of mono-iodoacetate (MIA) in the knee of rats to induce OA symptoms. Then, the PK properties of HA and CS after IA administration were characterized and each active ingredient was independently profiled: HA was labeled with tritium (3H-HA) and CS was labeled with carbon 14. (14C-CS) The final radio-labeled solution reproduced the cold HCS formulation. RESULTS: Four male Sprague-Dawley rats received a 1 mg MIA injection on day 1, then motor impairment was monitored from day 4 to day 18. Chondrocyte necrosis, loss of GAGs and other cartilage damage were observed. Twelve other rats received a MIA IA injection on day 1 then a radio-labeled HCS IA injection (50 µL) on day 8. Plasma and knee cartilage were collected postadministration and the terminal half-life was similar in both matrices (about 5 days), for both 3H-HA and 14C-CS. CONCLUSIONS: Despite differences in their molecular size, HA and CS showed PK behavior similarly characterized by prolonged residence inside the joint and slow release in plasma, favoring long-term beneficial effects. (Curr Ther Res Clin Exp. 2020; 92:XXX-XXX).

Toxicologic Pathology Forum*: Opinion on Integrating Innovative Digital Pathology Tools in the Regulatory Framework.

Digital pathology is defined as the ability to examine digitized microscopic slides and to generate qualitative and quantitative data. The field of digital pathology is rapidly evolving and has the potential to revolutionize toxicologic pathology. Techniques such as automated 2-D image analysis, whole slide imaging, and telepathology are already considered "mature" technologies and have been used for decades in exploratory studies; however, many organizations are reluctant to use digital pathology in regulatory toxicology studies. Innovative technologies using digitized slides including high-content imaging modalities and artificial intelligence are still under development but are increasingly used in toxicologic pathology. While software validation requirements are already described, clear guidance for application of these rules to the digital pathology field are few and the acceptance of these technologies by regulatory authorities remains necessary for successful adoption of digital pathology into the mainstream of toxicologic pathology. This topic was discussed during a roundtable at the 2018 Annual Congress of the French Society of Toxicologic Pathology. This opinion article summarizes the discussion regarding the current questions and challenges on the integration of innovative digital pathology tools within a good laboratory practice framework and is meant to stimulate further discussion among the toxicologic pathology community. *This is an opinion article submitted to the Toxicologic Pathology Forum and does not constitute an official position of the Society of Toxicologic Pathology or the journal Toxicologic Pathology. The views expressed in this article are those of the authors and do not necessarily represent the policies, positions, or opinions of their respective agencies and organizations. The Toxicologic Forum is designed to stimulate broad discussion of topics relevant to regulatory issues in Toxicologic pathology. Readers of Toxicologic Pathology are encouraged to send their thoughts on these articles or ideas for new topics to toxicologicpathologyforum@toxpath.org .

Intranodal Angiomyomatous Hamartoma in a Cynomolgus Monkey.

We describe here an angiomyomatous hamartoma in the right axillary lymph node of a three-year-old male cynomolgus monkey ( Macaca fascicularis), used as a control subject in a short-term toxicity study. This is a very rare lesion that has been reported almost exclusively in inguinal lymph nodes, and to date only in human beings. In the present case, light microscopy revealed partial replacement of the lymph node parenchyma by a disorganized, irregular vascular network, sparsely distributed smooth muscle cells, and a fibro-adipocytic stroma. This was considered to be fortuitous given the age of the animal, with no clinical or toxicological significance. To the best of our knowledge, this is the first report of an intranodal angiomyomatous hamartoma in a nonhuman animal species.

OBE022, an Oral and Selective Prostaglandin F2α Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor.

Preterm birth is the major challenge in obstetrics, affecting ∼10% of pregnancies. Pan-prostaglandin synthesis inhibitors [nonsteroidal anti-inflammatory drugs (NSAIDs)] prevent preterm labor and prolong pregnancy but raise concerns about fetal renal and cardiovascular safety. We conducted preclinical studies examining the tocolytic effect and fetal safety of the oral prodrug candidate OBE022 [(S)-2-amino-3-methyl-butyric acid (S)-3-{[(S)-3-(biphenyl-4-sulfonyl)-thiazolidine-2-carbonyl]-amino}-3-(4-fluoro-phenyl)-propyl ester] and its parent OBE002 [(S)-3-(biphenyl-4-sulfonyl)-thiazolidine-2-carboxylic acid [(S)-1-(4-fluoro-phenyl)-3-hydroxy-propyl]-amide], both potent and highly selective antagonist of the contractile prostaglandin F2α (PGF2α ) receptor (FP). Efficacy of OBE022 and OBE002, alone and in combination with other tocolytics, was assessed in human tissues and pregnant animal models for inhibition of uterine contraction and delay of parturition. Selective safety of OBE022 and/or OBE002, compared with NSAID indomethacin, was assessed on renal function, closure of the ductus arteriosus, and inhibition of platelet aggregation. In in vitro studies, OBE002 inhibited spontaneous, oxytocin- and PGF2α -induced human myometrial contractions alone and was more effective in combination with atosiban or nifedipine. In in vivo studies, OBE022 and OBE002 reduced spontaneous contractions in near-term pregnant rats. In pregnant mice, OBE022 delayed RU486 [(8S,11R,13S,14S,17S)-11-[4-(dimethylamino)phenyl]-17-hydroxy-13-methyl-17-prop-1-ynyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one] -induced parturition and exerted synergistic effects in combination with nifedipine. OBE022 and/or OBE002 did not show the fetal side effects of ductus arteriosus constriction, impairment of kidney function, or inhibition of platelet aggregation observed with indomethacin. Orally active OBE022 and OBE002 exhibits potent tocolytic effects on human tissues ex vivo and animal models in vivo without causing the adverse fetal side effects seen with indomethacin. Selectively targeting the FP receptor in combination with existing tocolytics may be an effective strategy for preventing or delaying preterm delivery.

A human relevance investigation of PPARα-mediated key events in the hepatocarcinogenic mode of action of propaquizafop in rats.

Propaquizafop is an herbicide with demonstrated hepatocarcinogenic activity in rodents. A rodent-specific mode of action (MOA) in the liver via activation of peroxisome proliferator-activated receptor α (PPARα) has been postulated based on existing data. Experience with PPARα-inducing pharmaceuticals indicates a lack of human relevance of this MOA. The objective of the present investigation was to evaluate the dependency of early key events leading to liver tumors on PPARα activation in wildtype (WT) compared to PPARα-knockout (KO) rats following 2 weeks exposure to 75, 500 and 1000 ppm propaquizafop in the diet. In WT rats, both WY-14643 (50 mg/kg bw/day) and propaquizafop (dose-dependently) induced marked increases in liver weights, correlating with liver enlargement and hepatocellular hypertrophy, along with increased CYP4A and acyl-CoA oxidase mRNA expression and enzyme activities versus controls, while in KO rats liver weight was mildly increased only at the high dose with minimal microscopic correlates and without any changes in liver peroxisomal or CYP4A activities. In addition, BrdU labeling resulted in higher numbers and density of positive hepatocytes versus controls in WT but not in KO rats, indicating increased mitotic activity and cell proliferation only in WT rats, thus confirming the PPARα-dependency of the biochemical and histological changes in the liver. Based on an assessment of the results of this investigation, together with existing propaquizafop data according to the MOA-Human Relevance Framework, we conclude that liver tumors observed in rodents after dietary administration of propaquizafop do not pose a relevant health risk to humans.

Systematic review of cost-effectiveness analyses for combinations of prevention strategies against human papillomavirus (HPV) infection: a general trend.

BACKGROUND: Due to the arrival of multi-valent HPV vaccines, it is more and more important to have a better understanding of the relationship between vaccination and screening programmes. This review aimed to: (1) collect published evidence on the cost-effectiveness profile of different HPV prevention strategies and, in particular, those combining vaccination with changes in screening practices; (2) explore the cost-effectiveness of alternative preventive strategies based on screening and vaccination. METHODS: A systematic literature review was conducted in order to identify the relevant studies regarding the cost-effectiveness of prevention strategies against HPV infection. Analysis comparing the modelling approaches between studies was made along with an assessment of the magnitude of impact of several factors on the cost-effectiveness of different screening strategies. RESULTS: A total of 18 papers were quantitatively summarised within the narrative. A high degree of heterogeneity was found in terms of how HPV prevention strategies have been assessed in terms of their economic and epidemiological impact, with variation in screening practice and valence of HPV vaccination found to have large implications in terms of cost-effectiveness. CONCLUSIONS: This review demonstrated synergies between screening and vaccination. New prevention strategies involving multi-valence vaccination, HPV DNA test screening, delayed commencement and frequency of screening could be implemented in the future. Strategies implemented in the future should be chosen with care, and informed knowledge of the potential impact of all possible prevention strategies. Highlighted in this review is the difficulty in assessing multiple strategies. Appropriate modelling techniques will need to be utilised to assess the most cost-effective strategies.

Carcinogenicity testing of eliglustat in mice and rats.

Eliglustat is a novel glucosylceramide synthase inhibitor for long-term oral treatment of type 1 Gaucher disease (GD1), an inherited metabolic disorder. The carcinogenic potential of this drug has been evaluated in lifetime carcinogenicity bioassays in mice and rats. Administration of eliglustat to Swiss CD-1 mice at 0, 10, 25 or 75 mg/kg/day for 104 weeks by dietary admixture did not influence survival or bodyweight evolution, or produce any clinical indication of poor condition. At histopathology, no increases in tumor incidence for any tumor type were attributed to treatment with eliglustat. Systemic exposure to eliglustat was confirmed by a reduction in circulating levels of glucosylceramide. Administration of eliglustat to Sprague-Dawley rats by oral gavage for 105 weeks at 0, 10, 25 or 75 mg/kg/day (males) or 103 weeks at 0, 5, 15 or 50 mg/kg/day (females) did not affect survival rates, but resulted in reduced bodyweight evolution in male rats (-18% at high dose), indicating that the MTD had been achieved. At histopathology, no increases in tumor incidence were attributed to treatment with eliglustat. Systemic exposure was confirmed by toxicokinetic analyses. In conclusion, eliglustat was not carcinogenic to mice or rats in standard lifetime bioassays.

Potentially inappropriate medications and anticholinergic and sedative burden in older community-dwelling patients with advanced chronic kidney disease

Objective: Regarding older patients, multiple chronic conditions lead to the intake of multiple medications, involving a higher risk of adverse drug events. In older patients with advanced chronic kidney disease, the medication exposure was poorly explored. The aim of this study was to describe the use of potentially inappropriate medications and medications with anticholinergic and sedative properties in older community-dwelling patients with advanced chronic kidney disease. Methods: An observational study was conducted in a geriatric day-care unit. All patients aged over 65 years with advanced chronic kidney disease, defined by estimated glomerular filtration rate < 20 mL/min/1.73 m2 or estimated glomerular filtration rate > 20 mL/min/1.73 m2 with rapid progression, and referred by nephrologist for pretransplant comprehensive geriatric assessment, were included in the study. Potentially inappropriate medications were identified using the EU(7)-PIM list, and he anticholinergic and sedative drug exposure was measured using the Drug Burden Index. Results: Overall, 139 patients were included in the study (mean age 74.4 ± 3.3 years, 32.4% females, 61.9% on dialysis). Potentially inappropriate medications were used by 74.1% (103/139) of patients and were mainly represented by proton pump inhibitors, alpha-1-blockers and central antihypertensive drugs. Regarding anticholinergic and / or sedative medications, 79.9% (111/139) of older patients were exposed. Conclusion: In older community-dwelling patients with advanced chronic kidney disease, the prevalence of potentially inappropriate medication exposure and anticholinergic and sedative exposure was high. Interventions focusing on deprescription of these inappropriate medications should be conducted in this specific population.

Objectif: Chez le patient âgé, la polypathologie est souvent associée à la prise de plusieurs médicaments, impliquant un risque élevé d'iatrogénie médicamenteuse. L'exposition médicamenteuse a été peu explorée chez les patients âgés atteints d'insuffisance rénale chronique. L'objectif de cette étude est de décrire l'exposition aux médicaments potentiellement inappropriés et aux médicaments présentant des propriétés anticholinergiques et sédatives chez ces patients. Méthodes: Il s'agit d'une étude observationnelle conduite au sein d'un hôpital de jour gériatrique. Tous les patients âgés de plus de 65 ans avec une maladie rénale chronique avancée, définie par un débit de filtration glomérulaire estimé inférieur à 20 mL/min/1,73 m² ou supérieur à 20 mL/min/1,73 m² avec une progression rapide, et adressés par un néphrologue pour la réalisation d'une évaluation gériatrique standardisée pré-transplantation rénale, ont été inclus dans l'étude. Les médicaments potentiellement inappropriés ont été identifiés à partir de la liste EU(7)-PIM, et l'exposition aux médicaments anticholinergiques et sédatifs a été mesurée à partir du Drug Burden Index. Résultats: Un total de 139 patients a été inclus dans l'étude (74,4 ± 3,3 ans, 32,4 % de femmes, 61,9 % dialysés). Des médicaments potentiellement inappropriés ont été retrouvés chez 74,1 % (103/139) des patients. Ils étaient principalement représentés par les inhibiteurs de la pompe à protons, les alpha-1-bloquants et les antihypertenseurs centraux. Concernant les médicaments anticholinergiques et/ou sédatifs, 79,9 % (111/139) des patients âgés étaient exposés. Conclusion: L'étude montre que la prévalence de l'exposition aux médicaments potentiellement inappropriés et aux médicaments anticholinergiques et/ou sédatifs est élevée chez les patients âgés atteints de maladie rénale chronique avancée. Des interventions portant sur la déprescription de ces médicaments devraient être menées auprès de cette population spécifique.

Polypharmacy and medication regimen complexity in older patients with hemophilia or von willebrand disease: the M'HEMORRH-AGE study.

BACKGROUND: In older patients, multiple chronic conditions lead topolypharmacy which is associated with a higher risk of adverse drug events. Nowadays, the medication exposure of older patients with bleeding disorders has been poorly explored. AIM: The aim of this study was to assess the prevalence of polypharmacy and the medication regimen complexity in older community-dwelling patients with hemophilia or von Willebrand Disease (VWD). METHOD: The M'HEMORRH-AGE study (Medication in AGEd patients with HEMORRHagic disease) is a multicenter prospective observational study. Community-dwelling patients over 65 years with hemophilia or VWD were included in the study. The rate of polypharmacy (use of 5 to 9 drugs daily) and excessive polypharmacy (use of 10 or more medications daily) was assessed. The complexity of prescribed medication regimens was assessed using the Medication Regimen Complexity Index (MRCI). RESULTS: Overall, 142 older community-dwelling patients with hemophilia (n = 89) or VWD (n = 53) were included (mean age: 72.8 (5.8) years). Prevalence of polypharmacy and excessive polypharmacy were 40.8% and 17.6%, respectively. The mean MRCI score was 16.9 (6.1). The mean MRCI score related to bleeding disorders medications was 6.9 (1.1). There was no significant difference between older hemophilia patients and VWD patients. CONCLUSION: The M'HEMORRH-AGE study showed that more than half of older community-dwelling patients were affected by polypharmacy. In addition, the high medication regimen complexity in this older population suggests that interventions focusing on medication review and deprescribing should be conducted to reduce polypharmacy with its negative health-related outcomes.

Amino Acid Solutions for 177Lu-Oxodotreotide Premedication: A Tolerance Study.

Background: The co-infusion of amino acid solutions during peptide receptor radionuclide therapy reduces the tubular reabsorption of 177Lu-oxodotreotide, thus minimizing nephrotoxicity. In our nuclear medicine department, the patients received two different types of amino acid perfusion over time: a commercial solution (CS) containing 10% amino acids, and a 2.5% lysine−arginine (LysArg) hospital preparation, produced by a referral laboratory. The aim of the present study was to analyze the tolerance of the two amino acid solutions. Methods: The patient files were analyzed and double-checked. The study parameters comprised the gender, age, primary tumor site, type of amino acid perfusion, adverse events (AE) and WHO AE grades, antiemetic premedication, creatinine, and serum potassium level. Results: From February 2016 to February 2019, 76 patients were treated, for a total 235 cycles. AEs occurred in 71% of the CS cycles (n = 82/116), versus 18% (n = 21/119) in the LysArg group (p < 0.0001). In the CS group, the AEs were mostly WHO grade 4 (n = 24/82), and mostly grade 1 in the LysArg group (n = 13/21). Poisson regression showed a higher risk of AE overall and of grades 3 and 4 in the females and with CS. The mean creatinine clearance was identical before and after the PRRT cycles, whichever amino acid perfusion was used. Conclusions: The lysine−arginine preparation showed better tolerance than the commercial solution. The change to LysArg reduced the antiemetic premedication from four molecules to one.

Drug-related problems in older patients with advanced chronic kidney disease identified during pretransplant comprehensive geriatric assessment.

BACKGROUND: Older patients with advanced chronic kidney disease may be exposed to a higher risk of adverse drug events due to chronic kidney disease and aging. The integration of clinical pharmacist into pretransplant comprehensive geriatric assessment is an opportunity to perform medication optimization. OBJECTIVE: The aim was to describe drug-related problems in older patients with advanced chronic kidney disease. METHODS: Observational study was conducted with retrospective data from July 2017 to April 2019. Patients≥65 years with advanced chronic kidney disease, referred by nephrologists for pretransplant comprehensive geriatric assessment were included. During medication optimization, the pharmacist evaluated the appropriateness of each medication prescribed and identified drug-related problems. Any drug-related problem identified lead to a pharmaceutical intervention. RESULTS: In total, 103 patients were included (74.5±2.9 years, 26.2% female, 47.6% on dialysis). Overall, 394 drug-related problems were identified in 93.2% of patients (3.8±2.4 drug-related problems per patient) during the medication optimization. Cardiovascular medications (25.1%), antithrombotics (13.5%) and drugs for peptic ulcer and reflux disease (10.2%) were the most involved drugs in drug-related problems. Drug-related problems mainly concerned drugs without indication (27.1%), inappropriate method of administration (24.4%) and non-conformity to guidelines (20.1%). CONCLUSION: A high prevalence of drug-related problems in older patients with advanced chronic kidney disease was identified during medication optimization. The systematic integration of a clinical pharmacist in the multidisciplinary team performing pretransplant comprehensive geriatric assessment may be relevant to detect inappropriate prescriptions and to prevent from adverse drug events.

Exposure to Anticholinergic and Sedative Drugs and Healthcare Costs in Older Patients with Neurocognitive Disorders.

BACKGROUND: Literature supports an increasing number of older patients living with neurocognitive disorders alongside with their annual worldwide costs. Therapeutic management of behavioral and psychological symptoms includes the use of anticholinergic and sedative drugs for which significant exposure is negatively associated with clinical outcomes. OBJECTIVE: The aim of this study was to assess the healthcare costs differences related to an increase in the exposure to anticholinergic and sedative drugs in older patients with neurocognitive disorder. METHODS: A longitudinal study was conducted during 3 years on 1,604 participants of the MEMORA cohort linked with both regional public health insurance and hospital discharge databases between 2012 and 2017. Direct medical and non-medical costs were included. Exposure to anticholinergic and sedative drugs was measured by the drug burden index (DBI). RESULTS: Costs difference associated with a DBI≥0.5 were + 338€ (p < 0.001). After adjustment on comorbidities, NCD stage, cognitive impairment, functional limitation, polypharmacy, and sociodemographic characteristics, a DBI≥0.5 was found to be an independent predictor of an increase of total healthcare costs by 22%(p < 0.001). CONCLUSION: Anticholinergic and sedative drugs have a substantial economic burden among older patients with neurocognitive disorder. More studies are required to assess the clinical and economic impact of an efficient strategy based on the reduction of the exposure to anticholinergic and sedative drugs and the promotion of non-pharmacological interventions.

Pretransplant Comprehensive Geriatric Assessment in Older Patients with Advanced Chronic Kidney Disease.

BACKGROUND: In older patients with advanced chronic kidney disease (CKD), the decision of kidney transplantation (KT) is a challenge for nephrologists. The use of comprehensive geriatric assessment (CGA) is increasingly gaining interest into the process of decision-making about treatment modality choice for CKD. The aim of this study was to assess the prevalence of geriatric impairment and frailty in older dialysis and nondialysis patients with advanced CKD using a pretransplant CGA model and to identify geriatric impairments influencing the geriatricians' recommendations for KT. METHODS: An observational study was conducted with retrospective data from July 2017 to January 2020. Patients aged ≥65 years with advanced CKD, treated or not with dialysis, and referred by the nephrologist were included in the study. The CGA assessed comorbidity burden, cognition, mood, nutritional status, (instrumental) activities of daily living, physical function, frailty, and polypharmacy. Geriatric impairments influencing the geriatricians' recommendations for KT were identified using univariate and multivariate logistic regressions. RESULTS: 156 patients were included (74.2 ± 3.5 years and 62.2% on dialysis). Geriatric conditions were highly prevalent in both dialysis and nondialysis groups. The rate of geriatric impairments was higher in dialysis patients regarding comorbidity burden, symptoms of depression, physical function, autonomy, and frailty. Geriatrician's recommendations for KT were as follows: favorable (79.5%) versus not favorable or multidisciplinary discussion needed with nephrologists (20.5%). Dependence for Instrumental Activities of Daily Living (IADL) (odds ratio [OR] = 3.01 and 95% confidence interval [CI] = 1.30-7.31), physical functions (OR = 2.91 and 95% CI = 1.08-7.87), and frailty (OR = 2.66 and 95% CI = 1.07-6.65) were found to be independent geriatric impairments influencing geriatrician's recommendations for KT. CONCLUSIONS: Understanding the burden of geriatric impairment provides an opportunity to direct KT decision-making and to guide interventions to prevent functional decline and preserve quality of life.

Genomics Integrated Systems Transgenesis (GENISYST) for gain-of-function disease modelling in Göttingen Minipigs.

Göttingen Minipigs show several anatomical, physiological, and pathogenetical similarities to humans and serve an important role in translational studies for example as large animal models of disease. In recent years, the number of transgenic Göttingen Minipigs models has increased, as advanced genetic techniques simplify the generation of animals with precisely tailored modifications. These modifications are designed to replicate genetic alterations responsible for human disease. In addition to serving as valuable large animal disease models, transgenic Göttingen Minipigs are also considered promising donors for xenotransplantation. Current technologies for generation of transgenic minipigs demand a long development and production time of typically 2-3 years. To overcome this limitation and expand the use of Göttingen Minipigs for disease modelling and drug testing, we developed the GENISYST (Genomics Integrated Systems Transgenesis) technology platform for rapid and efficient generation of minipigs based transgenic disease models. As proof of concept, we report the successful generation of transgenic minipigs expressing green fluorescent protein (GFP) in multiple disease-relevant tissues including liver, heart, kidney, lungs, and the central nervous system (CNS). Our data demonstrates the feasibility, efficiency, and utility of GENISYST for rapid one-step generation of transgenic minipigs for human disease modelling in drug discovery and development.

Medication exposure and frailty in older community-dwelling patients: a cross-sectional study.

Objective To investigate the association between the medication exposure, measured by the polypharmacy/excessive polypharmacy and the anticholinergic and/or sedative drug exposure, on frailty status among French older community-dwelling patients. Setting day-care unit in France (Lyon), with retrospective data from July, 2017 to March, 2018. Method This monocentric cross-sectional study included community-dwelling patients aged 65 years and over and admitted at the day-care unit for a geriatric evaluation. Frailty was assessed according to the frailty phenotype, described by Fried et al. Polypharmacy and excessive polypharmacy were defined as the concomitant use of 5-9 and 10 or more drugs, respectively. The cumulative anticholinergic and sedative exposure was measured using the drug burden index (DBI). The DBI score was presented in 4 differentiated scores: a null score (DBI = 0), a combined score (anticholinergic and sedative score), an anticholinergic score, and a sedative score. The association between medication and frailty was assessed by logistic regression models controlled for multiple potential confounders. Main outcome measure Association between medication exposure (polypharmacy, anticholinergic and sedative exposure) and frailty. Results In this study, 403 patients were included: 44.7% were frail and 40.7% were pre-frail. Polypharmacy and excessive polypharmacy affected 44.7% and 17.1% of the population respectively. The mean DBI was 0.33 ± 0.43, with 16.4% of patients with only sedative exposure, 9.7% with only anticholinergic exposure and 33.0% with both exposures. After adjustment, polypharmacy and excessive polypharmacy were associated with frailty with adjusted odds ratios (95% confidence interval) of 2.18 (1.03-4.22) and 2.72 (1.01-7.37) respectively. The cumulative exposure to anticholinergic and sedative drugs (combined score) was significantly associated to an increased risk for frailty with adjusted odds ratios (95% confidence interval) of 3.54 (1.47-8.57). Conclusion The study showed that polypharmacy and cumulative anticholinergic and sedative exposure are associated with frailty. Further research should address the potential benefit of collaborative medication review for preventing medication-associated frailty.

Comparative analysis of the oral mucosae from rodents and non-rodents: Application to the nonclinical evaluation of sublingual immunotherapy products.

BACKGROUND: A comparative characterization of the oral mucosa in various animals is needed to identify the best animal model(s) for nonclinical evaluation of sublingual immunotherapy products. With this aim, we studied the histological characteristics and immune cell infiltrates of oral mucosae from common animal species. METHODS: Three oral regions (i.e. ventral surface of the tongue, mouth floor and cheek) obtained from eight animal species, including rodents (i.e. mice, rats, hamsters, guinea pigs) and non-rodents (i.e. rabbits, dogs, minipigs and monkeys) were characterized by histology and immunohistology in comparison with a human tongue. RESULTS: Rodents exhibit a thin keratinized epithelium with low epithelial extensions, whereas non-rodents, most particularly minipigs and monkeys, display a non-keratinized epithelium with larger rete ridges, similarly to humans. Glycogen-rich cells in the superficial epithelial layers are observed in samples from both minipigs, monkeys and humans. Comparable immune subpopulations detected in the 3 oral regions from rodent and non-rodent species include MHC-II+ antigen presenting cells, mostly CD163+ macrophages, located in the lamina propria (LP) and muscle tissue in the vicinity of resident CD3+CD4+ T cells. Limited numbers of mast cells are also detected in the LP and muscle tissue from all species. CONCLUSION: The oral mucosae of minipigs and monkeys are closest to that of humans, and the immune networks are quite similar between all rodents and non-rodents. Taking into account the ethical and logistical difficulties of performing research in the latter species, rodents and especially mice, should preferentially be used for pharmacodynamics/efficacy studies. Our data also support the use of minipigs to perform biodistribution and safety studies of sublingual immunotherapy products.

A comparative public health and budget impact analysis of pneumococcal vaccines: The French case.

In 2002, a pneumococcal conjugate vaccine (PCV) was introduced to French infants and toddlers. A change has been witnessed in the incidence of pneumococcal diseases in adults: the incidence of invasive pneumococcal disease (IPD) of serotypes covered by PCV decreased, and serotypes not covered by PCV increased. This study aimed to quantify the public health and budget impact of pneumococcal vaccination strategies in at-risk adults in France over 5 years. A previously published population-based Markov model was adapted to the French situation. At-risk adults received either PPV23 (pneumococcal polysaccharide vaccine; for the immunocompetent) or PCV13 (for the immunosuppressed). The strategy was compared to PCV13 alone. Uncertainty was addressed using extreme scenario analyses. Between 2014 and 2018, vaccination with PPV23/PCV13 led to a higher reduction in terms of IPD and non-bacteremic pneumococcal pneumonia cases avoided in most scenarios analyzed when compared to PCV13 alone. For budget impact, none of the scenarios was in favor of PCV13. Under conservative coverage assumptions, the total incremental budget impact ranged from € 39.8 million to € 69.3 million if PCV13 were to replace PPV23 in the immunocompetent. With the epidemiological changes of pneumococcal diseases and the broader serotype coverage of PPV23, the current program remains an optimal strategy from public health perspective. Given the additional budget required for the use of PCV13 alone and its uncertain public health benefits, vaccination with PPV23 remains the preferred strategy.

Development of a Delayed-Type Hypersensitivity (DTH) Model in the Cynomolgus Monkey.

Although a T-dependent antibody response (TDAR) assay is generally recommended as the first-line immune function assay in nonclinical immunotoxicity evaluation, second-line assays such as delayed-type hypersensitivity (DTH) to measure cell-mediated responses can provide helpful additional information. In this study, male Cynomolgus monkeys were injected intramuscularly either once or twice with 1 mg Keyhole Limpet Hemocyanin (KLH) or twice with a commercially available tetanus vaccine (40 IU tetanus toxoid + 0.06 mg aluminum hydroxide). All animals were subsequently challenged by intradermal injections of the same antigen or aluminum hydroxide after 4, 6 and 8 weeks. Clinical reactions at the injection sites were scored 24, 48 and 72 h post challenge. Skin biopsies were taken on completion of the observation period after each challenge for standard histological examination and immunolabeling using CD3 (T lymphocytes), CD19 (B lymphocytes) and CD68 (macrophages) antibodies. Tetanus toxoid induced stronger clinical reactions than KLH, whereas aluminum hydroxide induced no clinical reaction. Perivascular mononuclear cell infiltrates, a histopathological finding consistent with a DTH reaction, were seen after all challenges with tetanus toxoid or KLH, but not with aluminum hydroxide. Immunohistochemistry evidenced the presence of T lymphocytes and macrophages within these infiltrates. These results suggest that tetanus toxoid adjuvanted with aluminum hydroxide can induce a consistent DTH response for use as a model of cell-mediated response in Cynomolgus monkeys.

The utility of the minipig as an animal model in regulatory toxicology.

In this article we review the value and utility of the minipig as an animal model in regulatory toxicity testing. Our review is based on detailed consideration of the comparative biology of the minipig, and of the practical features of toxicity testing in the minipig. The minipig presents a favourable profile as a non-rodent toxicology model, in terms of the similarity to man and also in terms of applicability to different study types. Studies of general toxicology can be performed in the minipig by oral, cutaneous, parenteral and inhalation routes. For reproductive toxicology studies the minipig offers numerous advantages as a non-rodent model although the lack of placental transfer of macromolecules may limit the role of the minipig in reproductive testing of biotechnology products. For safety pharmacology studies the minipig is an advantageous model, particularly as regards the cardiovascular system. The immune system of the pig is better characterized than that of the dog, making the pig an interesting alternative model to the nonhuman primate for therapeutic approaches based on manipulation of the immune system. Overall, this review leads us to believe that the minipig might be a better non-rodent toxicology model than the dog. At the present time, however, insufficient comparative data is available to permit a rigorous evaluation of the predictivity of the minipig for human drug-induced toxicities and research is urgently needed to provide experimental data for evaluation of the hypothesis that minipig studies may better reflect human drug-induced toxicities than studies performed in traditional non-rodent toxicology models. It would be of particular value to gain a better vision of the potential utility of the minipig as a model for the safety testing of new biologics, where the minipig could potentially replace the use of non-human primates in the testing of some new products.