Biorelevant media for transport experiments in the Caco-2 model to evaluate drug absorption in the fasted and the fed state and their usefulness

In this work we developed and characterized transport media that simulate the composition of micellar phase of intestinal fluids in the fasted and, especially, in the fed state and are appropriate for evaluating intestinal drug permeability characteristics using the Caco-2 model (FaSSIF-TM_Caco and FeSSIF-TM_Caco, respectively). Media composition was based on FaSSIF-V2 and FeSSIF-V2 and recently reported data on total lipid concentrations in the micellar phase of contents of the upper small intestine in the fasted and the fed state and was adapted for cell culture compatibility. Permeation data were evaluated by compartmental kinetic modeling. Permeability coefficients, P, of hydrophilic drugs were not affected by media composition. In contrast, P values of a series of lipophilic compounds measured with FaSSIF-TM_Caco and FeSSIF-TM_Caco, and reflecting transport by diffusion were smaller than those obtained with a purely aqueous reference transport medium, aq-TM_Caco, following the rank order aq-TM_Caco > FaSSIF-TM_Caco > FeSSIF-TM_Caco. The decline of permeability values was stronger as lipophilicity of the compounds increased. Compared with values estimated using aq-TM_Caco, permeability was reduced, depending on the compound, by more than 20- to 100-fold when measured with FeSSIF-TM_Caco whereas compound ranking in regard to the permeability characteristics was also affected. The impact of reduced P value on flux through the mucosa, hence on drug absorption, in combination with the drug amount loaded on colloidal particles needs to be taken into consideration in PBPK modeling especially when the food effect is evaluated.     

Tailoring Crohn's disease treatment: The impact of small bowel capsule endoscopy

Background and aimsSmall bowel capsule endoscopy (SBCE) may detect proximal small bowel lesions that have been previously missed by ileocolonoscopy and small bowel imaging in patients with known ileal and/or colonic Crohn's disease (CD). We aimed to evaluate whether the therapeutic management is influenced by SBCE findings.MethodsRetrospective single center study. Inclusion of consecutive patients with known non-stricturing and non-penetrating ileal and/or colonic CD, submitted to SBCE to evaluate disease extension and activity, with ≥ 1 year follow-up. Lesions were classified with the Lewis score (LS) as non-significant (LS < 135), mild (135 ≤ LS ≤ 790), or moderate-to-severe (LS > 790). Therapeutic changes were assessed three months after SBCE.ResultsFifty consecutive patients (35 ± 13 years, 52% females) were included. At ileocolonoscopy, disease location was ileal (L1) in 60%, colonic (L2) in 10% and ileocolonic (L3) in 30% of the patients. In 33 patients (66%) SBCE detected significant proximal lesions previously missed by other modalities. The proportion of patients on thiopurines and/or biologics before SBCE was 2/50 (4%); this was significantly higher three months after SBCE, 15/50 (30%), p = 0.023. Treatment with thiopurines and/or biologics was started more often in patients with proximal small bowel lesions [13/33 (39%) vs. 1/17 (6%), p = 0.011, relative risk (RR) 6.5], particularly when severe (6%, 36% and 45% of patients with non-significant, mild and moderate-to-severe inflammation, respectively).ConclusionsSBCE diagnoses previously undetected lesions and it influences therapeutic management of CD, triggering an earlier introduction of immunomodulators and/or biological therapy.     

National survey of physicians in Japan regarding their use of diagnostic tests for legionellosis

IntroductionBacterial culture remains the gold standard for the diagnosis of legionellosis. However, past reports indicate that most physicians use the urinary antigen test (UAT) alone. Combining it with other tests is important, especially in patients with negative UAT results. The aim of this study was to investigate the current situation of legionellosis diagnostics and clarify the issues that need to be addressed.MethodsBetween March 1, 2021 and April 30, 2021, a questionnaire survey was conducted in an anonymous manner among physicians working in Japan. Questionnaires were generated on a website and asked questions in a multiple-choice format.ResultsValid responses were received from 309 physicians during the study period. Most (92.9%) physicians reported using UAT as the initial test for patients suspected of having legionellosis, and <10% reported using other tests (e.g., culture, nucleic acid amplification test [NAAT], Gimenez staining, and serum antibody titer measurement [ATM]). When the initial test result was negative, 63% of physicians reported not conducting additional tests. Even when they chose to run additional tests, at most 27.8%, 23.6%, 12.3%, and 10.4% of all physicians used NAAT, culture, Gimenez staining, and serum ATM, respectively. The major reasons for not using tests other than UAT were “unavailability in the medical facility,” “long turn-around time,” and “difficult to collect sputum.”ConclusionsThe present survey revealed that most physicians in Japan used UAT alone for diagnosing legionellosis. Eliminating barriers to creating a reasonable environment and edification of physicians are needed to improve the current situation.     

Factors associated to repeated influenza vaccination in the Portuguese adults with chronic conditions

Annual influenza vaccination is recommended to people with chronic conditions. This study aimed to estimate the proportion of chronically ill adults vaccinated against influenza in consecutive seasons and to identify associated factors.We used data from the first National Health Examination Survey (INSEF), a cross-sectional study conducted in 2015 on a probabilistic sample of individuals aged 25–74 years. The population was restricted to individuals who self-reported diabetes, a respiratory, cardiovascular, liver or kidney disease. Self-reported vaccination in 4 consecutive seasons was categorized in 3 levels: unvaccinated, occasionally (vaccinated 1–3 seasons) and repeatedly vaccinated (in all 4 seasons). A multinomial logistic regression was applied to estimate odds-ratio (OR) of influenza vaccination according to sociodemographic factors, chronic condition, health care use and status.In the target population, the 2014/15 influenza vaccine coverage was 33.8% (95% CI: 29.8–38.1). The higher coverage was found in individuals reporting renal disease (66.7%) and diabetes (43.8%). The coverage decreased to 32.6%, 26.0% and 20.8% for individuals with respiratory, cardiovascular and liver diseases, respectively. The probability of being repeatedly vaccinated, compared to unvaccinated, was higher in males (OR = 2.14: 95% CI: 1.31–3.52); aged 65 and 74 (OR = 4.39; 95% CI: 1.99–9.69); whom had an appointment with a general practitioner (OR = 2.77; 95% CI: 1.00–7.66) or other physician (OR = 3.95: 95% CI: 2.53–6.16); with no smoking habits (OR = 1.58; 95% I: 1.02–2.46) and reporting diabetes (OR = 2.13; 95% CI: 1.02–4.45). Finally, having a self-reported cardiovascular condition decreased the likelihood of being occasionally (OR = 0.38; 95% CI = 0.22–0.65) vaccinated against influenza.Younger individuals, females and the ones with a self-reported cardiovascular condition were identified as more likely of non-compliance to the vaccine uptake recommendation. Future vaccination strategies should focus on the previous identified population subgroups. Also, the medical recommendation of the influenza vaccine uptake should continue and be reinforced particularly in individuals with a cardiovascular condition.