A finite element study comparing Advansync® and Twin Block in mandibular anterior repositioning.

OBJECTIVE: This study aims to utilize the finite element method (FEM) to compare the dentoalveolar and mandibular effects associated with anterior mandibular repositioning using AdvanSync® (ADV) and Twin Block (TB). METHODS: A patient with Class II skeletal malocclusion and mandibular retrognathism was selected. A TB appliance was subsequently applied. Computed Tomography (CT) scans were acquired at the beginning of treatment (T1) and 8 months later (T2). Concurrently, a numerical TB model was validated through FEM simulations, which were compared with the T2 results. The ADV appliance was virtually simulated to evaluate stress and deformation on the condyle, symphysis, first lower molar and lower central incisors. RESULTS: Both simulations demonstrated significant mandibular advancement. However, ADV led to less incisor proclination and more molar intrusion compared to TB. ADV exhibited increased stress in the lower molar area, while TB had higher stress in the lower incisor region. Stress and deformations in the condyle and mandibular symphysis were similar in both simulations, with the highest stress observed at the condylar neck and the lowest at the upper pole of the condylar head. CONCLUSIONS: Both appliances achieved similar levels of mandibular advancement, with greater proclination of the lower central incisors and more widespread distribution of stress and molar intrusion when using ADV compared to TB.

Prediction of the Renal Organic Anion Transporter 1 (OAT1)- Mediated Drug Interactions for LY404039, the Active Metabolite of Pomaglumetad Methionil.

PURPOSE: The objective of this work was to demonstrate that clinical OAT1-mediated DDIs can be predicted using physiologically based pharmacokinetic (PBPK) modeling. METHODS: LY404039 is a metabotropic glutamate receptor 2/3 agonist and the active moiety of the prodrug pomaglumetad methionil (LY2140023). After oral administration, pomaglumetad methionil is rapidly taken up by enterocytes via PEPT1 and once absorbed, converted to LY404039 via membrane dehydropeptidase 1 (DPEP1). LY404039 is renally excreted by both glomerular filtration and active secretion and in vitro studies showed that the active secretion of LY404039 was mediated by the organic anion transporter 1 (OAT1). Both clinical and in vitro data were used to build a PBPK model to predict OAT1-mediated DDIs. RESULTS: In vitro inhibitory potencies (IC50) of the known OAT inhibitors, probenecid and ibuprofen, were determined to be 4.00 and 2.63 µM, respectively. Subsequently, clinical drug-drug interaction (DDI) study showed probenecid reduced the renal clearance of LY404039 by 30 to 40%. The PBPK bottom-up model, predicted a renal clearance that was approximately 20% lower than the observed one. The middle-out model, using an OAT1 relative activity factor (RAF) of 3, accurately reproduced the renal clearance of LY404039 and pharmacokinetic (PK) changes of LY404039 in the presence of probenecid. CONCLUSIONS: OAT1- mediated DDIs can be predicted using in vitro measured IC50 and PBPK modeling. The effect of ibuprofen was predicted to be minimal (AUC ratio of 1.15) and not clinically relevant.

Identification of CD8+ T cell subsets that normalize in early-treated people living with HIV receiving antiretroviral therapy.

BACKGROUND: Although combined antiretroviral therapy (cART) has decreased the mortality associated with HIV infection, complete immune reconstitution is not achieved despite viral suppression. Alterations of CD8+ T cells and some of their subpopulations, such as interleukin (IL)-17-producing cells, are evidenced in treated individuals and are associated with systemic inflammation and adverse disease outcomes. We sought to evaluate if different CD8+ T cell subsets are differentially normalized during a clinical follow-up of people living with HIV (PLWH) receiving suppressive cART. METHODS: We explored the changes in the frequencies, activation/exhaustion phenotypes (HLA-DR, CD38, PD-1, and TIM-3), and function (total and HIV-specific cells expressing CD107a, perforin, granzyme B, interferon [IFN]-γ and IL-17) of CD8+ T cells from early-treated PLWH receiving cART in a 1-year follow-up, using a multidimensional flow cytometry approach. RESULTS: Despite continuous cART-induced viral suppression and recovery of CD4+ T cells, after a 1-year follow-up, the CD8+ T cell counts, CD4:CD8 ratio, PD-1 expression, and IL-17 production by CD8+ T cells exhibited incomplete normalization compared with seronegative controls. However, the proportion of CD8+ T cells with an exhausted phenotype (co-expressing PD-1 andTIM-3), and cells co-expressing cytotoxic molecules (Perforin and Granzyme B), reached normalization. CONCLUSIONS: Although suppressive cART achieves normalization of CD4+ T cell counts, only particular subsets of CD8+ T cells are more rapidly normalized in PLWH receiving cART, which could be routinely used as biomarkers for therapy efficiency in these patients.

The Effect of Promiscuous Aggregation on in Vitro Drug Metabolism Assays.

PURPOSE: Many bioactive molecules show a type of solution phase behavior, termed promiscuous aggregation, whereby at micromolar concentrations, colloidal drug-rich aggregates are formed in aqueous solution. These aggregates are known to be a major cause of false positives and false negatives in select enzymatic high-throughput screening assays. The goal of this study was to investigate the impact of drug-rich aggregates on in vitro drug screening metabolism assays. METHODS: Cilnidipine was selected as an aggregate former and its impact on drug metabolism was evaluated against rCYP2D6, rCYP1A2, rCYP2C9 and human liver microsomes. RESULTS: The cilnidipine aggregates were shown to non-specifically inhibit multiple cytochrome P450 enzymes with an IC50 comparable with the IC50 of potent model inhibitors. CONCLUSIONS: This newly demonstrated mode of "promiscuous inhibition" is of great importance as it can lead to false positives during drug metabolism evaluations and thus it needs to be considered in the future to better predict in vivo drug-drug interactions.

Analysis of the effect of methyl 2-acetamide-3-methylquinoxaline-7-carboxylate 1,4-di-N-oxide on the relative expression of the trypanothione reductase gene in Trypanosoma cruzi epimastigotes.

In recent decades, some quinoxaline 1,4-di-N-oxide derivatives have been shown to have better trypanocidal activity than the reference drugs; however, their mechanism of action is not yet clear, although it is suggested that they mainly produce reactive oxygen species that cause oxidative stress and parasite death. Trypanosoma cruzi relies on the enzyme trypanothione reductase, among others, to defend itself against oxidative stress. With the aim of contributing to the elucidation of the mechanism of action of quinoxaline 1,4-di-N-oxide derivatives on Trypanosoma cruzi, this study was carried out to evaluate the effect of methyl 2-amide-3-methylquinoxaline-7-carboxylate 1,4-di-N-oxide (compound M-8) on the expression of the trypanothione reductase gene in an in vitro model on Trypanosoma cruzi epimastigotes of the CL-Brener strain. The results show that compound M-8 does not cause a significant effect on the trypanothione reductase gene, suggesting a mechanism of action not related to oxidative stress.

Prediction of renal transporter mediated drug-drug interactions for pemetrexed using physiologically based pharmacokinetic modeling.

Pemetrexed, an anionic anticancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The in vitro to in vivo extrapolation approach used in this work was developed to predict possible drug-drug interactions (DDIs) that may occur after coadministration of pemetrexed and nonsteroidal anti-inflammatory drugs (NSAIDs), and it included in vitro assays, risk assessment models, and physiologically based pharmacokinetic (PBPK) models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing organic anion transporter (OAT) 3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC50) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp Simulator. The bottom-up model for pemetrexed underpredicted the clearance by 2-fold. The model we built using a scaling factor of 5.3 for the maximal uptake rate (Vmax) of OAT3, which estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m(2) of pemetrexed supplemented with folic acid and vitamin B12, recovered the clinical data adequately. The observed/predicted increases in Cmax and the area under the plasma-concentration time curve (AUC0-inf) of pemetrexed when ibuprofen was coadministered were 1.1 and 1.0, respectively. The coadministration of all other NSAIDs was predicted to have no significant impact on the AUC0-inf based on their DDI indexes. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen.

Investigation of the Effect of Lasmiditan on the Pharmacokinetics of P-Glycoprotein and Breast Cancer Resistance Protein Substrates.

Lasmiditan is an in vitro inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters. We aimed to confirm predictions from physiologically based pharmacokinetic models of lasmiditan, and assess the safety and tolerability of rosuvastatin and dabigatran co-administered with lasmiditan. In this open-label, post-marketing drug-drug interaction, phase 1 clinical trial, eligible participants were adults aged 21-70 years with a body mass index of 18.5-35.0 kg/m2 . Part 1 (P-gp, 150 mg dabigatran etexilate with 200 mg lasmiditan) and part 2 (BCRP, 10 mg rosuvastatin with 200 mg lasmiditan) employed similar designs: a single dose of probe substrate administered on day -2 with pharmacokinetic evaluation; 1-week washout; lasmiditan administered on days 8 and 9 alone; lasmiditan co-administered with a single dose of probe substrate on day 10, with pharmacokinetic evaluation of probe substrate and lasmiditan. Sixty-six participants were included in part 1 and 30 participants were included in part 2. Following dabigatran co-administration with lasmiditan, versus dabigatran alone, 90% confidence intervals for geometric least-squares (LS) mean ratios of area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞ ) and maximum observed drug concentration (Cmax ) were not contained within the non-effect boundaries (0.80 to 1.25). Dabigatran AUC0-∞ increased by 25% and Cmax increased by 22%. The median time of maximum observed drug concentration (tmax ) for dabigatran was 2.0 to 3.0 hours. Following rosuvastatin co-administration with lasmiditan, versus rosuvastatin alone, 90%CIs for geometric LS mean ratios of AUC0-∞ and Cmax were contained within non-effect boundaries (0.80-1.25). Rosuvastatin AUC0-∞ increased by 15% and Cmax increased by 7%. The median tmax for rosuvastatin was 4.0 hours. Results suggest that lasmiditan has a weak effect on P-gp substrates and no clinically relevant effect on BCRP substrates.

Relevance of PepT1 in the intestinal permeability and oral absorption of cefadroxil.

PURPOSE: To determine the contribution of intestinal PepT1 on the permeability and oral absorption of the ß-lactam antibiotic drug cefadroxil. METHODS: The effective permeability (P eff ) of cefadroxil was evaluated in wild-type and PepT1 knockout mice following in situ single-pass intestinal perfusions. The plasma concentration-time profiles of cefadroxil were also examined after oral gavage. RESULTS: The P eff (cm/s) of cefadroxil in wild-type mice was 0.49 × 10(-4) in duodenum, 0.80 × 10(-4) in jejunum, 0.88 × 10(-4) in ileum and 0.064 × 10(-4) in colon. The P eff (cm/s) in PepT1 knockout mice was significantly reduced in small intestine, but not in colon, as shown by values of 0.003 × 10(-4), 0.090 × 10(-4), 0.042 × 10(-4) and 0.032 × 10(-4), respectively. Jejunal uptake of cefadroxil was saturable (Km = 2-4 mM) and significantly attenuated by the sodium-proton exchange inhibitor 5-(N,N-dimethyl)amiloride. Jejunal permeability of cefadroxil was not affected by L-histidine, glycine, cephalothin, p-aminohippurate or N-methylnicotinamide. In contrast, cefadroxil permeability was significantly reduced by glycylproline, glycylsarcosine, or cephalexin. Finally, PepT1 ablation resulted in 23-fold reductions in peak plasma concentrations and 14-fold reductions in systemic exposure of cefadroxil after oral dosing. CONCLUSIONS: The findings are definitive in demonstrating that PepT1 is the major transporter responsible for the small intestinal permeability of cefadroxil as well as its enhanced oral drug performance.

In vivo absorption and disposition of cefadroxil after escalating oral doses in wild-type and PepT1 knockout mice.

PURPOSE: To determine the effect of PepT1 on the absorption and disposition of cefadroxil, including the potential for saturable intestinal uptake, after escalating oral doses of drug. METHODS: The absorption and disposition kinetics of [3H]cefadroxil were determined in wild-type and PepT1 knockout mice after 44.5, 89.1, 178, and 356 nmol/g oral doses of drug. The pharmacokinetics of [3H]cefadroxil were also determined in both genotypes after 44.5 nmol/g intravenous bolus doses. RESULTS: PepT1 deletion reduced the area under the plasma concentration-time profile (AUC0-120) of cefadroxil by 10-fold, the maximum plasma concentration (Cmax) by 17.5-fold, and increased the time to reach a maximum plasma concentration (Tmax) by 3-fold. There was no evidence of nonlinear intestinal absorption since AUC0-120 and Cmax values changed in a dose-proportional manner. Moreover, the pharmacokinetics of cefadroxil were not different between genotypes after intravenous bolus doses, indicating that PepT1 did not affect drug disposition. Finally, no differences were observed in the peripheral tissue distribution of cefadroxil (i.e., outside gastrointestinal tract) once these tissues were corrected for differences in perfusing blood concentrations. CONCLUSIONS: The findings demonstrate convincingly the critical role of intestinal PepT1 in both the rate and extent of oral administration for cefadroxil and potentially other aminocephalosporin drugs.

A proteomic focus on the alterations occurring at the human atherosclerotic coronary intima.

Coronary atherosclerosis still represents the major cause of mortality in western societies. Initiation of atherosclerosis occurs within the intima, where major histological and molecular changes are produced during pathogenesis. So far, proteomic analysis of the atherome plaque has been mainly tackled by the analysis of the entire tissue, which may be a challenging approach because of the great complexity of this sample in terms of layers and cell type composition. Based on this, we aimed to study the intimal proteome from the human atherosclerotic coronary artery. For this purpose, we analyzed the intimal layer from human atherosclerotic coronaries, which were isolated by laser microdissection, and compared with those from preatherosclerotic coronary and radial arteries, using a two-dimensional Differential-In-Gel-Electrophoresis (DIGE) approach. Results have pointed out 13 proteins to be altered (seven up-regulated and six down-regulated), which are implicated in the migrative capacity of vascular smooth muscle cells, extracellular matrix composition, coagulation, apoptosis, heat shock response, and intraplaque hemorrhage deposition. Among these, three proteins (annexin 4, myosin regulatory light 2, smooth muscle isoform, and ferritin light chain) constitute novel atherosclerotic coronary intima proteins, because they were not previously identified at this human coronary layer. For this reason, these novel proteins were validated by immunohistochemistry, together with hemoglobin and vimentin, in an independent cohort of arteries.

Pandemic play moderates the relation between caregiver stress and child emotional distress in contexts of economic adversity.

It is well-established that caregiver stress is linked to increased emotional distress among children, and recent evidence highlights similar associations between caregiver and child emotional well-being during the coronavirus (COVID-19) pandemic. Examining protective factors and coping mechanisms that are associated with resiliency in the face of pandemic-related stress can highlight potential strategies that may help children adapt to other unexpected hardships outside of a global pandemic. Previous research found that playing about the pandemic moderated an association between caregiver stress and children's emotional distress. However, few studies have explored "pandemic play" among children from low-income households, where pandemic-related stressors were often exacerbated. In the present study, 72 caregivers of Head Start preschoolers between 3 and 6 years of age were surveyed between late 2020 and early 2021. Results revealed that 32% of children engaged in pandemic play frequently. Caregiver stress was positively associated with child emotional distress, but only among children who did not engage in pandemic play frequently. These findings support the idea that child-directed play may be a developmentally appropriate and accessible coping mechanism to reduce the emotional burden of stressful events on children, regardless of economic context.

DPP4 Promotes Human Endothelial Cell Senescence and Dysfunction via the PAR2-COX-2-TP Axis and NLRP3 Inflammasome Activation.

BACKGROUND: Abnormal accumulation of senescent cells in the vessel wall leads to a compromised vascular function contributing to vascular aging. Soluble DPP4 (dipeptidyl peptidase 4; sDPP4) secretion from visceral adipose tissue is enhanced in obesity, now considered a progeric condition. sDPP4 triggers vascular deleterious effects, albeit its contribution to vascular aging is unknown. We aimed to explore sDPP4 involvement in vascular aging, unraveling the molecular pathway by which sDPP4 acts on the endothelium. METHODS: Human endothelial cell senescence was assessed by senescence-associated ß-galactosidase assay, visualization of DNA damage, and expression of prosenescent markers, whereas vascular function was evaluated by myography over human dissected microvessels. In visceral adipose tissue biopsies from a cohort of obese patients, we explored several age-related parameters in vitro and ex vivo. RESULTS: By a common mechanism, sDPP4 triggers endothelial cell senescence and endothelial dysfunction in isolated human resistance arteries. sDPP4 activates the metabotropic receptor PAR2 (protease-activated receptor 2), COX-2 (cyclooxygenase 2) activity, and the production of TXA2 (thromboxane A2) acting over TP (thromboxane receptor) receptors (PAR2-COX-2-TP axis), leading to NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3) inflammasome activation. Obese patients exhibited impaired microarterial functionality in comparison to control nonobese counterparts. Importantly, endothelial dysfunction in obese patients positively correlated with greater expression of DPP4, prosenescent, and proinflammatory markers in visceral adipose tissue nearby the resistance arteries. Moreover, when DPP4 activity or sDPP4-induced prosenescent mechanism was blocked, endothelial dysfunction was restored back to levels of healthy subjects. CONCLUSIONS: These results reveal sDPP4 as a relevant mediator in early vascular aging and highlight its capacity activating main proinflammatory mediators in the endothelium that might be pharmacologically tackled.

Synthesis and Preclinical Characterization of LY3154885, a Human Dopamine D1 Receptor Positive Allosteric Modulator with an Improved Nonclinical Drug-Drug Interaction Risk Profile.

Results from recently completed clinical studies suggest the dopamine D1 receptor positive allosteric modulator (PAM) mevidalen (1) could offer unique value for lewy body dementia (LBD) patients. In nonclinical assessments, 1 was mainly eliminated by CYP3A4-mediated metabolism, therefore at the risk of being a victim of drug-drug interactions (DDI) with CYP3A4 inhibitors and inducers. An effort was initiated to identify a new D1 PAM with an improved DDI risk profile. While attempts to introduce additional metabolic pathways mediated by other CYP isoforms failed to provide molecules with an acceptable profile, we discovered that the relative contribution of CYP-mediated oxidation and UGT-mediated conjugation could be tuned to reduce the CYP3A4-mediated victim DDI risk. We have identified LY3154885 (5), a D1 PAM that possesses similar in vitro and in vivo pharmacologic properties as 1, but is metabolized mainly by UGT, predicting it could potentially offer lower victim DDI risk in clinic.

Metabolomic profiling for identification of novel potential biomarkers in cardiovascular diseases.

Metabolomics involves the identification and quantification of metabolites present in a biological system. Three different approaches can be used: metabolomic fingerprinting, metabolic profiling, and metabolic footprinting, in order to evaluate the clinical course of a disease, patient recovery, changes in response to surgical intervention or pharmacological treatment, as well as other associated features. Characteristic patterns of metabolites can be revealed that broaden our understanding of a particular disorder. In the present paper, common strategies and analytical techniques used in metabolomic studies are reviewed, particularly with reference to the cardiovascular field.

[Thyroid suppression in patients with primary hyperparathyroidism: does it improve the pre-surgical scintigraphy localisation?]. / Supresión tiroidea en pacientes con hiperparatiroidismo primario: ¿mejora la localización gammagráfica preoperatoria?

INTRODUCTION: Scintigraphy with technetium-sestamibi (MIBI) is the test of choice for localising adenomas in patients with primary hyperparathyroidism (PHPT). In some studies it has emerged that the increase in sensitivity of this test could be associated with a decrease in the uptake of the radiotracer by the thyroid gland. The aim of this study is to analyse our experience in patients with a negative scintigraphy with MIBI, and in whom the study was repeated after suppression of thyroid function with thyroxine. MATERIAL AND METHODS: A prospective evaluation was performed on 17 patients who, between January 2006 and April 2011, had PHPT and negative imaging using scintigraphy with MIBI and who had the test repeated after the administration of thyroxine. The scintigraphy data and the correlation with the findings in the surgical intervention are reviewed. RESULTS: The mean TSH at the time of repeating the MIBI was 0.12+0.1mlU/L. Of the 17 patients included, the scintigraphy under thyroid suppression was positive in 13 of them (76.5%), and in the other 4 (23.5%) patients no image suggestive of adenoma was found. In the cases where the MIBI was positive after suppression, the positive predictive value (PPV) was 100%. CONCLUSION: Suppression of thyroid function by giving thyroxine can help to improve the sensitivity of MIBI in patients with previously negative scintigraphy studies and help in the minimally invasive treatment of patients with PHPT.

Development and Application of a Mechanistic Population Modeling Approach to Describe Abemaciclib Pharmacokinetics.

Abemaciclib is an oral anticancer drug that inhibits cyclin dependent kinases 4 and 6 and is metabolized by cytochrome P450 3A in the intestines and liver to active metabolites. The objectives were (1) to develop a mechanistic model to characterize the pharmacokinetics (PK) of the active moieties and investigate the effect of patient factors and (2) apply the model to dat from two phase III breast cancer trials of abemaciclib in combination with endocrine therapy. To develop the model, data from seven phase I studies and two phase II studies including 421 patients with cancer and 65 healthy individuals were pooled for nonlinear mixed effects modeling. The PK was similar between patients and healthy subjects, and the effects of diarrhea, formulation, race, and patient covariates on exposure were negligible. Application of the model confirmed its predictive performance and that abemaciclib PK did not change when coadministered with endocrine therapy.

Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling.

Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 and 6, is metabolized mainly by cytochrome P450 (CYP)3A4. Clinical studies were performed to assess the impact of strong inhibitor (clarithromycin) and inducer (rifampin) on the exposure of abemaciclib and active metabolites. A physiologically based pharmacokinetic (PBPK) model incorporating the metabolites was developed to predict the effect of other strong and moderate CYP3A4 inhibitors and inducers. Clarithromycin increased the area under the plasma concentration-time curve (AUC) of abemaciclib and potency-adjusted unbound active species 3.4-fold and 2.5-fold, respectively. Rifampin decreased corresponding exposures 95% and 77%, respectively. These changes influenced the fraction metabolized via CYP3A4 in the model. An absolute bioavailability study informed the hepatic and gastric availability. In vitro data and a human radiolabel study determined the fraction and rate of formation of the active metabolites as well as absorption-related parameters. The predicted AUC ratios of potency-adjusted unbound active species with rifampin and clarithromycin were within 0.7- and 1.25-fold of those observed. The PBPK model predicted 3.78- and 7.15-fold increases in the AUC of the potency-adjusted unbound active species with strong CYP3A4 inhibitors itraconazole and ketoconazole, respectively; and 1.62- and 2.37-fold increases with the concomitant use of moderate CYP3A4 inhibitors verapamil and diltiazem, respectively. The model predicted modafinil, bosentan, and efavirenz would decrease the AUC of the potency-adjusted unbound active species by 29%, 42%, and 52%, respectively. The current PBPK model, which considers changes in unbound potency-adjusted active species, can be used to inform dosing recommendations when abemaciclib is coadministered with CYP3A4 perpetrators.

Physiologically-Based Pharmacokinetic Models for Evaluating Membrane Transporter Mediated Drug-Drug Interactions: Current Capabilities, Case Studies, Future Opportunities, and Recommendations.

Physiologically-based pharmacokinetic (PBPK) modeling has been extensively used to quantitatively translate in vitro data and evaluate temporal effects from drug-drug interactions (DDIs), arising due to reversible enzyme and transporter inhibition, irreversible time-dependent inhibition, enzyme induction, and/or suppression. PBPK modeling has now gained reasonable acceptance with the regulatory authorities for the cytochrome-P450-mediated DDIs and is routinely used. However, the application of PBPK for transporter-mediated DDIs (tDDI) in drug development is relatively uncommon. Because the predictive performance of PBPK models for tDDI is not well established, here, we represent and discuss examples of PBPK analyses included in regulatory submission (the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA)) across various tDDIs. The goal of this collaborative effort (involving scientists representing 17 pharmaceutical companies in the Consortium and from academia) is to reflect on the use of current databases and models to address tDDIs. This challenges the common perceptions on applications of PBPK for tDDIs and further delves into the requirements to improve such PBPK predictions. This review provides a reflection on the current trends in PBPK modeling for tDDIs and provides a framework to promote continuous use, verification, and improvement in industrialization of the transporter PBPK modeling.

Impact of Biliopancreatic Limb Length (70 cm vs 120 cm), with Constant 150 cm Alimentary Limb, on Long-Term Weight Loss, Remission of Comorbidities and Supplementation Needs After Roux-En-Y Gastric Bypass: a Prospective Randomized Clinical Trial.

BACKGROUND: The best alimentary and biliopancreatic limb (BPL) lengths in the Roux-en-Y gastric bypass (RYGB) still remain unclear. The aim of this study was to compare the effect of a BPL of 70 vs 120 cm, with a constant AL of 150 cm on long-term weight loss, remission of comorbidities, and supplementation needs after RYGB. PATIENTS AND METHODS: A prospective randomized study of morbidly obese patients undergoing RYGB was performed. Patients were randomized into two groups: those patients undergoing RYGB with a BPL of 70 cm (BPL 70 cm) and those ones undergoing RYGB with a BPL of 120 cm (BPL 120 cm). BMI, excess BMI loss (EBMIL), remission of comorbidities and specific vitamin and mineral supplementation needs at 1, 2, and 5 years were analyzed. RESULTS: Two hundred fifty-three patients were included in each group. There were no significant differences in BMI, EBMIL and the remission of diabetes mellitus, hypertension, and dyslipidemia between groups at 1, 2, and 5 years after surgery. Patients from group BPL 120 cm required greater specific supplementation of vitamin B12, folic acid, and vitamin A during all the follow-up. CONCLUSION: A RYGB with 120 cm BPL does not achieve greater weight loss or remission of comorbidities than a RYGB with 70 cm BPL but is associated with greater deficiencies of vitamin B12, vitamin A, and folic acid. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03607305. https://clinicaltrials.gov/.