Oral delivery of peptide therapeutics in infants: Challenges and opportunities

Gleeson, John P.; Fein, Katherine C.; Whitehead, Kathryn A.

doi:10.1016/j.addr.2021.03.011

Cited by 23 publications

(20 citation statements)

References 148 publications

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“…Although the lives of experimental animals are much shorter than that of human, we still clarity that the drug transporter undergoes a dynamic change throughout the life. Thus, drug transporters should receive close attentions at fetal, neonatal, mature, and old ages during drug development and clinical use ( Andreollo et al, 2012 ; Sengupta, 2013 ; Gleeson et al, 2021 ; Vinarov et al, 2021 ).…”

Section: The Expressions Of Drug Transporters In Kidney Across Species Sex-gender and Agementioning

confidence: 99%

Drug Transporters in the Kidney: Perspectives on Species Differences, Disease Status, and Molecular Docking

et al. 2021

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The kidneys are a pair of important organs that excretes endogenous waste and exogenous biological agents from the body. Numerous transporters are involved in the excretion process. The levels of these transporters could affect the pharmacokinetics of many drugs, such as organic anion drugs, organic cationic drugs, and peptide drugs. Eleven drug transporters in the kidney (OAT1, OAT3, OATP4C1, OCT2, MDR1, BCRP, MATE1, MATE2-K, OAT4, MRP2, and MRP4) have become necessary research items in the development of innovative drugs. However, the levels of these transporters vary between different species, sex-genders, ages, and disease statuses, which may lead to different pharmacokinetics of drugs. Here, we review the differences of the important transports in the mentioned conditions, in order to help clinicians to improve clinical prescriptions for patients. To predict drug-drug interactions (DDIs) caused by renal drug transporters, the molecular docking method is used for rapid screening of substrates or inhibitors of the drug transporters. Here, we review a large number of natural products that represent potential substrates and/or inhibitors of transporters by the molecular docking method.

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Section: The Expressions Of Drug Transporters In Kidney Across Species Sex-gender and Agementioning

confidence: 99%

Drug Transporters in the Kidney: Perspectives on Species Differences, Disease Status, and Molecular Docking

et al. 2021

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“…Compared to traditional antibodies, Nbs possess several unique and favorable properties such as small size, high stability, strong antigen‐binding affinity, water solubility, and ease of production in bacteria (Dumoulin et al, 2002 ; Goldman et al, 2017 ; Jovcevska & Muyldermans, 2020 ; Muyldermans et al, 2001 , 2009 ; Van Der Linden et al, 1999 ; Van Der Vaart et al, 2006 ). Despite all these advantages, like any other protein and peptide biotherapeutics or preventatives, oral delivery of Nbs remains unsuccessful due to their degradation in the acidic and enzyme‐rich environment of the stomach (Dhalla et al, 2021 ; Gleeson et al, 2021 ). Desired efficacy also demands frequent administration at higher concentrations, which is not economically feasible.…”

Section: Introductionmentioning

confidence: 99%

Recombinant Limosilactobacillus (Lactobacillus) delivering nanobodies against Clostridium perfringens NetB and alpha toxin confers potential protection from necrotic enteritis

Gangaiah

Ryan

Hoesel³

et al. 2022

MicrobiologyOpen

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Necrotic enteritis (NE), caused by Clostridium perfringens , is an intestinal disease with devastating economic losses to the poultry industry. NE is a complex disease and predisposing factors that compromise gut integrity are required to facilitate C. perfringens proliferation and toxin production. NE is also characterized by drastic shifts in gut microbiota; C. perfringens is negatively correlated with Lactobacilli. Vaccines are only partially effective against NE and antibiotics suffer from the concern of resistance development. These strategies address only some aspects of NE pathogenesis. Thus, there is an urgent need for alternative strategies that address multiple aspects of NE biology. Here, we developed Limosilactobacillus ( Lactobacillus ) reuteri vectors for in situ delivery of nanobodies against NetB and α toxin, two key toxins associated with NE pathophysiology. We generated nanobodies and showed that these nanobodies neutralize NetB and α toxin. We selected L. reuteri vector strains with intrinsic benefits and demonstrated that these strains inhibit C. perfringens and secrete over 130 metabolites, some of which play a key role in maintaining gut health. Recombinant L. reuteri strains efficiently secreted nanobodies and these nanobodies neutralized NetB. The recombinant strains were genetically and phenotypically stable over 480 generations and showed persistent colonization in chickens. A two‐dose in ovo and drinking water administration of recombinant L. reuteri strains protected chickens from NE‐associated mortality. These results provide proof‐of‐concept data for using L. reuteri as a live vector for delivery of nanobodies with broad applicability to other targets and highlight the potential synergistic effects of vector strains and nanobodies for addressing complex diseases such as NE.

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“…The rejection of unpalatable pharmaceutical products is a basic biological reflex, which may lead to decreased medication compliance and inaccurate or even harmful dosage, thus hampering the ideal treatment efficacy. Studies have found that more than 50% of children aged less than 6 years had difficulty using pharmaceutical products ( Shimokawa et al, 2009 ); the potential factors resulting in this include how easy it is to swallow, formulation, size and shape, and factors related to palatability such as taste, flavor, and smell ( Forough et al, 2018 ; Min et al, 2019 ; Gleeson et al, 2021 ). Therefore, better palatability of pharmaceutical preparations is pivotal in improving medication compliance in pediatric patients ( Kim et al, 2020 ; Lopalco and Denora, 2020 ; Moreira and Sarraguça, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Palatability Assessment of Carbocysteine Oral Solution Strawberry Taste Versus Carbocysteine Oral Solution Mint Taste: A Blinded Randomized Study

et al. 2022

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Objective: To compare and evaluate the palatability of two carbocysteine oral solutions (strawberry vs. mint taste) among healthy children aged 2–12 years.Methods: A randomized, triple-blind, crossover, palatability trial in 42 children aged 2–12 years. All subjects received two preparations of carbocysteine oral solutions (strawberry vs. mint) according to randomized administration sequences, and the administration process was recorded by video. The palatability assessed by emotional valences was performed using a facial action coding system by FaceReader™, which reflected the quantification degree of emotion; a positive value represents positive emotion, and a negative value represents negative emotion. At the same time, a face-to-face interview was conducted for 5- to 12-year-old participants. Then, the taste preferential rates were compared to assess the palatability of two carbocysteine oral solutions.Results: Forty-two children were enrolled in this study. Twenty children first tasted the carbocysteine oral solution mint taste and then the strawberry taste preparation (M-S sequence), while 22 children tasted the strawberry preparation first and then the mint one (S-M sequence). The emotional valence of mint preparation (−0.9 in M-S and −1.2 in S-M) was both relatively lower than that of strawberry taste (both −0.7 in M-S and S-M) in two sequences; 69.0% (29/42) of participants’ emotional valences for strawberry preparation were higher than those for mint preparation. Among 27 participants aged ≥5 years, the taste preference rate was 88.5% (23/26) for the strawberry preparation (one missing value for the taste preference), and 77.8% of participants (21/27) chose the strawberry preparation if they had to take the medicine one more time.Conclusion: The carbocysteine oral solution with strawberry taste is an appealing preparation since it was better received by children. The facial action coding system could be an effective alternative for palatability assessment of pediatric pharmaceutical products.

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Oral delivery of peptide therapeutics in infants: Challenges and opportunities

Cited by 23 publications

References 148 publications

Drug Transporters in the Kidney: Perspectives on Species Differences, Disease Status, and Molecular Docking

Drug Transporters in the Kidney: Perspectives on Species Differences, Disease Status, and Molecular Docking

Recombinant Limosilactobacillus (Lactobacillus) delivering nanobodies against Clostridium perfringens NetB and alpha toxin confers potential protection from necrotic enteritis

Palatability Assessment of Carbocysteine Oral Solution Strawberry Taste Versus Carbocysteine Oral Solution Mint Taste: A Blinded Randomized Study

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