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Nihon Yakurigaku Zasshi. Folia... 2024Pertuzumab and trastuzumab are anti-HER2 humanized monoclonal antibodies with different mechanisms of action. Their combination is expected to suppress intracellular... (Review)
Review
[Pharmacological properties and clinical development overview of pertuzumab (genetical recombination), trastuzumab (genetical recombination) and vorhyaluronidase alfa (genetical recombination) (PHESGO combination for subcutaneous injection MA, IN)].
Pertuzumab and trastuzumab are anti-HER2 humanized monoclonal antibodies with different mechanisms of action. Their combination is expected to suppress intracellular HER2 signaling additively or synergistically. Their combination is widely recommended worldwide and has been established as a standard of care for HER2-positive breast cancer. However, improvement is required because of the prolonged time of intravenous infusion. Vorhyaluronidase alfa (rHuPH20) depolymerizes hyaluronan in the subcutaneous connective tissue. It's reported to increase the permeability and absorption levels of drugs. PHESGO combination for subcutaneous injection MA/IN (PHESGO) is a fixed-dose combination of pertuzumab, trastuzumab, and rHuPH20. A confirmatory phase III study (FeDeriCa) was conducted following a dose-finding phase I study (BO30185). Patients with HER2-positive early breast cancer were randomly assigned to receive either intravenous infusion of pertuzumab and trastuzumab or subcutaneous injection of PHESGO, in combination with chemotherapy, to compare the pharmacokinetics (PK), efficacy and safety. A phase II study (PHranceSCa) was also conducted to assess patients' preference and satisfaction. Based on these results, population PK analysis, and other data, PHESGO obtained marketing approval in Japan in September 2023 with indications for "HER2-positive breast cancer" and "advanced or recurrent HER2-positive colorectal cancer that has progressed following cancer chemotherapy and is not amenable to curative resection". By reducing the administration time, PHESGO is expected to contribute to various needs of patients and improvement of their daily lives. Since drug preparation is not required, it can provide convenience to healthcare professionals, leading to stress reduction of medical resources as well.
Topics: Humans; Trastuzumab; Antibodies, Monoclonal, Humanized; Hyaluronoglucosaminidase; Injections, Subcutaneous; Breast Neoplasms; Drug Combinations; Clinical Trials as Topic; Receptor, ErbB-2; Female; Recombinant Proteins; Cell Adhesion Molecules
PubMed: 38945908
DOI: 10.1254/fpj.24022 -
Yakugaku Zasshi : Journal of the... 2024The Japanese package insert (J-PI) for nirmatrelvir/ritonavir (N/r) (specially approved pharmaceutical) includes numerous warnings about drug interactions. However,...
The Japanese package insert (J-PI) for nirmatrelvir/ritonavir (N/r) (specially approved pharmaceutical) includes numerous warnings about drug interactions. However, discrepancies in the information on drug interaction are reported between J-PI and foreign databases. This study aimed to evaluate various information sources on N/r drug interactions. We categorized and compared information on N/r drug interactions from the J-PI, prescribing information from foreign regulatory agencies, guidance from the National Institutes of Health and University Health Network, the Ontario coronavirus disease 2019 (COVID-19) Science Advisory Table, University of Liverpool, Lexicomp, and the Japanese Society of Pharmaceutical Health Care and Sciences (JSPHCS). We assessed information quantity, missing data in J-PI, predicted change of the area under the blood concentration-time curve (AUC) for nirmatrelvir or co-administered drugs, and the information source consistency. From these information sources, we compiled a dataset with 115 contraindications and 203 precautions for N/r co-administration, and 51 contraindications are missing in J-PI. Among them, at least 12 drugs have large predicted AUC changes with N/r (AUC ≥5-fold or <1/5 of the baseline value). Nine of these 12 drugs are included as contraindications in Lexicomp and the JSPHCS. The consistency among the information sources is low. Information in the J-PI alone may be insufficient and Lexicomp or the JSPHCS guidelines should be useful because of their large amounts of information and wide coverage of drugs with large AUC changes. Due to low source consistency, multiple sources are needed for clinical management.
Topics: Ritonavir; Humans; Drug Interactions; Drug Combinations; COVID-19 Drug Treatment; Lopinavir; Area Under Curve; Japan; Indazoles
PubMed: 38945847
DOI: 10.1248/yakushi.23-00204 -
Food Research International (Ottawa,... Aug 2024Finger millet, like other cereals, contains high amounts of antinutrients that bind minerals, making them unavailable for absorption. This study explores the effect of...
Finger millet, like other cereals, contains high amounts of antinutrients that bind minerals, making them unavailable for absorption. This study explores the effect of traditional fermentation on nutritional, antinutritional, and subsequent mineral bioaccessibility (specifically iron, zinc, and calcium) of finger millet based Injera. Samples of fermented dough and Injera prepared from light brown and white finger millet varieties were analyzed for nutritional composition, antinutritional content, and mineral bioaccessibility following standard procedures. With some exceptions, the proximate composition of fermented dough was significantly affected by fermentation time. Compared to unfermented flour, the phytate and condensed tannin content significantly (p < 0.05) decreased for fermented dough and Injera samples. A strong decline in phytate and condensed tannin content was observed in white finger millet Injera as fermentation time increased, compared to light brown finger millet based Injera. The mineral bioaccessibility of Injera prepared from finger millet and maize composite flour increased with fermentation time, leading to a significant increase in bioaccessible iron, zinc, and calcium, ranging from 15.4-40.0 %, 26.8-50.8 %, and 60.9-88.5 %, respectively. The results suggest that traditional fermentation can be an effective method to reduce phytate and condensed tannin content, simultaneously increasing the bioaccessibility of minerals in the preparation of finger millet based Injera.
Topics: Fermentation; Nutritive Value; Phytic Acid; Eleusine; Biological Availability; Flour; Minerals; Ethiopia; Food Handling; Proanthocyanidins; Zinc
PubMed: 38945624
DOI: 10.1016/j.foodres.2024.114635 -
Food Research International (Ottawa,... Aug 2024Iron deficiency is widespread throughout the world, supplementing sufficient iron or improving the bioavailability of iron is the fundamental strategy to solve the...
Iron deficiency is widespread throughout the world, supplementing sufficient iron or improving the bioavailability of iron is the fundamental strategy to solve the problem of iron scarcity. Herein, we explored a new form of iron supplement, iron chelates of silver carp scales (SCSCP-Fe) were prepared from collagen peptide of silver carp scales (SCSCP) and FeCl·4HO, the effects of external environment and simulated gastrointestinal digestive environment on the stability of SCSCP-Fe and the structural changes of peptide iron chelates during digestion were investigated. The results of in vitro iron absorption promotion showed that the iron bioavailability of SCSCP-Fe was higher than that of FeSO. Two potential high iron chelating peptides DTSGGYDEY (DY) and LQGSNEIEIR (LR) were screened and synthesized from the SCSCP sequence by molecular dynamics and LC-MS/MS techniques. The FTIR results displayed that the binding sites of DY and LR for Fe were the carboxyl group, the amino group, and the nitrogen atom on the amide group on the peptide. ITC results indicated that the chelation reactions of DY and LR with Fe were mainly dominated by electrostatic interactions, forming chelates in stoichiometric ratios of 1:2 and 1:1, respectively. Both DY and LR had a certain ability to promote iron absorption. The transport of DY-Fe chelate may be a combination of the three pathways: PepT1 vector pathway, cell bypass, and endocytosis, while LR-Fe chelate was dominated by bivalent metal ion transporters. This study is expected to provide theoretical reference and technical support for the high-value utilization of silver carp scales and the development of novel iron supplements.
Topics: Carps; Animals; Iron Chelating Agents; Collagen; Digestion; Iron; Animal Scales; Biological Availability; Peptides; Intestinal Absorption; Humans; Fish Proteins; Ferrous Compounds; Tandem Mass Spectrometry
PubMed: 38945620
DOI: 10.1016/j.foodres.2024.114612 -
Food Research International (Ottawa,... Aug 2024To meet the high consumer demand, butter production has increased over the last few years. As a result, the buttermilk (BM) co-produced volumes require new ways of...
To meet the high consumer demand, butter production has increased over the last few years. As a result, the buttermilk (BM) co-produced volumes require new ways of adding value, such as in cheese manufacturing. However, BM use in cheese milk negatively influences the cheesemaking process (e.g., altered coagulation properties) and the product's final quality (e.g., high moisture content). The concentration of BM by ultrafiltration (UF) could potentially facilitate its use in cheese manufacturing through an increased protein content while maintaining the milk salt balance. Simultaneously, little is known about the digestion of UF BM cheese. Therefore, this study aimed to characterize the impact of UF BM on cheese manufacture, its structure, and its behavior during in vitro digestion. A 2-fold UF concentrated BM was used for cheese manufacture (skim milk [SM] - control). Compositional, textural, and microstructural analyses of cheeses were first conducted. In a second step, the cheeses were fed into an in vitro TNO gastrointestinal digestion model (TIM-1) of the stomach and small intestine and protein and phospholipid (PL) bioaccessibility was studied. The results showed that UF BM cheese significantly differed from SM cheese regarding its composition, hardness (p < 0.05) and microstructure. However, in TIM-1, UF BM and SM cheeses showed similar digestion behavior as a percentage of protein and PL intake. Despite relatively more non-digested and non-absorbed PL in the ileum efflux of UF BM cheese, the initially higher PL concentration contributes to an enhanced nutritional value compared to SM cheese. To our knowledge, this study is the first to compare the bioaccessibility of proteins and PL from UF BM and SM cheeses.
Topics: Cheese; Digestion; Phospholipids; Buttermilk; Ultrafiltration; Food Handling; Animals; Milk Proteins; Gastrointestinal Tract; Biological Availability
PubMed: 38945574
DOI: 10.1016/j.foodres.2024.114606 -
Food Research International (Ottawa,... Aug 2024There is an increasing amount of research into the development of a third generation of iron supplementation using peptide-iron chelates. Peptides isolated from mung...
There is an increasing amount of research into the development of a third generation of iron supplementation using peptide-iron chelates. Peptides isolated from mung bean were chelated with ferrous iron (MBP-Fe) and tested as a supplement in mice suffering from iron-deficiency anemia (IDA). Mice were randomly divided into seven groups: a group fed the normal diet, the IDA model group, and IDA groups treated with inorganic iron (FeSO), organic iron (ferrous bisglycinate, Gly-Fe), low-dose MBP-Fe(L-MBP-Fe), high-dose MBP-Fe(H-MBP-Fe), and MBP mixed with FeSO (MBP/Fe). The different iron supplements were fed for 28 days via intragastric administration. The results showed that MBP-Fe and MBP/Fe had ameliorative effects, restoring hemoglobin (HGB), red blood cell (RBC), hematocrit (HCT), and serum iron (SI) levels as well as total iron binding capacity (TIBC) and body weight gain of the IDA mice to normal levels. Compared to the inorganic (FeSO) and organic (Gly-Fe) iron treatments, the spleen coefficient and damage to liver and spleen tissues were significantly lower in the H-MBP-Fe and MBP/Fe mixture groups, with reparative effects on jejunal tissue. Gene expression analysis of the iron transporters Dmt 1 (Divalent metal transporter 1), Fpn 1 (Ferroportin 1), and Dcytb (Duodenal cytochrome b) indicated that MBP promoted iron uptake. These findings suggest that mung bean peptide-ferrous chelate has potential as a peptide-based dietary supplement for treating iron deficiency.
Topics: Animals; Vigna; Anemia, Iron-Deficiency; Biological Availability; Mice; Ferrous Compounds; Peptides; Iron; Male; Iron Chelating Agents; Hemoglobins; Dietary Supplements; Cation Transport Proteins; Disease Models, Animal; Glycine
PubMed: 38945571
DOI: 10.1016/j.foodres.2024.114602 -
Gastroenterology Jun 2024Interleukin-23 (IL-23), a member of the IL-12 family of cytokines, maintains intestinal homeostasis but is also implicated in the pathogenesis of inflammatory bowel... (Review)
Review
Interleukin-23 (IL-23), a member of the IL-12 family of cytokines, maintains intestinal homeostasis but is also implicated in the pathogenesis of inflammatory bowel diseases (IBD). The IL-23 receptor (IL-23R) is a heterodimer composed of disulfide-linked p19- and p23-subunits. Humanized monoclonal antibodies selectively targeting the p19-subunit of IL-23 are poised to become prominent drugs in IBD. In this review, we discuss pharmacodynamic and pharmacokinetic properties of the currently available IL-23p19 inhibitors and discuss the mechanistic underpinnings of their therapeutic effects, including the mechanism of action, epitope affinity, potency, and downstream signaling. Furthermore, we address available data on the efficacy, safety, and tolerability of IL-23-specific p19-inhibitors in the treatment of IBD and discuss important studies performed in other immune-mediated inflammatory diseases. Finally, we evaluate the potential for combining classes of biological therapies and provide future directions on the development of precision medicine-guided positioning of IL-23p19 inhibitors in IBD.
PubMed: 38945499
DOI: 10.1053/j.gastro.2024.05.036 -
Journal of Ethnopharmacology Jun 2024Lablab Semen Album (lablab), the white and dried mature fruit of Lablab purpureus in the Lablab genus of the Fabaceae family, is a renowned traditional medicinal herb... (Review)
Review
ETHNOPHARMACOLOGICAL RELEVANCE
Lablab Semen Album (lablab), the white and dried mature fruit of Lablab purpureus in the Lablab genus of the Fabaceae family, is a renowned traditional medicinal herb with a long history of use in China. In Chinese medicine, lablab is often combined with other drugs to treat conditions such as weak spleen and stomach, loss of appetite, loose stools, excessive leucorrhoea, summer dampness and diarrhea, chest tightness, and abdominal distension.
MATERIALS AND METHODS
Comprehensive information on lablab was gathered from databases including Web of Science, Science Direct, Google Scholar, Springer, PubMed, CNKI, Wanfang, and ancient materia medica.
RESULTS
Lablab, a member of the lentil family, thrives in warm and humid climates, and is distributed across tropical and subtropical regions worldwide. Traditionally, lablab is used to treat various ailments, such as spleen and stomach weakness, loss of appetite, and diarrhea. Phytochemical analyses reveal that lablab is a rich source of triterpenoid saponins, glucosides, volatile oils, polysaccharides, and amino acids. Lablab extracts exhibit diverse biological activities, including hypolipidemic, hypoglycemic, immunomodulatory, antioxidant, hepatoprotective, antitumoral, antiviral properties, and more. Besides its medicinal applications, lablab is extensively used in the food industry due to its high nutrient content. Additionally, the quality of lablab can be regulated by determining the levels of key chemical components pivotal to its medicinal effects, ensuring the herb's overall quality.
CONCLUSION
Lablab is a promising medicinal and edible plant ingredient with diverse pharmacological effects, making it a valuable ingredient for food, pharmaceuticals, and animal husbandry. However, it has inherent toxicity if not properly prepared. Additionally, some traditional uses and pharmacological activities lack scientific validation due to incomplete methods, unclear results, and insufficient clinical data. Thus, further in vivo and in vitro studies on its pharmacology, pharmacokinetics, and toxicology, along with clinical efficacy evaluations, are needed to ensure lablab's safety and effectiveness. As an important traditional Chinese medicine, lablab deserves more attention.
PubMed: 38945467
DOI: 10.1016/j.jep.2024.118507 -
International Journal of Pharmaceutics Jun 2024Rhein, a natural anthraquinone compound derived from traditional Chinese medicine, exhibits potent anti-inflammatory properties via modulating the level of Reactive...
Rhein, a natural anthraquinone compound derived from traditional Chinese medicine, exhibits potent anti-inflammatory properties via modulating the level of Reactive oxygen or nitrogen species (RONS). Nevertheless, its limited solubility in water, brief duration of plasma presence, as well as its significant systemic toxicity, pose obstacles to its in vivo usage, necessitating the creation of a reliable drug delivery platform to circumvent these difficulties. In this study, an esterase-responsive and mitochondria-targeted nano-prodrug was synthesized by conjugating Rhein with the polyethylene glycol (PEG)-modified triphenyl phosphonium (TPP) molecule, forming TPP-PEG-RH, which could spontaneously self-assemble into RPT NPs when dispersed in aqueous media. The TPP outer layer of these nanoparticles enhances their pharmacokinetic profile, facilitates efficient delivery to mitochondria, and promotes cellular uptake, thereby enabling enhanced accumulation in mitochondria and improved therapeutic effects in vitro. The decline in RONS was observed in IL-1β-stimulated chondrocyte after RPT NPs treating. RPT NPs also exert excellent anti-inflammatory (IL-1β, TNF-α, IL-6 and MMP-13) and antioxidative effects (Cat and Sod) via the Nrf2 signalling pathway, upregulation of cartilage related genes (Col2a1 and Acan). Moreover, RPT NPs shows protection of mitochondrial membrane potential and inhibition of chondrocyte apoptosis. Moreover, These findings suggest that the mitochondria-targeted polymer-Rhein conjugate may offer a therapeutic solution for patients suffering from chronic joint disorders, by attenuating the progression of osteoarthritis (OA).
PubMed: 38945463
DOI: 10.1016/j.ijpharm.2024.124397 -
European Journal of Pharmaceutics and... Jun 2024Liposomes represent one of the most extensively studied nano-carriers due to their potential in targeted drug delivery. However, the complex in vivo fate, particularly...
Liposomes represent one of the most extensively studied nano-carriers due to their potential in targeted drug delivery. However, the complex in vivo fate, particularly under pathological conditions, presents challenges for clinical translation of liposomal therapeutics. Liver serves as the most important organ for liposome accumulation and metabolism. Unfortunately, the fate of liposomes under pathological liver conditions has been significantly overlooked. This study aimed to investigate the in vivo pharmacokinetic profile and biodistribution profile of liposomes under drug-induced liver injury (DILI) conditions. Two classic DILI animal models, i.e. acetaminophen-induced acute liver injury (AILI) and triptolide-induced subacute liver injury (TILI), were established to observe the effect of pathological liver conditions on the in vivo performance of liposomes. The study revealed significant changes in the in vivo fate of liposomes following DILI, including prolonged blood circulation and enhanced hepatic accumulation of liposomes. Changes in the composition of plasma proteins and mononuclear phagocyte system (MPS)-related cell subpopulations collectively led to the altered in vivo fate of liposomes under liver injury conditions. Despite liver injury, macrophages remained the primary cells responsible for liposomes uptake in liver, with the recruited monocyte-derived macrophages exhibiting enhanced ability to phagocytose liposomes under pathological conditions. These findings indicated that high capture of liposomes by the recruited hepatic macrophages not only offered potential solutions for targeted delivery, but also warned the clinical application of patients under pathological liver conditions.
PubMed: 38945407
DOI: 10.1016/j.ejpb.2024.114389