المؤلفون: El Gammal RN; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., Elmansi H; Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., El-Emam AA; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., Belal F; Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., Hammouda MEA; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt (HUE), New Damietta, Egypt.

المصدر: Luminescence : the journal of biological and chemical luminescence [Luminescence] 2024 Jun; Vol. 39 (6), pp. e4792.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Wiley & Sons Country of Publication: England NLM ID: 100889025 Publication Model: Print Cited Medium: Internet ISSN: 1522-7243 (Electronic) Linking ISSN: 15227235 NLM ISO Abbreviation: Luminescence Subsets: MEDLINE

مواضيع طبية MeSH: Pyrazines*/chemistry , Pyrazines*/metabolism , Amides*/chemistry , Amides*/metabolism , Adenine Nucleotides*/chemistry , Adenine Nucleotides*/metabolism , Antiviral Agents*/chemistry , Antiviral Agents*/pharmacology , Antiviral Agents*/metabolism , Thermodynamics*, Spectroscopy, Fourier Transform Infrared ; Spectrometry, Fluorescence ; Fluorescence Resonance Energy Transfer ; Spectrophotometry, Ultraviolet ; Binding Sites ; Adenine/chemistry ; Adenine/metabolism

مستخلص: Favipiravir (FVP) is an oral antiviral drug approved in 2021 for the treatment of COVID-19. It is a pyrazine derivative that can be integrated into anti-viral RNA products to inhibit viral replication. While, adenine is a purine nucleobase that is found in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) to generate genetic information. For the first time, the binding mechanism between FVP and adenine was determined using different techniques, including UV-visible spectrophotometry, spectrofluorimetry, synchronous fluorescence (SF) spectroscopy, Fourier transform infrared (FTIR), fluorescence resonance energy transfer (FRET), and metal ion complexation. The fluorescence spectra indicated that FVP is bound to adenine via Van der Waals forces and hydrogen bonding through a spontaneous binding process (ΔG ^ο  < 0). The quenching mechanism was found to be static. Various temperature settings were used to investigate thermodynamic characteristics, such as binding forces, binding constants, and the number of binding sites. The reaction parameters, including the enthalpy change (ΔH ^ο ) and entropy change (ΔS ^ο ), were calculated using Van't Hoff's equation. The findings demonstrated that the adenine-FVP binding was endothermic. Furthermore, the results of the experiments revealed that some metal ions (K ⁺ , Ca ⁺² , Co ⁺² , Cu ⁺² , and Al ⁺³ ) might facilitate the binding interaction between FVP and adenine. Slight changes are observed in the FTIR spectra of adenine, indicating the binding interaction between adenine and FVP. This study may be useful in understanding the pharmacokinetic characteristics of FVP and how the drug binds to adenine to prevent any side effects.
(© 2024 John Wiley & Sons Ltd.)

المؤلفون: Choi Y; Department of Biomedical Science, Graduate School of Ajou University, Worldcup-ro 164, Yeoungtong-gu, Suwon-si 16499, South Korea. Electronic address: rkddpf1123@naver.com., Kim SH; Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Worldcup-ro 164, Yeoungtong-gu, Suwon-si 16499, South Korea. Electronic address: oh4038@naver.com., Jun Shin S; Department of Biomedical Science, Graduate School of Ajou University, Worldcup-ro 164, Yeoungtong-gu, Suwon-si 16499, South Korea. Electronic address: 01075871087t@gmail.com., Park HS; Department of Biomedical Science, Graduate School of Ajou University, Worldcup-ro 164, Yeoungtong-gu, Suwon-si 16499, South Korea; Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Worldcup-ro 164, Yeoungtong-gu, Suwon-si 16499, South Korea. Electronic address: hspark@ajou.ac.kr., Seob Shin Y; Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Worldcup-ro 164, Yeoungtong-gu, Suwon-si 16499, South Korea. Electronic address: drsys93@naver.com.

المصدر: International immunopharmacology [Int Immunopharmacol] 2024 May 10; Vol. 132, pp. 111903. Date of Electronic Publication: 2024 Apr 04.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 100965259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-1705 (Electronic) Linking ISSN: 15675769 NLM ISO Abbreviation: Int Immunopharmacol Subsets: MEDLINE

مواضيع طبية MeSH: Adenine*/*analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase*/antagonists & inhibitors , Asthma*/drug therapy , Asthma*/immunology , Mice, Inbred BALB C* , Piperidines*/therapeutic use , Piperidines*/pharmacology , Ovalbumin*/immunology , Disease Models, Animal* , Adenine*/therapeutic use , Adenine*/pharmacology , Immunoglobulin E*/blood , Immunoglobulin E*/immunology , Cytokines*/metabolism , Eosinophils*/immunology , Eosinophils*/drug effects , Protein Kinase Inhibitors*/pharmacology , Protein Kinase Inhibitors*/therapeutic use, Animals ; Mice ; Pyrimidines/therapeutic use ; Pyrimidines/pharmacology ; Female ; Pyrazoles/therapeutic use ; Pyrazoles/pharmacology ; Bronchoalveolar Lavage Fluid/cytology ; Bronchoalveolar Lavage Fluid/immunology ; Immunoglobulin G/blood ; Anti-Asthmatic Agents/therapeutic use ; Anti-Asthmatic Agents/pharmacology ; Cells, Cultured ; Humans ; Mast Cells/drug effects ; Mast Cells/immunology

مستخلص: Bruton's Tyrosine kinase (BTK) plays a pivotal role as the key mediator in B cell signaling. Recent research has revealed that it is also expressed in cells critical to asthma development, such as T cells, and eosinophils. This study aims to investigate the potential of BTK inhibitor in eosinophilic asthma mouse model. BALB/c mice were sensitized with ovalbumin (OVA) via intraperitoneal injections and followed by OVA nebulizations. The mice were treated with 250 µg/ml or 500 µg/ml of ibrutinib before the second intraperitoneal injection and the first nebulization. Two days after the last OVA challenge, airway hyperresponsiveness (AHR) was assessed with methacholine, and differential cell count in bronchoalveolar lavage fluid (BALF) was performed. The cytokines were measured in BALF, and serum OVA-specific IgE and IgG antibody levels were evaluated by ELISA. The inhibitory effect of ibrutinib was also evaluated in splenic mononuclear cells, mast cells, eosinophils, and T cells in vitro. Treatment with ibrutinib significantly attenuated AHR and airway inflammation, compared to the OVA-induced positive control. The treatment also reduced IL-4, IL-5, IL-13 and IFN-γ cytokine levels and suppressed OVA-specific IgE and IgG production compared to the OVA-induced positive control. Additionally, ibrutinib decreased beta-hexosaminidase release from mast cells, type 2 cytokine productions from mononuclear cells and T cells, and eosinophilic activation markers in vitro. The results of this study suggest that ibrutinib treatment could exert anti-allergic effects by inactivating B cells and other BTK-expressing cells. Further studies are needed to investigate the potential therapeutic effect of ibrutinib on allergic diseases.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier B.V.)

المؤلفون: Shadman M; Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA. mshadman@fredhutch.org., Tedeschi A; ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy., Mohseninejad L; BeiGene, Netherlands B.V., Schiphol, The Netherlands., Yang K; BeiGene USA Inc, San Mateo, CA, USA., Lamanna N; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA., Xu S; BeiGene (Beijing) Co. Ltd., Beijing, China., Cohen A; BeiGene USA Inc, San Mateo, CA, USA., Challagulla S; BeiGene USA Inc, San Mateo, CA, USA., Xue M; BeiGene USA Inc, San Mateo, CA, USA., Williams R; BeiGene USA Inc, San Mateo, CA, USA., O'Brien SM; Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA., Brown JR; Dana-Farber Cancer Institute, Boston, MA, USA., Tam C; The Alfred Hospital and Monash University, Melbourne, VIC, Australia.

المصدر: Blood cancer journal [Blood Cancer J] 2024 May 02; Vol. 14 (1), pp. 77. Date of Electronic Publication: 2024 May 02.

نوع المنشور: Letter; Research Support, Non-U.S. Gov't; Comparative Study

بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101568469 Publication Model: Electronic Cited Medium: Internet ISSN: 2044-5385 (Electronic) Linking ISSN: 20445385 NLM ISO Abbreviation: Blood Cancer J Subsets: MEDLINE

مواضيع طبية MeSH: Adenine*/*analogs & derivatives, Leukemia, Lymphocytic, Chronic, B-Cell*/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell*/mortality , Adenine*/therapeutic use , Piperidines*/therapeutic use, Humans ; Male ; Pyrazoles/therapeutic use ; Female ; Pyrimidines/therapeutic use ; Aged ; Treatment Outcome ; Middle Aged

المؤلفون: Konttinen O; Biomolecular Science and Engineering, University of California, Santa Barbara, Santa Barbara, CA, USA., Carmody J; Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, CA, USA., Kurnik M; Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, CA, USA., Johnson KA; Life Sciences Interdisciplinary Graduate Program, Department of Molecular Biosciences, University of Texas, Austin, TX, USA., Reich N; Biomolecular Science and Engineering, University of California, Santa Barbara, Santa Barbara, CA, USA.; Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, CA, USA.

المصدر: Nucleic acids research [Nucleic Acids Res] 2023 Jul 21; Vol. 51 (13), pp. 6883-6898.

نوع المنشور: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.

بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

مواضيع طبية MeSH: Site-Specific DNA-Methyltransferase (Adenine-Specific)*/metabolism , DNA*/chemistry, Humans ; DNA Methylation ; DNA Modification Methylases/genetics ; DNA Modification Methylases/metabolism ; Methyltransferases/genetics ; Methyltransferases/metabolism ; Adenine/metabolism ; Kinetics ; Substrate Specificity

مستخلص: Strand-separation is emerging as a novel DNA recognition mechanism but the underlying mechanisms and quantitative contribution of strand-separation to fidelity remain obscure. The bacterial DNA adenine methyltransferase, CcrM, recognizes 5'GANTC'3 sequences through a DNA strand-separation mechanism with unusually high selectivity. To explore this novel recognition mechanism, we incorporated Pyrrolo-dC into cognate and noncognate DNA to monitor the kinetics of strand-separation and used tryptophan fluorescence to follow protein conformational changes. Both signals are biphasic and global fitting showed that the faster phase of DNA strand-separation was coincident with the protein conformational transition. Non-cognate sequences did not display strand-separation and methylation was reduced > 300-fold, providing evidence that strand-separation is a major determinant of selectivity. Analysis of an R350A mutant showed that the enzyme conformational step can occur without strand-separation, so the two events are uncoupled. A stabilizing role for the methyl-donor (SAM) is proposed; the cofactor interacts with a critical loop which is inserted between the DNA strands, thereby stabilizing the strand-separated conformation. The results presented here are broadly applicable to the study of other N6-adenine methyltransferases that contain the structural features implicated in strand-separation, which are found widely dispersed across many bacterial phyla, including human and animal pathogens, and some Eukaryotes.
(© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

المؤلفون: Fujisawa K; Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.

المصدر: International journal of molecular sciences [Int J Mol Sci] 2023 Mar 14; Vol. 24 (6). Date of Electronic Publication: 2023 Mar 14.

نوع المنشور: Journal Article; Review

بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

مواضيع طبية MeSH: Adenine Nucleotides*/metabolism , Adenylate Kinase*/metabolism, Animals ; Humans ; Nucleotides ; Adenine ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Adenosine Monophosphate ; Adenosine Triphosphate/metabolism

مستخلص: Adenylate kinase (AK) regulates adenine nucleotide metabolism and catalyzes the ATP + AMP ⇌ 2ADP reaction in a wide range of organisms and bacteria. AKs regulate adenine nucleotide ratios in different intracellular compartments and maintain the homeostasis of the intracellular nucleotide metabolism necessary for growth, differentiation, and motility. To date, nine isozymes have been identified and their functions have been analyzed. Moreover, the dynamics of the intracellular energy metabolism, diseases caused by AK mutations, the relationship with carcinogenesis, and circadian rhythms have recently been reported. This article summarizes the current knowledge regarding the physiological roles of AK isozymes in different diseases. In particular, this review focused on the symptoms caused by mutated AK isozymes in humans and phenotypic changes arising from altered gene expression in animal models. The future analysis of intracellular, extracellular, and intercellular energy metabolism with a focus on AK will aid in a wide range of new therapeutic approaches for various diseases, including cancer, lifestyle-related diseases, and aging.

المؤلفون: Campbell L; King's College Hospital NHS Foundation Trust.; King's College London., Barbini B; King's College Hospital NHS Foundation Trust.; King's College London., Cromarty B; UK Community Advisory Board., Hamzah L; St George's Healthcare NHS Trust, London., Williams D; Brighton and Sussex University Hospitals, Brighton., Winston A; Imperial College Healthcare NHS Trust.; Imperial College, London, UK., Post FA; King's College Hospital NHS Foundation Trust.; King's College London.

مؤلفون مشاركون: FANTA trial team

المصدر: AIDS (London, England) [AIDS] 2024 Jul 15; Vol. 38 (9), pp. 1442-1445. Date of Electronic Publication: 2024 Jun 27.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Lippincott Williams & Wilkins Country of Publication: England NLM ID: 8710219 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1473-5571 (Electronic) Linking ISSN: 02699370 NLM ISO Abbreviation: AIDS Subsets: MEDLINE

مواضيع طبية MeSH: Tenofovir*/adverse effects , Tenofovir*/therapeutic use , Tenofovir*/analogs & derivatives , Alanine*/adverse effects , Alanine*/therapeutic use , Anti-HIV Agents*/adverse effects , Anti-HIV Agents*/therapeutic use , HIV Infections*/drug therapy , HIV Infections*/complications , Adenine*/analogs & derivatives , Adenine*/adverse effects , Adenine*/therapeutic use , Fanconi Syndrome*/chemically induced, Humans ; Male ; Female ; Adult ; Middle Aged

مستخلص: Twenty-eight individuals who experienced proximal renal tubulopathy (PRT, Fanconi syndrome) while receiving tenofovir disoproxil initiated tenofovir alafenamide (TAF) and were followed for 5 years. None developed recurrent PRT or experienced significant changes in estimated glomerular filtration rate (by creatinine or cystatin-C), albuminuria, proteinuria, retinol-binding proteinuria, fractional excretion of phosphate, alkaline phosphatase, or bone mineral density at the lumbar spine. These data suggest that TAF is a well tolerated treatment option for individuals vulnerable to developing PRT.
(Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

المؤلفون: Kim SM; Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do, 17546, Republic of Korea., Han GU; Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do, 17546, Republic of Korea., Kim SG; Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do, 17546, Republic of Korea., Moon SH; Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do, 17546, Republic of Korea., Shin SH; Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do, 17546, Republic of Korea., Ryu BY; Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do, 17546, Republic of Korea. Electronic address: byryu@cau.ac.kr.

المصدر: Ecotoxicology and environmental safety [Ecotoxicol Environ Saf] 2024 Jul 15; Vol. 280, pp. 116544. Date of Electronic Publication: 2024 Jun 04.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 7805381 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2414 (Electronic) Linking ISSN: 01476513 NLM ISO Abbreviation: Ecotoxicol Environ Saf Subsets: MEDLINE

مواضيع طبية MeSH: Phthalic Acids*/toxicity , Autophagy*/drug effects , Apoptosis*/drug effects , Reactive Oxygen Species*/metabolism , Sesquiterpenes*/pharmacology , Acetylcysteine*/pharmacology , Adenine*/analogs & derivatives , Adenine*/pharmacology , Adenine*/toxicity , Cell Proliferation*/drug effects, Male ; Animals ; Mice ; Cell Line ; Plasticizers/toxicity ; Spermatogonia/drug effects

مستخلص: Benzyl butyl phthalate (BBP) is a widely used plasticizer that poses various potential health hazards. Although BBP has been extensively studied, the direct mechanism underlying its toxicity in male germ cells remains unclear. Therefore, we investigated BBP-mediated male germ cell toxicity in GC-1 spermatogonia (spg), a differentiated mouse male germ cell line. This study investigated the impact of BBP on reactive oxygen species (ROS) generation, apoptosis, and autophagy regulation, as well as potential protective measures against BBP-induced toxicity. A marked dose-dependent decrease in GC-1 spg cell proliferation was observed following treatment with BBP at 12.5 μM. Exposure to 50 μM BBP, approximating the IC 50 of 53.9 μM, markedly increased cellular ROS generation and instigated apoptosis, as evidenced by augmented protein levels of both intrinsic and extrinsic apoptosis-related markers. An amount of 50 μM BBP induced marked upregulation of autophagy regulator proteins, p38 MAPK, and extracellular signal-regulated kinase and substantially downregulated the phosphorylation of key kinases involved in regulating cell proliferation, including phosphoinositide 3-kinase, protein kinase B, mammalian target of rapamycin (mTOR), c-Jun N-terminal kinase. The triple combination of N-acetylcysteine, parthenolide, and 3-methyladenine markedly restored cell proliferation, decreased BBP-induced apoptosis and autophagy, and restored mTOR phosphorylation. This study provides new insights into BBP-induced male germ cell toxicity and highlights the therapeutic potential of the triple inhibitors in mitigating BBP toxicity.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier Inc.)

المؤلفون: Killock D; Nature Reviews Clinical Oncology, . nrclinonc@nature.com.

المصدر: Nature reviews. Clinical oncology [Nat Rev Clin Oncol] 2024 Jul; Vol. 21 (7), pp. 483.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101500077 Publication Model: Print Cited Medium: Internet ISSN: 1759-4782 (Electronic) Linking ISSN: 17594774 NLM ISO Abbreviation: Nat Rev Clin Oncol Subsets: MEDLINE

مواضيع طبية MeSH: Piperidines*/therapeutic use , Adenine*/analogs & derivatives , Adenine*/therapeutic use , Pyrazoles*/therapeutic use , Pyrimidines*/therapeutic use , Antineoplastic Combined Chemotherapy Protocols*/therapeutic use , Lymphoma, Mantle-Cell*/drug therapy, Humans ; Treatment Outcome ; Hematopoietic Stem Cell Transplantation

المؤلفون: Dong Q; Department I of Pharmacology, Center for Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Straße 24, Cologne, 50931, Germany. qdong2@smail.uni-koeln.de., Chen C; Department I of Pharmacology, Center for Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Straße 24, Cologne, 50931, Germany.; Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, 150030, People's Republic of China., Taubert M; Department I of Pharmacology, Center for Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Straße 24, Cologne, 50931, Germany., Bilal M; Department I of Pharmacology, Center for Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Straße 24, Cologne, 50931, Germany.; Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany., Kinzig M; Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany., Sörgel F; Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany., Scherf-Clavel O; Department Pharmazie, Ludwig-Maximilians-Universität München, Butenandtstr. 5, 81377, München, Germany., Fuhr U; Department I of Pharmacology, Center for Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Straße 24, Cologne, 50931, Germany., Dokos C; Department I of Pharmacology, Center for Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Straße 24, Cologne, 50931, Germany.

المصدر: European journal of clinical pharmacology [Eur J Clin Pharmacol] 2024 Jul; Vol. 80 (7), pp. 1069-1078. Date of Electronic Publication: 2024 Mar 28.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Springer Country of Publication: Germany NLM ID: 1256165 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-1041 (Electronic) Linking ISSN: 00316970 NLM ISO Abbreviation: Eur J Clin Pharmacol Subsets: MEDLINE

مواضيع طبية MeSH: Organophosphonates*/pharmacokinetics , Organophosphonates*/blood , Organophosphonates*/administration & dosage , Adenine*/analogs & derivatives , Adenine*/pharmacokinetics , Adenine*/administration & dosage , Models, Biological*, Humans ; Male ; Adult ; Female ; Organic Anion Transport Protein 1/metabolism ; Organic Anion Transport Protein 1/genetics ; Drug Interactions ; Phenotype ; Middle Aged ; Young Adult ; Digoxin/pharmacokinetics ; Digoxin/blood ; Digoxin/administration & dosage ; Metformin/pharmacokinetics ; Metformin/administration & dosage ; Metformin/blood ; Sitagliptin Phosphate/pharmacokinetics ; Biological Availability

مستخلص: Purpose: Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CL R ) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail.
Methods: Data from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination.
Results: A one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29 h ^-1 vs. 5.18 h ^-1 ) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (K m ) of the nonlinear renal elimination was 170 nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (V max ) of nonlinear renal elimination was 2.40 µmol/h at the median absolute estimated glomerular filtration rate of 105 mL/min.
Conclusion: The popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high K m value suggests that assessing renal OAT1 activity by CL R has no relevant misspecification error with the cocktail doses used.
(© 2024. The Author(s).)

المؤلفون: Jyani G; Department of Community Medicine and School of Public Health, Postgraduate Institute of Medical Education and Research, Chandigarh, India., Gupta N; Department of Radiation Oncology, Government Medical College and Hospital, Chandigarh, India. Electronic address: nidhiguptaonco@gmail.com.

المصدر: Value in health regional issues [Value Health Reg Issues] 2024 Jul; Vol. 42, pp. 100991. Date of Electronic Publication: 2024 May 08.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Elsevier Country of Publication: United States NLM ID: 101592642 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2212-1102 (Electronic) Linking ISSN: 22121099 NLM ISO Abbreviation: Value Health Reg Issues Subsets: MEDLINE

مواضيع طبية MeSH: Leukemia, Lymphocytic, Chronic, B-Cell*/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell*/economics , Adenine*/analogs & derivatives , Adenine*/therapeutic use , Adenine*/economics , Cost-Benefit Analysis*/methods , Piperidines*/therapeutic use , Piperidines*/economics , Pyrimidines*/economics , Pyrimidines*/therapeutic use , Pyrazoles*/economics , Pyrazoles*/therapeutic use, Humans ; India/epidemiology ; Antineoplastic Agents/economics ; Antineoplastic Agents/therapeutic use

مستخلص: In recent years, newer drugs, such as ibrutinib, have shown promising improvements in the survival of patients with chronic lymphocytic leukemia (CLL). Despite their effectiveness, concerns about their cost have arisen, prompting the need for an evaluation of their cost-effectiveness. However, recent assessments of ibrutinib's cost-effectiveness for treating CLL in India reveal divergent conclusions. The discord centers on divergent cost-effectiveness thresholds, comparator regimens, cost calculations, and outcome valuation approaches. Such discrepancies affect public health decisions and patient care. The recommendation calls for adherence to methodological guidelines by future studies, fostering consistent findings to empower policy makers and clinicians in leveraging economic evidence for informed decision making in CLL treatment strategies.
Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section.
(Copyright © 2024 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)