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Caffeine and arousal: a biobehavioral theory of physiological, behavioral, and emotional effects
Published in B.S. Gupta, Uma Gupta, Caffeine and Behavior, 2020
Barry D. Smith, Kenneth Tola, Mark Mann
Caffeine is a base analog that acts to antagonize adenosine receptors, thereby affecting a variety of cell populations by partially counteracting many of the effects of adenosine. It acts primarily on the A2a adenosine receptors, elevating energy metabolism in the brain29–31 and producing a 30% decrease in whole-brain CBF, with no regional differences.32 Caffeine also modulates neural activity through its inhibitory effect on ionotropic GABA receptors33 and, like other methylxanthines, acts on serotonin and noradrenaline neurons and affects local dopamine release.31 These actions further explain its stimulating effects, which include activation of major components of the hypothalamic-pituitary-adrenal (HPA) axis response. In particular, caffeine increases adrenocorticotropin (ACTH) release at the pituitary, resulting in elevated Cortisol production.34
Complications of Intravesical Therapy
Published in Kevin R. Loughlin, Complications of Urologic Surgery and Practice, 2007
Michael A. O’Donnell, José L. Maymí
Gemcitabine is a pyrimidine antimetabolite, analogous to cytosine arabinoside, with a molecular weight of 300 Da. Its mechanism of action involves incorporation of the pyrimidine base analog into DNA by one of the metabolites [2′, 2′-difluorodeoxycytidine (dFdCTP)], resulting in chain termination (79). In addition, gemcitabine inhibits ribonucleotide reductase, an enzyme necessary for DNA synthesis (80). It was first approved in the United States to treat pancreatic cancer (81) but has since been found to be effective in other tumors such as non-small-cell lung cancer, leiomyosarcoma, and ovarian cancer (82). Phase III clinical trial revealed similar survival rates in patients but reduced toxicity with metastatic urothelial cancer treated with gemcitabine plus cisplatin versus the conventional treatment with methotrexate, vinblastine, doxorubicin, and cisplatin (83).
Clinical development of retroviral replicating vector Toca 511 for gene therapy of cancer
Published in Expert Opinion on Biological Therapy, 2021
Sara A. Collins, Ashish H. Shah, Derek Ostertag, Noriyuki Kasahara, Douglas J. Jolly
RRV can also be used to deliver various other prodrug activator enzymes, most of which were originally developed for use in conventional non-replicating vectors. Since RRV retain their full-length retroviral genome, additional insertion of transgene cassettes up to ~1.3 kb in size can be readily accommodated. However, larger transgenes incur genomic instability and are rapidly deleted upon serial passage of the virus. Within this size limitation, other prodrug activator genes that have shown promising results with RRV delivery in preclinical cancer models include: Herpes simplex virus thymidine kinase (HSV-TK), which converts anti-herpetic prodrugs such as ganciclovir or valacyclovir into nucleotide analog antimetabolites by phosphorylation [50,70]. However, these phosphorylated nucleotide analogs are hydrophilic and do not diffuse freely across cell membranes, and hence require intercellular gap junctions to exert an efficient bystander effect.E. coli purine nucleoside phosphorylase (PNP), which converts ribonucleoside prodrugs such as 6-methylpurine deoxyriboside or fludarabine phosphate to purine base analog antimetabolites such as 6-methylpurine and 2-fluoroadenine, respectively [33,37]; these free base compounds are highly hydrophobic and can readily diffuse across cell membranes. However, intestinal bacteria can also catalyze prodrug conversion and the prodrugs themselves exhibit some toxicity.E. coli nitroreductase (NTR), which converts prodrugs such as the dinitrobenzamide CB1954 ((5-(aziridin-1-yl)-2,4-dinitro-benzamide) into a potent alkylating agent causing DNA adducts and crosslinks [71]. This results in very rapid cell killing, but there is also prodrug conversion by intestinal bacteria.