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Light-activatable cannabinoid prodrug for combined and target-specific photodynamic and cannabinoid therapy.
Ling X, Zhang S, Liu Y, Bai M
(2018) J Biomed Opt 23: 1-9
MeSH Terms: Animals, Antineoplastic Agents, Cannabinoids, Cell Line, Tumor, Cell Survival, HEK293 Cells, Humans, Indoles, Mice, Organosilicon Compounds, Photochemotherapy, Photosensitizing Agents, Prodrugs, Reactive Oxygen Species
Show Abstract · Added April 2, 2019
Cannabinoids are emerging as promising antitumor drugs. However, complete tumor eradication solely by cannabinoid therapy remains challenging. In this study, we developed a far-red light activatable cannabinoid prodrug, which allows for tumor-specific and combinatory cannabinoid and photodynamic therapy. This prodrug consists of a phthalocyanine photosensitizer (PS), reactive oxygen species (ROS)-sensitive linker, and cannabinoid. It targets the type-2 cannabinoid receptor (CB2R) overexpressed in various types of cancers. Upon the 690-nm light irradiation, the PS produces cytotoxic ROS, which simultaneously cleaves the ROS-sensitive linker and subsequently releases the cannabinoid drug. We found that this unique multifunctional prodrug design offered dramatically improved therapeutic efficacy, and therefore provided a new strategy for targeted, controlled, and effective antitumor cannabinoid therapy.
(2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).
0 Communities
1 Members
0 Resources
14 MeSH Terms
Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase.
Hunter RW, Hughey CC, Lantier L, Sundelin EI, Peggie M, Zeqiraj E, Sicheri F, Jessen N, Wasserman DH, Sakamoto K
(2018) Nat Med 24: 1395-1406
MeSH Terms: Adenosine Monophosphate, Aminoimidazole Carboxamide, Animals, Base Sequence, Chickens, Disease Models, Animal, Fructose-Bisphosphatase, Glucose, Glucose Intolerance, Homeostasis, Humans, Hypoglycemia, Liver, Metformin, Mice, Inbred C57BL, Mutation, Obesity, Prodrugs, Ribonucleotides
Show Abstract · Added March 26, 2019
Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5'-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet-fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects.
1 Communities
1 Members
0 Resources
19 MeSH Terms
Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.
Hubers SA, Brown NJ
(2016) Circulation 133: 1115-24
MeSH Terms: Abnormalities, Drug-Induced, Aminobutyrates, Angioedema, Angiotensin Receptor Antagonists, Biphenyl Compounds, Bradykinin, Contraindications, Drug Combinations, Drug Costs, Drug Synergism, Enalapril, Enzyme Inhibitors, Female, Follow-Up Studies, Heart Failure, Humans, Hyperkalemia, Hypertension, Kidney, Multicenter Studies as Topic, Natriuretic Peptides, Neprilysin, Pregnancy, Prodrugs, Prospective Studies, Pyridines, Randomized Controlled Trials as Topic, Stroke Volume, Tetrazoles, Thiazepines, Valsartan
Show Abstract · Added April 6, 2017
Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.
© 2016 American Heart Association, Inc.
0 Communities
1 Members
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31 MeSH Terms
Synthesis and in vitro efficacy of MMP9-activated NanoDendrons.
Samuelson LE, Scherer RL, Matrisian LM, McIntyre JO, Bornhop DJ
(2013) Mol Pharm 10: 3164-74
MeSH Terms: Animals, Cell Line, Tumor, Dipeptides, Doxorubicin, Drug Delivery Systems, Humans, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Paclitaxel, Prodrugs, Rats
Show Abstract · Added March 7, 2014
Chemotherapeutics such as doxorubicin (DOX) and paclitaxel (PXL) have dose-limiting systemic toxicities, including cardiotoxicity and peripheral neuropathy. Delivery strategies to minimize these undesirable effects are needed and could improve efficacy, while reducing patient morbidity. Here, DOX and PXL were conjugated to a nanodendron (ND) through an MMP9-cleavable peptide linker, producing two new therapies, ND2(DOX) and ND2(PXL), designed to improve delivery specificity to the tumor microenvironment and reduce systemic toxicity. Comparative cytotoxicity assays were performed between intact ND-drug conjugates and the MMP9 released drug in cell lines with and without MMP9 expression. While ND2(DOX) was found to lose cytotoxicity due to the modification of DOX for conjugation to the ND; ND2(PXL) was determined to have the desired properties for a prodrug delivery system. ND2(PXL) was found to be cytotoxic in MMP9-expressing mouse mammary carcinoma (R221A-luc) (53%) and human breast carcinoma (MDA-MB-231) (66%) at a concentration of 50 nM (in PXL) after 48 h. Treating ND2(PXL) with MMP9 prior to the cytotoxicity assay resulted in a faster response; however, both cleaved and intact versions of the drug reached the same efficacy as the unmodified drug by 96 h in the R221A-luc and MDA-MB-231 cell lines. Further studies in modified Lewis lung carcinoma cells that either do (LLC(MMP9)) or do not (LLC(RSV)) express MMP9 demonstrate the selectivity of ND2(PXL) for MMP9. LLC(MMP9) cells were only 20% viable after 48 h of treatment, while LLC(RSV) were not affected. Inclusion of an MMP inhibitor, GM6001, when treating the LLC(MMP9) cells with ND2(PXL) eliminated the response of the MMP9 expressing cells (LLC(MMP9)). The data presented here suggests that these NDs, specifically ND2(PXL), are nontoxic until activated by MMP9, a protease common in the microenvironment of tumors, indicating that incorporation of chemotherapeutic or cytostatic agents onto the ND platform have potential for tumor-targeted efficacy with reduced in vivo systemic toxicities.
1 Communities
2 Members
0 Resources
11 MeSH Terms
Pharmacokinetics of acyclovir and its metabolites in cerebrospinal fluid and systemic circulation after administration of high-dose valacyclovir in subjects with normal and impaired renal function.
Smith JP, Weller S, Johnson B, Nicotera J, Luther JM, Haas DW
(2010) Antimicrob Agents Chemother 54: 1146-51
MeSH Terms: Acyclovir, Adult, Aged, Antiviral Agents, Chronic Disease, Female, Guanine, Humans, Kidney, Kidney Diseases, Kidney Function Tests, Male, Medical Futility, Middle Aged, Prodrugs, Valacyclovir, Valine, Young Adult
Show Abstract · Added August 21, 2013
Valacyclovir, the L-valyl ester prodrug of acyclovir (ACV), is widely prescribed to treat infections caused by varicella-zoster virus or herpes simplex virus. Rarely, treatment is complicated by reversible neuropsychiatric symptoms. By mechanisms not fully understood, this occurs more frequently in the setting of renal impairment. We characterized the steady-state pharmacokinetics of ACV and its metabolites 9-[(carboxymethoxy)methyl]guanine (CMMG) and 8-hydroxy-acyclovir (8-OH-ACV) in cerebrospinal fluid (CSF) and the systemic circulation. We administered multiple doses of high-dose valacyclovir to 6 subjects with normal renal function and 3 subjects with chronic renal impairment (creatinine clearance [CrCl], approximately 15 to 30 ml/min). Dosages were 2,000 mg every 6 h and 1,500 mg every 12 h, respectively. Indwelling intrathecal catheters allowed serial CSF sampling throughout the dosing interval. The average steady-state concentrations of acyclovir, CMMG, and 8-OH-ACV were greater in both the systemic circulation and the CSF among subjects with impaired renal function than among subjects with normal renal function. However, the CSF penetration of each analyte, reflected by the CSF-to-plasma area under the concentration-time curve over the 6- or 12-h dosing interval (AUC(tau)) ratio, did not differ based on renal function. Renal impairment does not alter the propensity for ACV or its metabolites to distribute to the CSF, but the higher concentrations in the systemic circulation, as a result of reduced elimination, are associated with proportionally higher concentrations in CSF.
0 Communities
2 Members
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18 MeSH Terms
Preclinical efficacy of a carboxylesterase 2-activated prodrug of doxazolidine.
Barthel BL, Zhang Z, Rudnicki DL, Coldren CD, Polinkovsky M, Sun H, Koch GG, Chan DC, Koch TH
(2009) J Med Chem 52: 7678-88
MeSH Terms: Animals, Antineoplastic Agents, Blotting, Western, Carbamates, Carboxylesterase, Cell Line, Tumor, Cell Proliferation, Doxorubicin, Drug Evaluation, Preclinical, Female, Gene Expression Regulation, Enzymologic, Humans, Mice, Myocytes, Cardiac, Neoplasms, Oxazoles, Prodrugs, Rats, Regression Analysis
Show Abstract · Added November 17, 2011
Doxazolidine (Doxaz) is a functionally distinct formaldehyde conjugate of doxorubicin (Dox) that induces cancer cell death in Dox-sensitive and resistant cells. Pentyl PABC-Doxaz (PPD) is a prodrug of Doxaz that is activated by carboxylesterase 2 (CES2), which is expressed by liver, non-small-cell lung, colon, pancreatic, renal, and thyroid cancer cells. Here, we demonstrate that in two murine models, PPD was effective at slowing tumor growth and demonstrated markedly reduced cardiotoxic and nephrotoxic effects, as well as better tolerance, relative to Dox. Hepatotoxicity, consistent with liver expression of the murine CES2 homologue, was induced by PPD. Unlike irinotecan, a clinical CES2-activated prodrug, PPD produced no visible gastrointestinal damage. Finally, we demonstrate that cellular response to PPD may be predicted with good accuracy using CES2 expression and Doxaz sensitivity, suggesting that these metrics may be useful as clinical biomarkers for sensitivity of a specific tumor to PPD treatment.
0 Communities
1 Members
0 Resources
19 MeSH Terms
Endogenous NO regulates plasminogen activator inhibitor-1 during angiotensin-converting enzyme inhibition.
Brown NJ, Muldowney JA, Vaughan DE
(2006) Hypertension 47: 441-8
MeSH Terms: Adult, Aldosterone, Angiotensin-Converting Enzyme Inhibitors, Arginine, Double-Blind Method, Drug Combinations, Enzyme Inhibitors, Female, Fibrinolysis, Hemodynamics, Humans, Infusions, Intravenous, Male, Middle Aged, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Synthase, Plasminogen Activator Inhibitor 1, Prodrugs, Ramipril, Reference Values, Renin-Angiotensin System
Show Abstract · Added December 10, 2013
To test the hypothesis that NO contributes to effects of angiotensin-converting enzyme inhibitors on fibrinolysis, fibrinolytic balance was assessed in 17 normal subjects during placebo and after randomized, double-blind 4-week treatment with the NO precursor L-arginine (3 g TID), ramipril (10 mg QD), or L-arginine+ramipril. Neither L-arginine nor ramipril alone affected basal plasminogen activator inhibitor-1 or tissue-type plasminogen activator (t-PA) antigen in these salt-replete subjects in whom plasma renin activity was suppressed (mean+/-SD 0.7+/-0.5 ng angiotensin I/mL per hour). In contrast, L-arginine+ramipril reduced morning plasminogen activator inhibitor-1 antigen (10.8+/-9.5 ng/mL) and the molar ratio of plasminogen activator inhibitor-1:t-PA (2.3+/-1.6) compared with placebo (13.5+/-10.8 ng/mL, P=0.006; ratio 2.9+/-2.1, P=0.015) or ramipril alone (15.2+/-13.2 ng/mL, P=0.009; ratio 3.7+/-3.3, P=0.005). L-arginine and ramipril synergistically increased d-dimers (23.1+/-31.5, 29.7+/-50.0, 35.1+/-50.0, and 57.1+/-144.8 ng/mL during placebo, L-arginine, ramipril, and L-arginine+ramipril, respectively; P<0.05 for L-arginine+ramipril versus any other group). During ramipril, the NO synthase inhibitor L-NG-nitro-arginine-methyl-ester (2 mg/kg) significantly increased plasminogen activator inhibitor-antigen after 2 hours (from 9.4+/-8.6 ng/mL during vehicle to 13.5+/-11.0 ng/mL during L-NG-nitro-arginine-methyl-ester; P=0.020), consistent with an effect on expression but rapidly increased t-PA activity (from 0.4+/-0.3 to 0.5+/-0.4 IU/mL; P=0.031), consistent with an effect on release. Both effects of L-NG-nitro-arginine-methyl-ester were reversed by L-arginine. During angiotensin-converting enzyme inhibition, endogenous NO decreases plasminogen activator inhibitor-1 antigen and improves fibrinolytic balance in normotensive salt-replete subjects.
0 Communities
1 Members
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22 MeSH Terms
Embryonic endothelial progenitor cells armed with a suicide gene target hypoxic lung metastases after intravenous delivery.
Wei J, Blum S, Unger M, Jarmy G, Lamparter M, Geishauser A, Vlastos GA, Chan G, Fischer KD, Rattat D, Debatin KM, Hatzopoulos AK, Beltinger C
(2004) Cancer Cell 5: 477-88
MeSH Terms: Animals, Bone Neoplasms, Bystander Effect, Carcinoma, Lewis Lung, Cell Hypoxia, Cytosine Deaminase, Embryonic and Fetal Development, Endothelium, Vascular, Fluorouracil, Gene Targeting, Genes, Transgenic, Suicide, Genetic Therapy, Genetic Vectors, Injections, Intravenous, Killer Cells, Natural, Lung Neoplasms, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Neovascularization, Pathologic, Osteosarcoma, Pentosyltransferases, Prodrugs, Recombinant Fusion Proteins, Stem Cells, Survival Rate, Uracil, Vascular Endothelial Growth Factor A
Show Abstract · Added November 18, 2010
We show that mouse embryonic endothelial progenitor cells (eEPCs) home preferentially to hypoxic lung metastases when administered intravenously. This specificity is inversely related to the degree of perfusion and vascular density in the metastasis and directly related to local levels of hypoxia and VEGF. Ex vivo expanded eEPCs that were genetically modified with a suicide gene specifically and efficiently eradicated lung metastases with scant patent blood vessels. eEPCs do not express MHC I proteins, are resistant to natural killer cell-mediated cytolysis, and can contribute to tumor vessel formation also in nonsyngeneic mice. These results indicate that eEPCs can be used in an allogeneic setting to treat hypoxic metastases that are known to be resistant to conventional therapeutic regimes.
1 Communities
1 Members
0 Resources
29 MeSH Terms
Hydrolysis of bimatoprost (Lumigan) to its free acid by ocular tissue in vitro.
Davies SS, Ju WK, Neufeld AH, Abran D, Chemtob S, Roberts LJ
(2003) J Ocul Pharmacol Ther 19: 45-54
MeSH Terms: Amides, Animals, Bimatoprost, Ciliary Body, Cloprostenol, Cornea, Dinoprost, Eye, Humans, Hydrolysis, In Vitro Techniques, Iris, Kinetics, Lipid Metabolism, Lipids, Prodrugs, Sclera, Swine, Time Factors
Show Abstract · Added December 10, 2013
We determined whether bimatoprost, which has been reported to act via putative prostamide receptors, could be hydrolyzed to its free acid (17-phenyl-PGF(2 alpha)), a potent FP receptor agonist, by human ocular tissue in vitro. We developed a gas chromatography/mass spectrometric method to measure 17-phenyl-PGF(2 alpha) levels at sub-picomolar levels. We then analyzed the amount of 17-phenyl-PGF(2 alpha) present after incubation of 50 microl Lumigan (0.03% bimatoprost) with eye tissue using this assay. We found that cornea, sclera, iris, and ciliary body, all rapidly hydrolyzed bimatoprost to 17-phenyl-PGF(2 alpha) with linear kinetics at a rate of 6.3, 2.0, 2.8, and 1.5 pmol mg tissue(-1) hr(-1), respectively. For cornea, sclera, and ciliary body, this linear rate of hydrolysis continued over a period of at least three hours, while iris-induced hydrolysis did not continue beyond one hour. Our findings suggest that bimatoprost can act as prodrug for FP receptor activation and questions the concept of a "prostamide receptor" agonist.
1 Communities
2 Members
0 Resources
19 MeSH Terms
Cytochrome P450 enzymes in the generation of commercial products.
Guengerich FP
(2002) Nat Rev Drug Discov 1: 359-66
MeSH Terms: Animals, Biodegradation, Environmental, Biosensing Techniques, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Drug Industry, Humans, Prodrugs
Show Abstract · Added March 5, 2014
Cytochrome P450 enzymes are remarkably diverse oxygenation catalysts that are found throughout nature. Although most of the interest in the pharmaceutical industry has focused on the role of cytochrome P450s in drug development, these enzymes also offer potential in the discovery not only of drugs, but also of other useful chemicals. Potential applications range from the use of cytochrome P450s as drug targets, to the use of randomly generated mutants of cytochrome P450s to produce libraries of new chemicals and drugs.
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8 MeSH Terms