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[]
["TTD - Therapeutic Targets Database"]
["Version 4.3.02 (2011.08.25)"]
["File Name: Pharmacodynamically synergistic drug combinations due to facilitating actions."]
["Synergy has been determined by well established synergy/additive analysis methods and its molecular mechanism has been revealed."]
[]
["Combination target relationship","Drug A (mechanism of actions related to synergy)","Drug B (mechanism of actions related to synergy )","Reported synergistic effect","Synergism determination method","Possible mechanism of synergism in promoting facilitating actions"]
["Different targets of related pathways","Ampicillin (blocked penicillin-binding protein 2A and thus bacterial cell wall synthesis (1))","Daptomycin (disrupted bacterial membrane structure (2))","Significant antibacterial synergy (3)","Checkerboard method, fractional inhibitory concentration","Most penicilling-binding proteins are associated with membrane (4), membrane disruption by daptomyci (2) likely hinders the functions of penicilling-binding proteins and further expose them to ampicillin binding."]
[null,"Gentamicin (targeted bacterial ribosome, caused misreading of the genetic code and inhibited translocation, thereby disrupted protein synthesis (5))","Vancomycin (inhibited bacterial cell wall peptidoglycan synthesis (6), altered permeability of cell membrane and selectively inhibited ribonucleic acid synthesis (7))","Synergistic action against penicillin- resistant bacteria strains (8)","Checkerboard method, fractional inhibitory concentration indices","Vancomycin altered membrane permeability (7) thereby enhanced gentamicin penetration into bacterial cells and its bioavailability."]
[null,"Daptomycin (disrupted bacterial membrane function without penetrating into the cytoplasm (9), depolarized membrane (10), and inhibited lipoteichoic acid synthesis (11))","Rifampicin (interfered with bacterial nucleic acid synthesis by binding to the beta subunit of prokaryotic RNA polymerases (12))","Significant antibacterial synergy (3)","Checkerboard method, fractional inhibitory concentration","Depolarization of bacterial membrane by daptomycin (10) enhanced rifamapicin penetration into bacterial cells and thus its bioavailability."]
["Different targets of related pathways that regulate the same target","BQ-123 (Endothelin A receptor antagonist, mediated vasodilatation (13))","Enalapril (angiotensin converting enzyme inhibitor, up-regulated Endothelin B (14), vasodilation is mediated by both ACE inhibition (15) and Endothelin B1 upregulation (16))","Synergistic endothelium-dependent vasodilation enhancing actions (17)","Randomized, double-blind, crossover studies","Enalapril up-regulated ETB as well as inhibited ACE leading to vasodilation (14, 16), BQ-123 antagonism of ETA caused vasodilation (13) and displaced endogenous ET-1 from ETA onto upregulated ETB to enhance its activity by effectively increasing ETB agonist concentration (17)."]
[null,"Candesartan-cilexetil (angiotensin AT1 receptor antagonist (18))","Ramipril (angiotensin converting enzyme inhibitor (19), reduced angiotensin II formation (20))","Synergistically reduced systolic blood pressure (21)","Dose-response curve shifted 6.6-fold leftwards compared to hypothetic additive curve","Candesartan-cilexetil reduced systolic blood pressure by antagonizing angiotensin AT1 receptor (18), ramipril reduced systolic blood pressure by inhibiting angiotensin converting enzyme (19), ramipril inhibited AT1 receptor agonist formation (20) thereby facilitating the action of candesartan-cilexetil by reducing AT1 agonist-antagonist competition."]
[null,"Salmeterol (beta 2-adrenoceptor agonist(22) that activated T-cell subtypes (23) and promoted apoptosis via adrenoreceptor- and cAMP-independent, Ca2+-dependent mechanism (24))","Fluticasone (glucocorticoid receptor binder (25) that induced apoptosis (26), up-regulated beta2- adrenoceptor (27))","Synergistic in vitro T-cell activation and apoptosis induction in asthma (28)","Comparison of activity and protein levels","Salmeterol’s agonistic activity on beta 2-adrenoceptor (22) is facilitated by fluticasone’s up-regulation of beta2- adrenoceptor (27), leading to synergistic T-cell activation and apoptosis induction."]
[null,"Erythromycin (binds to bacterial 70S ribosomal complex to inhibit bacterial protein synthesis (29))","Penicillin (binds to DD-transpeptidase that links peptidoglycan, which weakens bacterial cell wall (30))","Combination inhibited 80% of the S. somaliensis strains both synergically and additively (31)","Chequerboard","Weakening of bacterial cell wall by penicillin (29) enhanced erythromycin penetration into bacterial cells, thereby enhancing its bioavailability."]
[null,"Efavirenz (Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (32))","Nelfinavir or NFV (Protease Inhibitors (PIs) (32))","CIs of combinations of NNRTIs and NFV in twocompound combinations against the replication of HIV-1 (RF) at IC50 are reported as 0.98 in the combination ratio of 1:1 (32)","Combination indices","Synergy between inhibitors of the HIV-1 RT and protease may be the result of effects on reduced virus levels in later rounds of infection in in vitro assays caused by agents that act early instead of late in the virus replication cycle. Reverse transcriptase reduces the incorporation of virus DNA into human DNA, thereby reduce the peptide production which is the HIV protease substrate. Simultaneously, reduction of protease substrate may lead to synergy effect (32)."]
[null,"DPC082 (Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (32))","Nelfinavir or NFV (Protease Inhibitors (PIs) (32))","CIs of combinations of NNRTIs and NFV in twocompound combinations against the replication of HIV-1 (RF) at IC50 are reported as 0.73 in the combination ratio of 3:1 (32)","Combination indices","Synergy between inhibitors of the HIV-1 RT and protease may be the result of effects on reduced virus levels in later rounds of infection in in vitro assays caused by agents that act early instead of late in the virus replication cycle. Reverse transcriptase reduces the incorporation of virus DNA into human DNA, thereby reduce the peptide production which is the HIV protease substrate. Simultaneously, reduction of protease substrate may lead to synergy effect (32)."]
[null,"DPC083 (Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (32))","Nelfinavir or NFV (Protease Inhibitors (PIs) (32))","CIs of combinations of NNRTIs and NFV in twocompound combinations against the replication of HIV-1 (RF) at IC50 are reported as 1.19 in the combination ratio of 1:1 (32)","Combination indices","Synergy between inhibitors of the HIV-1 RT and protease may be the result of effects on reduced virus levels in later rounds of infection in in vitro assays caused by agents that act early instead of late in the virus replication cycle. Reverse transcriptase reduces the incorporation of virus DNA into human DNA, thereby reduce the peptide production which is the HIV protease substrate. Simultaneously, reduction of protease substrate may lead to synergy effect (32)."]
[null,"DPC961 (Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (32))","Nelfinavir or NFV (Protease Inhibitors (PIs) (32))","CIs of combinations of NNRTIs and NFV in two compounds combinations against the replication of HIV-1 (RF) at IC50 are reported as 0.28 in the combination ratio of 1:1 (32)","Combination indices","Synergy between inhibitors of the HIV-1 RT and protease may be the result of effects on reduced virus levels in later rounds of infection in in vitro assays caused by agents that act early instead of late in the virus replication cycle. Reverse transcriptase reduces the incorporation of virus DNA into human DNA, thereby reduce the peptide production which is the HIV protease substrate. Simultaneously, reduction of protease substrate may lead to synergy effect (32)."]
[null,"DPC963 (Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (32))","Nelfinavir or NFV (Protease Inhibitors (PIs) (32))","CIs of combinations of NNRTIs and NFV in twocompound combinations against the replication of HIV-1 (RF) at IC50 are reported as 0.99 in the combination ratio of 3:1 (32)","Combination indices","Synergy between inhibitors of the HIV-1 RT and protease may be the result of effects on reduced virus levels in later rounds of infection in in vitro assays caused by agents that act early instead of late in the virus replication cycle. Reverse transcriptase reduces the incorporation of virus DNA into human DNA, thereby reduce the peptide production which is the HIV protease substrate. Simultaneously, reduction of protease substrate may lead to synergy effect (32)."]
["Same target","Saquinavir (HIV protease inhibitor (33), Pgp substrate (34))","Lopinavir (HIV protease inhibitor (35), inhibited Pgp in CACO-2 cells (34))","Synergistic inhibition of HIV1 replication in MT4 cells (34)","Combination indices","As a Pgp substrate, HIV protease inhibitor saquinavir may be removed by Pgp mediated drug efflux, making it less available for HIV protease inhibition (34). Inhibition of Pgp by another HIV protease inhibitor lopinavir facilitates the therapeutic action of saquinavir by blocking its efflux (34), leading to synergistic action."]
[null,"Methotrexate (dihydrofolate reductase inhibitor (36))","Fluorouracil (anticancer, metabolite inhibited thymidylate synthase that stopped DNA synthesis (37), stabilized and activated P53 by blocking MDM2 feedback inhibition through ribosomal proteins (38))","Synergism in inhibiting viability of L1210 murine tumor cells (39)","Comparison of activity","Apart from methotrexate’s anticancer dihydrofolate reductase inhibitory activity (36), methotrexate metabolite formed reversible ternary complexes with fluorouracil on one site of thymidylate synthase to enhance its binding to the enzyme (40), thereby facilitating fluorouracil’s anticancer thymidylate synthase inhibitory activity."]
[null,"Efavirenz (Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (32))","3TC or 3TC-TP (nucleoside RT inhibitors (NRTIs) (32))","Combination indices (CIs) against HIV replication at IC50 are reported as 0.59 at the combination ratio of 3:1. Combination indices (CIs) against RT activity at IC50 are reported as 0.63 at the combination ratio of 3:1 (32)","Combination indices","The interaction of the NNRTI with the RT at the NNRTI binding site, which has been shown to cause conformational distortion of the catalytic aspartate triad, may allow improved incorporation of the NRTI into the growing DNA molecule, leading to more efficient chain termination or decreased rates of phosphorolytic removal of the terminator (32)."]
[null,"DPC083 (Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (32))","3TC or 3TC-TP (nucleoside RT inhibitors (NRTIs) (32))","Combination indices (CIs) against HIV replication at IC50 are reported as 0.46 at the combination ratio of 3:1. Combination indices (CIs) against RT activity at IC50 are reported as 0.43 at the combination ratio of 1:1 (32)","Combination indices","The interaction of the NNRTI with the RT at the NNRTI binding site, which has been shown to cause conformational distortion of the catalytic aspartate triad, may allow improved incorporation of the NRTI into the growing DNA molecule, leading to more efficient chain termination or decreased rates of phosphorolytic removal of the terminator (32)."]
[null,"DPC961 (Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (32))","3TC or 3TC-TP (nucleoside RT inhibitors (NRTIs) (32))","Combination indices (CIs) against RT activity at IC50 are reported as 0.41 at the combination ratio of 1:1 (32)","Combination indices","The interaction of the NNRTI with the RT at the NNRTI binding site, which has been shown to cause conformational distortion of the catalytic aspartate triad, may allow improved incorporation of the NRTI into the growing DNA molecule, leading to more efficient chain termination or decreased rates of phosphorolytic removal of the terminator (32)."]
[null,"DPC963 (Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (32))","3TC or 3TC-TP (nucleoside RT inhibitors (NRTIs) (32)","Combination indices (CIs) against RT activity at IC50 are reported as 0.51 at the combination ratio of 1:1 (32)","Combination indices","The interaction of the NNRTI with the RT at the NNRTI binding site, which has been shown to cause conformational distortion of the catalytic aspartate triad, may allow improved incorporation of the NRTI into the growing DNA molecule, leading to more efficient chain termination or decreased rates of phosphorolytic removal of the terminator (32)."]
[null,"Efavirenz (Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (32))","AZT or AZT-TP (nucleoside RT inhibitors (NRTIs) (32))","Combination indices (CIs) against HIV replication at IC50 are reported as 0.71 at the combination ratio of 3:1. Combination indices (CIs) against RT activity at IC50 are reported as 0.71 at the combination ratio of 1:1 (32)","Combination indices","The interaction of the NNRTI with the RT at the NNRTI binding site, which has been shown to cause conformational distortion of the catalytic aspartate triad, may allow improved incorporation of the NRTI into the growing DNA molecule, leading to more efficient chain termination or decreased rates of phosphorolytic removal of the terminator (32)."]
[null,"DPC083 (Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (32))","AZT or AZT-TP (nucleoside RT inhibitors (NRTIs) (32)","Combination indices (CIs) against HIV replication at IC50 are reported as 0.81 at the combination ratio of 1:1. Combination indices (CIs) against RT activity at IC50 are reported as 0.55 at the combination ratio of 1:3 (32)","Combination indices","The interaction of the NNRTI with the RT at the NNRTI binding site, which has been shown to cause conformational distortion of the catalytic aspartate triad, may allow improved incorporation of the NRTI into the growing DNA molecule, leading to more efficient chain termination or decreased rates of phosphorolytic removal of the terminator (32)."]
[null,"DPC961 (Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (32))","AZT or AZT-TP (nucleoside RT inhibitors (NRTIs) (32))","Combination indices (CIs) against HIV replication at IC50 are reported as 0.74 at the combination ratio of 1:1. Combination indices (CIs) against RT activity at IC50 are reported as 0.63 at the combination ratio of 1:1 (32)","Combination indices","The interaction of the NNRTI with the RT at the NNRTI binding site, which has been shown to cause conformational distortion of the catalytic aspartate triad, may allow improved incorporation of the NRTI into the growing DNA molecule, leading to more efficient chain termination or decreased rates of phosphorolytic removal of the terminator (32)."]
[null,"DPC963 (Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (32))","AZT or AZT-TP (nucleoside RT inhibitors (NRTIs) (32))","Combination indices (CIs) against HIV replication at IC50 are reported as 0.78 at the combination ratio of 3:1. Combination indices (CIs) against RT activity at IC50 are reported as 0.57 at the combination ratio of 3:1 (32)","Combination indices","The interaction of the NNRTI with the RT at the NNRTI binding site, which has been shown to cause conformational distortion of the catalytic aspartate triad, may allow improved incorporation of the NRTI into the growing DNA molecule, leading to more efficient chain termination or decreased rates of phosphorolytic removal of the terminator (32)."]
[]
["References:"]
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[8,"Cottagnoud P, Cottagnoud M, & Tauber MG (2003) Vancomycin acts synergistically with gentamicin against penicillin-resistant pneumococci by increasing the intracellular penetration of gentamicin. Antimicrobial Agents and Chemotherapy 47(1):144-147."]
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[10,"Silverman JA, Perlmutter NG, & Shapiro HM (2003) Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus. Antimicrob Agents Chemother 47(8):2538-2544."]
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[12,"Wegrzyn A, Szalewska-Palasz A, Blaszczak A, Liberek K, & Wegrzyn G (1998) Differential inhibition of transcription from sigma70- and sigma32-dependent promoters by rifampicin. FEBS Lett 440(1-2):172-174."]
[13,"Verhaar MC, et al. (1998) Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation 97(8):752-756."]
[14,"Moridaira K, et al. (2003) ACE inhibition increases expression of the ETB receptor in kidneys of mice with unilateral obstruction. Am J Physiol Renal Physiol 284(1):F209-217."]
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[17,"Goddard J, et al. (2004) Endothelin A receptor antagonism and angiotensin-converting enzyme inhibition are synergistic via an endothelin B receptor-mediated and nitric oxide-dependent mechanism. Journal of the American Society of Nephrology 15(10):2601-2610."]
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[21,"Raasch W, Johren O, Schwartz S, Gieselberg A, & Dominiak P (2004) Combined blockade of AT1-receptors and ACE synergistically potentiates antihypertensive effects in SHR. J Hypertens 22(3):611-618."]
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[23,"Loza MJ, Foster S, Peters SP, & Penn RB (2006) Beta-agonists modulate T-cell functions via direct actions on type 1 and type 2 cells. (Translated from eng) Blood 107(5):2052-2060 (in eng)."]
[24,"Mamani-Matsuda M, et al. (2004) Long-acting beta2-adrenergic formoterol and salmeterol induce the apoptosis of B-chronic lymphocytic leukaemia cells. (Translated from eng) Br J Haematol 124(2):141-150 (in eng)."]
[25,"Meltzer EO (1997) The pharmacological basis for the treatment of perennial allergic rhinitis and non-allergic rhinitis with topical corticosteroids. (Translated from eng) Allergy 52(36 Suppl):33-40 (in eng)."]
[26,"Zhang X, Moilanen E, & Kankaanranta H (2000) Enhancement of human eosinophil apoptosis by fluticasone propionate, budesonide, and beclomethasone. (Translated from eng) Eur J Pharmacol 406(3):325-332 (in eng)."]
[27,"Barnes PJ (2002) Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids. (Translated from eng) Eur Respir J 19(1):182-191 (in eng)."]
[28,"Pace E, et al. (2004) Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma. (Translated from eng) J Allergy Clin Immunol 114(5):1216-1223 (in eng)."]
[29,"Dinos GP, Connell SR, Nierhaus KH, & Kalpaxis DL (2003) Erythromycin, roxithromycin, and clarithromycin: use of slow-binding kinetics to compare their in vitro interaction with a bacterial ribosomal complex active in peptide bond formation. (Translated from eng) Mol Pharmacol 63(3):617-623 (in eng)."]
[30,"Rojo F, Ayala JA, De Pedro MA, & Vazquez D (1984) Analysis of the different molecular forms of penicillin-binding protein 1B in Escherichia coli ponB mutants lysogenized with specialized transducing lambda (ponB+) bacteriophages. (Translated from eng) Eur J Biochem 144(3):571-576 (in eng)."]
[31,"Nasher MA & Hay RJ (1998) Synergy of antibiotics against Streptomyces somaliensis isolates in vitro. (Translated from eng) J Antimicrob Chemother 41(2):281-284 (in eng)."]
[32,"King RW, Klabe RM, Reid CD, & Erickson-Viitanen SK (2002) Potency of nonnucleoside reverse transcriptase inhibitors (NNRTIs) used in combination with other human immunodeficiency virus NNRTIs, NRTIs, or protease inhibitors. (Translated from eng) Antimicrob Agents Chemother 46(6):1640-1646 (in eng)."]
[33,"Patick AK, Boritzki TJ, & Bloom LA (1997) Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro. (Translated from eng) Antimicrob Agents Chemother 41(10):2159-2164 (in eng)."]
[34,"Molla A, et al. (2002) In vitro antiviral interaction of lopinavir with other protease inhibitors. (Translated from eng) Antimicrob Agents Chemother 46(7):2249-2253 (in eng)."]
[35,"Sham HL, et al. (1998) ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. (Translated from eng) Antimicrob Agents Chemother 42(12):3218-3224 (in eng)."]
[36,"Haller DG (1997) Trimetrexate: experience with solid tumors. (Translated from eng) Semin Oncol 24(5 Suppl 18):S18-71-S18-76 (in eng)."]
[37,"Pinedo HM & Peters GF (1988) Fluorouracil: biochemistry and pharmacology. (Translated from eng) J Clin Oncol 6(10):1653-1664 (in eng)."]
[38,"Sun XX, Dai MS, & Lu H (2007) 5-fluorouracil activation of p53 involves an MDM2-ribosomal protein interaction. J Biol Chem 282(11):8052-8059."]
[39,"Vendsborg PB & Bach-Mortensen N (1977) Fat cell size and blood lactate in humans. (Translated from eng) Scand J Clin Lab Invest 37(4):317-320 (in eng)."]
[40,"Fernandes DJ & Bertino JR (1980) 5-fluorouracil-methotrexate synergy: enhancement of 5-fluorodeoxyridylate binding to thymidylate synthase by dihydropteroylpolyglutamates. (Translated from eng) Proc Natl Acad Sci U S A 77(10):5663-5667 (in eng)."]

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