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[]
["TTD - Therapeutic Targets Database"]
["Version 4.3.02 (2011.08.25)"]
["File Name: Pharmacodynamically additive drug combinations."]
["Additive action has been determined by well established synergy/additive analysis methods and its molecular mechanism has been revealed."]
[]
["Action type","Combination target relationship","Drug A (mechanism of action related to additive effect)","Drug B (mechanism of action related to additive effect )","Reported additive effect","Additism determination method","Possible mechanism of additive effect"]
["Equivalent or overlapping actions","Different targets of the same pathways that regulate the same target","Citicoline (increased BCL-2 expression (1), regulated Bcl-2 antiapoptotic pathway for neuron cell survival (2). Bcl-2 interacted with IP(3) receptor Ca(2+) channels on ER, regulating their opening in response to IP(3) and thus inhibiting IP(3)-mediated Ca(2+) signals that induce apoptosis (3))","Nimodipine (L-type voltage sensitive calcium channel blocker (1), reduced Ca(2+) influx to rescue cortical neurons from apoptosis (4))","Additive neuroprotective effect (1)","Measurement of infarct volume","Citicoline upregulated Bcl-2 (1), thereby enhanced inhibition of IP(3)-mediated Ca(2+) signals which reduced apoptosis (3).Nimodipine reduced Ca(2+) influx to rescue cortical neurons from apoptosis (4). "]
[null,null,"CP55940 (cannabinoid antagonist (5), coupling to postsynaptic GIRK2 potassium channels (6))","Dexmedetomidine (alpha2 adrenoceptor agonist (7), coupling to postsynaptic GIRK2 potassium channels (8))","Additive antinociceptive actions in some cases and synergistic actions in other cases (5)","Isobolographic analysis","Both produced therapeutic actions via coupling to postsynaptic GIRK2 potassium channels (6, 8)."]
[null,null,"CP55940 (cannabinoid antagonist (5), coupling to postsynaptic GIRK2 potassium channels (6))","Morphine (mu opioid receptor agonist (9), coupling to postsynaptic GIRK2 potassium channels (10))","Additive antinociceptive actions in some cases and synergistic actions in other cases (5)","Isobolographic analysis","Both via their coupling to postsynaptic GIRK2 potassium channel (6, 10)."]
[null,null,"Diazoxide (ATP-sensitive K+ channel activator (11), enhanced ATPase activity of channel regulatory subunits sulphonylurea receptors (12))","Sodium nitroprusside (activated ATP-sensitive K+ channel (11), acted as the donor of nitric oxide which subsequently opened channel (13))","Additive antinociceptive effect (14)","ANOVA synergism & dose effect data analysis","Diazoxide enhanced ATPase activity of channel regulatory subunits (12), Sodium nitroprusside opened the channel by acting as the donor of nitric oxide (13)."]
[null,null,"Diazoxide (ATP-sensitive K+ channel opener (11), enhanced ATPase activity of channel regulatory subunits sulphonylurea receptors (12))","Dibutyryl-cGMP (activated ATP-sensitive K+ channel (11), activated channel via a cGMP-dependent protein kinase (15),(16)) ","Additive antinociceptive effect (14)","ANOVA synergism & dose effect data analysis","Diazoxide enhanced ATPase activity of channel regulatory subunits (12), Dibutyryl-cGMP activated channel via a cGMP-dependent protein kinase (15, 16)."]
[null,null,"Methylene blue (inhibited heme polymerization (17-20); selectively inhibited glutathione reductase)","Mefloquine and quinine (heme polymerase inhibitor (21))","Additive antimalarial effect in chloroquine-sensitive and -resistant P. falciparum strains (22)","Isobolographic analysis","Both acted redundantly at the heme polymerization pathway."]
[null,null,"Retinoic acid (activated and up-regulated retinoic acid receptor beta, a tumor suppressor that promote apoptosis (23))","Trichostatin A (histone deacetylase inhibitor, reactivated retinoic acid receptor beta mRNA expression (24))","Additive inhibition of cell proliferation (25) ","ANOVA synergism & dose effect data analysis","Retinoic acid activated and up-regulated the target (23), Trichostatin A up-regulated the target (24)."]
[null,"Different targets of related pathways","Niacin (niacin receptor HM74A agonist that inhibited hepatocyte diacylglycerol acyltransferase and triglyceride synthesis leading to increased intracellular apo B degradation and subsequent decreased secretion of VLDL and LDL cholesterol (26))","Simvastatin (HMG-CoA reductase inhibitor that reduced synthesis of LDL cholesterol and triglycerides and increased HDL-cholesterol (27))","Combination reduced LDL and VLDL, and increased HDL cholesterol (28)","Comparison of activity and protein levels","Niacin reduced secretion of VLDL and LDL cholesterol (26), simvastatin reduced synthesis of LDL cholesterol and triglycerides (27), both drugs equivalently reduced the level of LDL cholesterol."]
[null,"Same target (different sites with direct contact with agonist site)","Propofol (interacted with GABA A receptor, acting on at TM3 segment of the beta2 subunit (29))","Sevoflurane (interacted with GABA A receptor at Ser270 of the alpha1 and alpha2 subunits (30))","Additive action in producing consciousness and movement to skin incision during general anesthesia (31)","Dixon up-down method","Propofol binds to TM3 segment of the beta2 subunit (29), Sevoflurane binds to Ser270 of the alpha1 subunit (30). As agonist binding site is located between alpha1 and beta2 subunits (32), both drugs likely hinder agonist activity, thereby producing mutually substitutable actions."]
[null,"Same target (same site)","Ampicillin (blocked penicillin-binding protein 2A and thus bacterial cell wall synthesis) (33)","Imipenem (inhibited penicillin-binding protein -1A, -1B, -2, -4 and -5 and thus bacterial cell wall synthesis) (34)","Additive antibacterial effect (35)","Checkerboard method, fractional inhibitory concentration","Both acted at the same active site of penicillin-binding protein 2A (36) but at relatively high MICs of ≥32 microg/ml (33). The relatively high MICs make it less likely for both drugs to saturate target sites, thereby maintaining additive antibacterial effect."]
["Independent actions","Different targets of unrelated pathways","Anidulafungin (inhibitor of beta-(1,3)-dglucan synthase, an essential component of fungal cell wall) (37)","Amphotericin B (formed ion channels in fungal membranes) (38)","Additive antifungal effect (39)","Checkerboard method, fractional inhibitory concentration","Anidulafungin disrupted cell wall formation during reproductive cycle (37), Amphotericin B disrupted membranes of mature fungi (38). They act at different stages and different sites in non-interfering manner."]
[null,null,"Artemisinin (interfered with parasite transport proteins PfATP6, disrupted parasite mitochondrial function, modulated host immune function) (40)","Curcumin (generated ROS and down-regulated PfGCN5 histone acetyltransferase activity, producing cytotoxicity for malaria parasites) (41)","Additive antimalarial activities (42)","Fractional inhibitory concentrations","Artemisinin blocked calcium transport to endoplasmic reticulum (40), Curcumin induced DNA damage and histone hypoacetylation (41). They act at different sites in non-interfering manner."]
[null,"Same target (different sites)","Doxorubicin (DNA intercalator (43), preferred AT regions (43))","Trabectedin (formed covalent guanine adduct at specific sites in DNA minor grove (44), interacted with DNA repair system)","Additive anticancer effect (45)","Isobolographic analysis","Both bind to DNA in non-interfering manner, one preferred AT regions (43), the other alkylated guanines (44). Recent progresses in designing dual platinum- intercalator conjugates (46) suggested that it is possible for both drugs to act without hindering each other’s binding mode."]
["Independent actions at dosages significantly lower than MICs, complementary actions at higher dosages","Different targets of unrelated pathways","Azithromycin (hindered bacterial protein synthesis by binding to 50S component of 70S ribosomal subunit (47))","Imipenem (inhibited penicillin-binding protein -1A, -1B, -2, -4 and -5 and thus bacterial cell wall synthesis) (34)","Additive antibacterial effect (48)","Checkerboard method, fractional inhibitory concentration","Azithromycin hindered bacterial protein synthesis (47) at MIC of 0.12 microg/ml (49). Imipenem blocked bacterial cell wall formation (34) at MICs of ≥32 microg/ml (33). At dosages significantly lower than MICs for both drugs, azithromycin’s reduction of penicillin-binding proteins (34) may be insufficient for imipenem to saturate these proteins, allowing its unhindered inhibition of these proteins (34), thereby these actions proceed in non-interfering manner."]
[]
["References:"]
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[2,"Hansen MR, Roehm PC, Xu N, & Green SH (2007) Overexpression of Bcl-2 or Bcl-xL prevents spiral ganglion neuron death and inhibits neurite growth. Dev Neurobiol 67(3):316-325."]
[3,"Rong Y & Distelhorst CW (2007) Bcl-2 Protein Family Members: Versatile Regulators of Calcium Signaling in Cell Survival and Apoptosis. Annu Rev Physiol."]
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[6,"Blednov YA, Stoffel M, Alva H, & Harris RA (2003) A pervasive mechanism for analgesia: activation of GIRK2 channels. Proc Natl Acad Sci U S A 100(1):277-282."]
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[8,"Hara K, Yamakura T, Sata T, & Harris RA (2005) The effects of anesthetics and ethanol on alpha2 adrenoceptor subtypes expressed with G protein-coupled inwardly rectifying potassium channels in Xenopus oocytes. Anesth Analg 101(5):1381-1388."]
[9,"Raehal KM & Bohn LM (2005) Mu opioid receptor regulation and opiate responsiveness. Aaps J 7(3):E587-591."]
[10,"Marker CL, Lujan R, Loh HH, & Wickman K (2005) Spinal G-protein-gated potassium channels contribute in a dose-dependent manner to the analgesic effect of mu- and delta- but not kappa-opioids. J Neurosci 25(14):3551-3559."]
[11,"Alves DP, et al. (2004) Additive antinociceptive effect of the combination of diazoxide, an activator of ATP-sensitive K+ channels, and sodium nitroprusside and dibutyryl-cGMP. Eur J Pharmacol 489(1-2):59-65."]
[12,"Russ U, Lange U, Loffler-Walz C, Hambrock A, & Quast U (2003) Binding and effect of K ATP channel openers in the absence of Mg2+. Br J Pharmacol 139(2):368-380."]
[13,"Tsuura Y, et al. (1994) Nitric oxide opens ATP-sensitive K+ channels through suppression of phosphofructokinase activity and inhibits glucose-induced insulin release in pancreatic beta cells. J Gen Physiol 104(6):1079-1098."]
[14,"Alves DS, Perez-Fons L, Estepa A, & Micol V (2004) Membrane-related effects underlying the biological activity of the anthraquinones emodin and barbaloin. Biochem Pharmacol 68(3):549-561."]
[15,"Soares AC & Duarte ID (2001) Dibutyryl-cyclic GMP induces peripheral antinociception via activation of ATP-sensitive K(+) channels in the rat PGE2-induced hyperalgesic paw. Br J Pharmacol 134(1):127-131."]
[16,"Deka DK & Brading AF (2004) Nitric oxide activates glibenclamide-sensitive K+ channels in urinary bladder myocytes through a c-GMP-dependent mechanism. Eur J Pharmacol 492(1):13-19."]
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[25,"Touma SE, et al. (2005) Retinoic acid and the histone deacetylase inhibitor trichostatin a inhibit the proliferation of human renal cell carcinoma in a xenograft tumor model. Clinical Cancer Research 11(9):3558-3566."]
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