Table 2.

Efficacy of drugs in NF-κB, MMP-13, and bone remodeling assays

Drug	Test range (μM)	Overlapping effective and nontoxic rangea (μM)	NF-κB	MMP-13	Bone	Tested in vivo
Alendronate	0.625–40	Bone control	N/A	NE	1.25 and 20 μΜb	MMT/MCLT
Amrinone	0.625–80	80	NE	80	NE	No
Ascomycin	0.01–40	1.25–40	E	NE	E	TBD
BAY-117082	0.188–192	6–192	NE	E	E	Proprietary
BMS-345541	0.24–15.6	0.244	NE	E	E	Proprietary
Boswellic acid	0.61–680	40–680	E	E	E	Purity an issue
Clonidine	0.156–100	10–100	NE	NE	E	MMT/MCLT and MIA
CORM-2	0.625–40	20–40+	N/A	E	E	Proprietary
Curcumin	0.84–108	13.5–54	E	E	E	MMT/MCLT and MIA
Curcumin-14	1.25–80	2.5–10	E	E	NE	TBD
Diacerein	1.5–217	Toxic to chondrocytes	E	E	E	Toxicity and purity issues
EGCG	0.688–44	5.5–44	E	E	NE	Purity an issue
Fluocinolonec	0.010–100	3.1–100	E	E	E	MMT/MCLT and MIA
GM6001	0.33–25	NA	NA	25	NE	No
NF-κB activation inhibitor IV	0.156–10	NA	7.7	NE	N/A	No
IKK inhibitor Vd (IMMD-0354)	0.025–26	1.625–26		E	E	Cost-prohibitive/proprietary
IKK inhibitor VI	0.028–15.2	0.24–15.2	E	E	E	Cost-prohibitive/proprietary
IKK inhibitor VIII (ACHP)	0.25–16	4 (toxicity to synovial cells)	N/A	E	E	Cost-prohibitive/proprietary
Meloxicam	0.125–32	16–32	E	NE	NE	MIA
Pimecrolimus (ELIDEL; Meda Pharma, Luxembourg)	0.625–40	2.5–20	E	NE	E	TBD
Resveratrol	3.125–200	6.25–200	NE	E	E	TBD
Rhein	0.625– 40	N/A	NE	E	NE	Lack of potency
SC514	0.125–32	NE in nontoxic range	NE	NE	NE	Proprietary
Sulfasalazined	12.5–1600	150–1600		E	E	Lack of potency
Sulindac	4.35–280	280	E	E	E	Lack of potency
Tacrolimuse (FK506)	0.813–100	50	E	E	E	MMT/MCLT and MIA
Tranilast	0.125–8	1–8	NE	E	E	MIA
Triamcinolone acetonide	0.7–2000	250–500	E	E	E	Aristospan (TH) tested instead
Triamcinolone hexacetonidee	3.125–3750	62.5–3750	E	E	E	MMT/MCLT and MIA
Withaferin Af	0.25–17	4.25–17	E	E	E	MMT/MCLT model

ACHP 2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-(4-piperidinyl)-3-pyridinecarbonitrile, E effective nontoxic concentration that overlaps with other tested agents, EGCG epigallocatechin gallate, FK506 tacrolimus, IKK inhibitor of nuclear factor κB kinase, MIA monoiodoacetic acid, MMP matrix metalloproteinase, MMT/MCLT medial meniscal tear/medial collateral ligament tear, N/A not applicable, NF-κB nuclear factor κ-light-chain-enhancer of activated B cells, NE not effective and nontoxic within the effective/nontoxic range for the other tested drugs, SC514 selective reversible inhibitor of inhibitor of nuclear factor κB kinase 2, TBD to be determined, TH triamcinolone hexacetonide

The overlapping dose range that was effective and nontoxic is also shown. If effective in vitro, it is noted whether in vivo testing occurred and in which models. See Figs. 1, 2 and 3 and Additional file 1 for results in the specific assays

^aDose found to inhibit with minimal or no toxicity to synovium or cartilage. Values reflect overlapping range if agent was effective in more than one assay

^bUsed as a bone remodeling control; not tested <1.25 μM in the bone assay

^cFluocinolone was effective at much lower doses in both the bone and MMP-13 assays

^dEffective in the MMP-13 and bone assays; at higher concentrations, this compound blocked NF-κB activity in the HeLa assay but also blocked expression of the Renilla plasmid luciferase. At lower concentrations, it was not effective against NF-κB

^eTacrolimus and TH were effective at much lower doses in the bone assay. For TH, lower doses may have been effective in the NF-κB assay but were not tested

^fBecause of the promising results, especially in the bone and MMP-13 assays, and in spite of its slight toxicity in the synovial and chondrocyte assays, Withaferin A was tested in the MMT/MCLT model