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BACKGROUND: The formulation investigated as reference contains thioctic acid which is known to be poorly soluble in water and have some instability during storage at high temperature. To overcome these limitations, a new piperazine dithioctate (PDT) tablet formulation was developed by a domestic pharmaceutical company in Korea. OBJECTIVE: The aim of this clinical study was to evaluate the pharmacokinetic characteristics of PDT in healthy volunteers. METHODS: This study consisted of two clinical trials. In the part 1 study, a randomized, singledose, parallel study was performed with 24 healthy volunteers. All of the subjects were administered one of the three study formulations, Thioctacid® HR (High Release) as the reference, PDT-1 or PDT-2 (each containing thioctic acid 600 mg), respectively. To determine the harmacokinetic characteristics, blood samples were serially collected at pre-dose and at pre-defined timepoints after dosing. In the part 2 study, a randomized, single-dose, two-way crossover study was conducted with 48 subjects. All of the subjects were administered both the reference and PDT-2 formulations, with a 7-day washout period between the two medications. Blood samples were collected at the same timepoints as in the part 1 study. Tolerability was evaluated throughout the study. RESULTS: 23 volunteers completed the part 1 study. The maximum plasma concentration (Cmax) of thioctic acid after administration of the reference tablet was 4.08 ± 2.35 µg/mL (means ± SD), and the Cmax of PDT-1 and PDT-2 was 3.53 ± 2.87 µg/mL and 4.15 ± 1.62 µg/mL, respectively. The AUClast value was 2.96 ± 1.13 µg x h/mL for the reference, 2.84 ± 1.12 µg x h/mL for PDT-1, and 3.30 ± 1.32 µg x h/mL for PDT-2. 42 volunteers completed the part 2 study. The Cmax of reference and PDT-2 was 5.59 ± 3.07 µg/mL and 5.14 ± 3.18 µg/mL, respectively. The AUClast value was 4.01 ± 1.65 µg x h/mL for the reference and 3.96 ± 1.47 µg x h/mL for PDT-2. The geometric mean ratios (PDT-2/reference) and the 90% CI for Cmax and AUClast were 0.93 (0.78 - 1.11) and 1.01 (0.94 - 1.09), respectively. CONCLUSION: Both studies suggested that the pharmacokinetic profile of the newly developed piperazine dithioctate formulation was comparable to the pharmacokinetic profile of the reference tablet. Both study tablets were well tolerated in all of the subjects.
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Piperazinas/farmacocinética , Adulto , Área Bajo la Curva , Química Farmacéutica , Estudios Cruzados , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Purpose: Postherpetic neuralgia (PHN) is the most common chronic complication of herpes zoster, associated with poor quality of life and increased patient and healthcare resource expenditure. This randomized controlled trial aims to evaluate the efficacy and safety of SIKD1977 (Sogeonjungtang) in combination with standard treatment and estimate an effective dose for treating PHN. Patients and Methods: This is a protocol for a randomized, placebo-controlled, double-blind, multicenter trial. A total of 90 eligible participants with PHN will be recruited from three hospitals and randomly allocated to high-dose group, low-dose group, or placebo group in a 1:1:1 ratio. The trial will involve a 6-week oral administration of SIKD1977/placebo, and a 1-week follow-up period. The primary outcome will be the weekly average change in average daily pain score (ADPS) from baseline to the end of treatment. The secondary outcomes will include the weekly average changes in ADPS from baseline to week 2, 4, and 7, differences in Short-Form McGill Pain Questionnaire, Visual analogue scale, 5-level EuroQol-5 dimensions, Patient Global Impression of Change, and consumption of rescue drugs. All adverse events will be assessed during the trial. Conclusion: This study will provide evidence for the efficacy and safety of SIKD1977, and an effective dose for PHN. Trial Registration: This protocol has been registered in the Clinical Research Information Service with the identification code KCT0007939.
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Leaves of Eriobotrya japonica Lindl. (Rosaceae) (LEJL) have been used as traditional medicines for inflammatory diseases and chronic bronchitis. However, its effect on mast cell-mediated anaphylactic reaction is not known. The anaphylactic allergic reaction is involved in many allergic diseases such as asthma and allergic rhinitis. In this report, we investigate the effect of LEJL on the anaphylactic allergic reaction and studied its possible mechanisms of action. LEJL inhibited compound 48/80-induced systemic anaphylactic reactions and serum histamine release in mice. LEJL dose-dependently decreased the IgE-mediated passive cutaneous anaphylaxis and histamine release from mast cells. Furthermore, LEJL decreased the production of tumor necrosis factor-alpha in phorbol 12-myristate 13-acetate and A23187-stimulated human mast cells. These findings provide evidence that LEJL could be a candidate as an anti-allergic agent.
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Anafilaxia/terapia , Antialérgicos/inmunología , Eriobotrya/inmunología , Liberación de Histamina/inmunología , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Calcimicina/farmacología , Histamina/sangre , Histamina/inmunología , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Masculino , Mastocitos/efectos de los fármacos , Ratones , Ratones Endogámicos ICR , Hojas de la Planta/inmunología , Ratas , Ratas Sprague-Dawley , Acetato de Tetradecanoilforbol/farmacología , p-Metoxi-N-metilfenetilamina/inmunologíaRESUMEN
We investigated whether the snake venom toxin (SVT) from Vipera lebetina turanica inhibits cell growth of human prostate cancer cells by inducing apoptosis and also studied possible signaling pathways involved in this cell death. SVT inhibited growth of PC-3 and DU145 cells, androgen-independent prostate cancer cells, but not LNCaP cells, a human androgen-dependent prostate cancer cell. Cells were arrested in the G(2)-M phase by SVT with a concomitant decrease in the expression of the G(2)-M phase regulatory protein cyclin B1 and were also arrested in the G(1)-S phase with decreasing expression of cyclin-dependent kinase 4, cyclin D1 and cyclin E. In addition to the growth-inhibitory effect, SVT increased the induction of apoptotic cell death. Untreated PC-3 cells show high DNA binding activity of nuclear factor kappaB (NF-kappaB), an antiapoptotic transcriptional factor, but this was inhibited by SVT and accompanied by a significant inhibition of p50 translocation into the nucleus, as well as phosphorylation of inhibitory kappaB. Consistent with the induction of apoptosis and inhibition of NF-kappaB, this toxin increased the expression of proapoptotic proteins such as p53, Bax, caspase-3, and caspase-9, but down-regulated antiapoptotic protein Bcl-2. However, SVT did not show an inhibitory effect on cell growth and caspase-3 activity in cells carrying mutant p50 and inhibitory kappaB kinase plasmids. Confocal microscopy analysis showed that SVT is taken up into the nucleus of the cells. These findings suggest that a nanogram concentration range of SVT from V. lebetina turanica could inhibit hormone-refractory human prostate cancer cell growth, and the effect may be related to NF-kappaB signal-mediated induction of apoptosis.
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Apoptosis/efectos de los fármacos , FN-kappa B/metabolismo , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Venenos de Serpiente/farmacología , Toxinas Biológicas/farmacología , Viperidae , Animales , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Núcleo Celular , Ciclinas/metabolismo , Humanos , Masculino , FN-kappa B/genética , Fosforilación/efectos de los fármacos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Transporte de ProteínasRESUMEN
PURPOSE: Previously, we have reported that the newly synthesized octahedral Pt(IV) compound, trans,cis-Pt(acetato)(2)Cl(2)(1,4-butanediamine), K101 and trans,cis-Pt(trifluoroacetato)(2)Cl(2)(1,4-butanediamine), K102 showed potent antitumor activities in vitro and in vivo. In order to compare the nephrotoxicity of the newly synthesized Pt(IV) complexes, K102 and K102 with cisplatin, we performed various tests. MATERIALS AND METHODS: We performed a single dose acute toxicity test for LD(50) values determination, biochemical assays in blood serum, acid phosphatase enzyme histochemistry and transmission electron microscopic studies in renal proximal tubular cells in mice in vivo. The route of drugs administration is intraperitoneal injection. RESULTS: In biochemical assays, the serum levels of BUN were significantly elevated at 6 h (p < 0.001), 1 day (p < 0.05) and 3 days (p < 0.001) after injection in cisplatin treated mice (6 mg/kg, single dose, i.p.). On the other hand, the serum levels of BUN were slightly elevated at 6 h (p < 0.01) only in K101 treated mice (8.2 mg/kg, single dose, i.p.), and were significantly raised at 6 h, 1 and 3 days (p < 0.05) after injection in K102 treated mice (6.2 mg/kg, single dose, i.p.). The higher serum BUN level in K102 treated mice is considered that K102 possesses more lipophilic fluoro group than acetyl group in K101. The values of creatinine and uric acid were similar in all groups. The ultrastructural morphological changes of K101- or K102-administrated mice were less remarkable than cisplatin-administrated mice. In acid phosphatase enzyme histochemistry, cisplatin treatment induced relevant changes in the distribution pattern of enzyme activity compared with K101 or K102 treatment at 7 days after injection. CONCLUSIONS: In conclusion, these results show that K101 is less nephrotoxic than cisplatin and a promising new platinum complex.
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Antineoplásicos/toxicidad , Cisplatino/toxicidad , Enfermedades Renales/inducido químicamente , Compuestos Organoplatinos/toxicidad , Fosfatasa Ácida/metabolismo , Animales , Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Desmosomas/efectos de los fármacos , Desmosomas/ultraestructura , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intraperitoneales , Enfermedades Renales/patología , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/enzimología , Túbulos Renales Proximales/patología , Dosificación Letal Mediana , Masculino , Ratones , Ratones Endogámicos ICR , Microscopía Electrónica de Transmisión , Compuestos Organoplatinos/farmacocinéticaRESUMEN
BACKGROUND: The newly synthesized octahedral Pt(IV) complex series showed potent antitumor activities, both in vitro and in vivo. Carboplatin, possessing a soluble leaving ligand, is known to be less toxic than cisplatin. The synthesized K104 is a Pt(IV) complex with a malonato leaving group and seven-membered ring structure between the central platinum and amine carrier ligands. In this study, the histoculture drug response assay (HDRA) of K104 on human cancer tissues was investigated in vitro and nephrotoxicity was examined in vivo. MATERIALS AND METHODS: Cytotoxicity was tested in various cancer cell lines, and the HDRA of K104 was evaluated by MTT assay in vitro using colorectal and breast cancer tissues from patients. In order to compare the nephrotoxicity of K104 with cisplatin and carboplatin, blood serum levels of BUN, creatinine and uric acid in ICR mice were measured. RESULTS: K104 showed more effective anticancer activities than carboplatin in most cancer cell lines. In HDRA, K104 showed a 50.0-66.7% efficacy rate compared with 33.3% of cisplatin and 58.3% of carboplatin against colorectal cancer patient tissues. In breast cancer tissues, K104 only showed an efficacy rate above 50%. The serum levels of BUN, creatinine and uric acid did not change after a single intraperitoneal administration of K104 (90 mg/kg) in ICR mice. CONCLUSION: K104 showed more effective anticancer activities than carboplatin. Cisplatin was associated with nephrotoxic effects, but K104 did not change the serum levels of BUN, creatinine and uric acid in vivo. These results suggest that K104 is a promising anticancer agent in view of its high efficacy against human solid cancer and lower toxicity in vivo.
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Antineoplásicos/farmacología , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Compuestos Organoplatinos/farmacología , Animales , Nitrógeno de la Urea Sanguínea , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Neoplasias del Colon/sangre , Neoplasias del Colon/tratamiento farmacológico , Creatinina/sangre , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HCT116 , Células HL-60 , Humanos , Leucemia L1210/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos ICR , Ácido Úrico/sangreRESUMEN
BACKGROUND: Chlorphenesin carbamate is a skeletal muscle relaxant approved in Korea for use in the treatment of pain and discomfort related to skeletal muscle trauma and inflammation. OBJECTIVE: The aim of this study was to assess the bioequivalence of a generic formulation of chlorphenesin carbamate at doses of 250 and 500 mg and 2 branded formulations of the same doses in healthy Korean adults. METHODS: This single-dose, randomized-sequence, open-label, 2-period crossover study was conducted in healthy Korean male and female volunteers. Subjects were assigned to receive, in a randomized sequence, a single dose of the generic (test) and branded (reference) formulations of chlorphenesin carbamate at a dose of 250 or 500 mg. Blood samples were drawn at 0, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 9, 12, and 15 hours after administration. Pharmacokinetic properties (C(max), T(max), AUC(0-t) AUC(0-infinity), t(1/2), and ke) were determined using HPLC. The formulations were to be considered bioequivalent if the 90% CIs of the treatment ratios of the geometric means of C(max) and AUC(0-t) were within a predetermined range of log 0.80 to log 1.25 based on regulatory criteria. Tolerability was assessed by monitoring for adverse events (AEs) on physical examination and/or e-mail and personal interview at the beginning and end of each study period. RESULTS: Twenty-eight subjects (22 men, 6 women) received chlorphenesin carbamate at the 250-mg dose, and 24 male subjects received the 500-mg dose. The mean (SD) ages of the subjects were 24.0 (2.6) and 24.0 (1.9) years in the 250- and 500-mg groups, respectively. No significant differences were found between the test and reference formulations (90% CIs: C(max), 1.0048-1.1153 with the 250-mg dose and 0.9630-1.1189 with the 500-mg dose; AUC(0-t), 0.9882-1.0546 and 0.9842-1.0578, respectively). No clinically significant AEs (upper gastric pain, abdominal bloating, pyrexia, edema, nausea, heartburn, constipation, headache, dizziness, drowsiness, or fatigue) were reported throughout the study. CONCLUSION: In this single-dose study in these healthy Korean subjects, the generic and branded formulations of chlorphenesin carbamate 250 and 500 mg met the regulatory criteria for bioequivalence. All formulations were well tolerated.
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Clorfenesina/análogos & derivados , Relajantes Musculares Centrales/administración & dosificación , Relajantes Musculares Centrales/farmacocinética , Adolescente , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Química Farmacéutica , Clorfenesina/administración & dosificación , Clorfenesina/efectos adversos , Clorfenesina/farmacocinética , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Femenino , Semivida , Humanos , Masculino , Persona de Mediana Edad , Relajantes Musculares Centrales/efectos adversos , Reproducibilidad de los Resultados , Comprimidos , Equivalencia Terapéutica , Adulto JovenRESUMEN
With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized new piperidine derivatives having dual action of acetylcholinesterase (AChE) and beta-amyloid peptide (Abeta) aggregation inhibition. For binding with the catalytic site of AChE, an ester with aromatic group was designed, and for the peripheral site, another aromatic group was considered. And for intercalating amyloid-beta oligomerization, long and linear conformation with a lipophilic group was considered. The synthetic methods employed for the structure with dual action depended on alcohols with an aromatic ring and the substituted benzoic acids, which are esterificated in the last step of the synthetic pathway. We screened these new derivatives through inhibition tests of acetylcholinesterase, butyrylcholinesterase (BChE), and Abeta(1-42) peptide aggregation, AChE-induced Abeta(1-42) aggregation. Our results displayed that compound 12 showed the best inhibitory potency and selectivity of AChE, and 29 showed the highest selectivity of BChE inhibition. Compounds 15 and 12 had inhibitory activities against Abeta(1-42) aggregation and AChE-induced Abeta aggregation. In the docking model, we confirmed that 4-chlorobenzene of 12 plays the parallel pi-pi stacking against the indole ring of Trp84 in the bottom gorge of AChE. Because the benzyhydryl moiety of 12 covered the peripheral site of AChE in a funnel-like shape, 12 showed good inhibitory potency against AChE and could inhibit AChE-induced Abeta(1-42) peptide aggregation.
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Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Fragmentos de Péptidos/antagonistas & inhibidores , Piperidinas/química , Piperidinas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Butirilcolinesterasa/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/química , Donepezilo , Humanos , Indanos/síntesis química , Indanos/química , Indanos/farmacocinética , Modelos Moleculares , Estructura Molecular , Fragmentos de Péptidos/metabolismo , Piperidinas/síntesis química , Piperidinas/farmacocinética , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
Recently, the synthesized octahedral Pt(IV) compound trans,cis-Pt(acetato)2Cl2(1,4-butanediamine), K101, showed potent anti-tumor activity in vitro and in vivo. For the further investigation of K101-induced anti-cancer activity, we tested cytotoxicity against various cancer cell lines and performed the histoculture drug response assay (HDRA) against human colorectal tumor tissues in vitro. We investigated the signaling pathway of K101-induced apoptosis via expression of p53 and ERK1/2 in the human colon cell line HCT116. The cytotoxicity and the three-dimensional HDRA of K101 were evaluated using the MTT assay. To study the K101-induced apoptosis pathway, we performed FACS analysis and immunoblotting of p53, p21, Bax, Fas and ERK1/2 in HCT116 cells treated with or without K101. The cytotoxic IC50 values of K101 ranged from 1.15 to 2.38 micromol/l, compared to cisplatin ranging from 2.13 to 13.1 micromol/l. Among several cancer cell lines, K101 showed greater potency than cisplatin in colon cancer cell lines. In the HDRA, K101 showed 80.0-91.4% efficacy rates compared with 48.6% for cisplatin against colorectal cancer patient tissues. In the signaling pathway, the expression of p53 and phospho-ERK1/2 was increased in a time-dependent manner by treatment with K101 in the HCT116 cells. When K101 was treated with MEK inhibitor U0126, the cell death rate was increased. The octahedral Pt(IV) complex K101 could be an attractive candidate as a chemotherapeutic agent against colon cancer. ERK1/2 activation and the p53 pathway may play significant functions in mediating K101-induced apoptosis in human colon cancer cells.
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Antineoplásicos/farmacología , Neoplasias del Colon/tratamiento farmacológico , Compuestos Organoplatinos/farmacología , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Butadienos/farmacología , Línea Celular Tumoral , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Activación Enzimática/efectos de los fármacos , Humanos , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Nitrilos/farmacología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Novel platinum(IV) complexes were synthesized having octahedral structure for new antitumor agents. The series of (1,4-butanediamine)Pt(IV) complexes of the type trans,cis-[PtA(2)Cl(2)(1,4-butanediamine)] (A=hydroxo 9, acetato 12, trifluoroacetato 13 as axial ligands) and trans-[PtA(2)(malonate)(1,4-butanediamine)] (A=hydroxo 16, acetato 17, trifluoroacetato 18) were synthesized and characterized by IR, NMR and elemental analysis. The molecular structures of 12, 13 and 18 have been determined by X-ray diffraction methods. The crystals are monoclinic, P2 1/c with a=21.165 (5), b=9.050 (3), c=15.293 (3) A, beta=103.89 (2) degrees and Z=8 for 12, a=10.178 (5), b=12.894 (9), c=12.182 (8) A, beta=91.01 (5) degrees and Z=4 for 13 and a=10.460 (5), b=11.199 (8), c=15.641 (7) A, beta=98.41 (5) degrees, Z=4 for 18. Three crystallographically independent molecules of 12, 13 and 18 have octahedral coordination around Pt(IV) cation. The trans,cis-[PtA(2)Cl(2)(1,4-butanediamine)] were prepared by acetylation or trifluoroacetylation of trans,cis-[Pt(OH)(2)Cl(2)(1,4-butanediamine)]. The trans-[PtA(2)malonate(1,4-butanediamine)] 17 and 18 was prepared by a similar method. The in vitro cytotoxicity of theses Pt(IV) complexes have been evaluated against 12 cancer cell lines assayed by MTS method. The IC(50) values of the compounds 12 and 13 were shown to be lower than those of cisplatin. The in vivo antitumor activity of the Pt(IV) complexes was evaluated using mice bearing L1210 leukemia, B16 melanoma and L1210/cis-DDP cancer animal models. The compound 18 was found to highest activity against cisplatin-resistant cancer cells, L1210/cis-DDP, in vivo.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/farmacología , Animales , Antineoplásicos/química , Peso Corporal , Cisplatino/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Isomerismo , Espectroscopía de Resonancia Magnética , Melanoma Experimental , Ratones , Estructura Molecular , Compuestos Organoplatinos/química , Espectrofotometría Infrarroja , Células Tumorales CultivadasRESUMEN
The aim of this study was to evaluate the effect of estrogen on matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, and tissue inhibitor of metalloproteinase (TIMP)-1 in osteoarthritic chondrocytes. Chondrocytes from the knee cartilage of 25 postmenopausal osteoarthritic (OA) patients were cultured under various conditions: 0 pg/mL, 50 pg/mL, 500 pg/mL, and 5,000 pg/mL of 17beta-estradiol, with or without 10-1,000 pg/mL of either interleukin (IL)-1beta or tumor necrosis factor alpha (TNFalpha). MMP-1, MMP-3, MMP-13, and TIMP-1 in the conditioned media were analyzed with immunoblot or enzyme-linked immunosorbent assay (ELISA). Type II collagenolytic activity was measured by fluorogenic type II collagenolytic activity assay. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) using SYBR Green I dye was performed for the quantification of mRNA. Without cytokine stimulation, the secretion of MMP-1 was significantly reduced by 50 pg/mL of 17beta-estradiol (in immunoblot by a median of 12.3%, P=0.007; in ELISA by a median of 18.4%, P=0.001), and 500 pg/mL (in immunoblot by a median of 23.1%, P=0.001; in ELISA by a median of 21.0%, P=0.001). Additionally, under 10 pg/mL TNFalpha, 17beta-estradiol also significantly suppressed the secretion of MMP-1 (in immunoblot by a median of 39.0%, P=0.016; in ELISA by a median of 38.4%, P=0.041). Estrogen did not exert any significant effect on MMP-3, MMP-13, or TIMP-1 expression. With IL-1beta or TNFalpha above 10 pg/mL stimulation, 17beta-estradiol demonstrated no effect on MMP-1, MMP-3, MMP-13, or TIMP-1 secretion. Type II collagenolytic activity in the 50 pg/mL estradiol group decreased by 9.6% (-51.5-5.5%, P>0.05). 17beta-estradiol showed a tendency to decrease in MMP-1 mRNA. Estrogen may improve the imbalance between the amounts of MMPs and TIMP in chondrocytes, and these results suggest that hormone replacement therapy may provide some chondroprotective effect.