Tetracycline up-regulates COX-2 expression and prostaglandin E2 production independent of its effect on nitric oxide.
(1/884)
Tetracyclines (doxycycline and minocycline) augmented (one- to twofold) the PGE2 production in human osteoarthritis-affected cartilage (in the presence or absence of cytokines and endotoxin) in ex vivo conditions. Similarly, bovine chondrocytes stimulated with LPS showed (one- to fivefold) an increase in PGE2 accumulation in the presence of doxycycline. This effect was observed at drug concentrations that did not affect nitric oxide (NO) production. In murine macrophages (RAW 264.7) stimulated with LPS, tetracyclines inhibited NO release and increased PGE2 production. Tetracycline(s) and L-N-monomethylarginine (L-NMMA) (NO synthase inhibitor) showed an additive effect on inhibition of NO and PGE2 accumulation, thereby uncoupling the effects of tetracyclines on NO and PGE2 production. The enhancement of PGE2 production in RAW 264.7 cells by tetracyclines was accompanied by the accumulation of both cyclooxygenase (COX)-2 mRNA and cytosolic COX-2 protein. In contrast to tetracyclines, L-NMMA at low concentrations (< or = 100 microM) inhibited the spontaneous release of No in osteoarthritis-affected explants and LPS-stimulated macrophages but had no significant effect on the PGE2 production. At higher concentrations, L-NMMA (500 microM) inhibited NO release but augmented PGE2 production. This study indicates a novel mechanism of action of tetracyclines to augment the expression of COX-2 and PGE2 production, an effect that is independent of endogenous concentration of NO. (+info)
In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936).
(2/884)
The 9-t-butylglycylamido derivative of minocycline (TBG-MINO) is a recently synthesized member of a novel group of antibiotics, the glycylcyclines. This new derivative, like the first glycylcyclines, the N,N-dimethylglycylamido derivative of minocycline and 6-demethyl-6-deoxytetracycline, possesses activity against bacterial isolates containing the two major determinants responsible for tetracycline resistance: ribosomal protection and active efflux. The in vitro activities of TBG-MINO and the comparative agents were evaluated against strains with characterized tetracycline resistance as well as a spectrum of recent clinical aerobic and anaerobic gram-positive and gram-negative bacteria. TBG-MINO, with an MIC range of 0.25 to 0.5 microgram/ml, showed good activity against strains expressing tet(M) (ribosomal protection), tet(A), tet(B), tet(C), tet(D), and tet(K) (efflux resistance determinants). TBG-MINO exhibited similar activity against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococci, and vancomycin-resistant enterococci (MICs at which 90% of strains are inhibited, < or = 0.5 microgram/ml). TBG-MINO exhibited activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to tetracycline and minocycline. The in vivo protective effects of TBG-MINO were examined against acute lethal infections in mice caused by Escherichia coli, S. aureus, and Streptococcus pneumoniae isolates. TBG-MINO, administered intravenously, demonstrated efficacy against infections caused by S. aureus including MRSA strains and strains containing tet(K) or tet(M) resistance determinants (median effective doses [ED50s], 0.79 to 2.3 mg/kg of body weight). TBG-MINO demonstrated efficacy against infections caused by tetracycline-sensitive E. coli strains as well as E. coli strains containing either tet(M) or the efflux determinant tet(A), tet(B), or tet(C) (ED50s, 1.5 to 3.5 mg/kg). Overall, TBG-MINO shows antibacterial activity against a wide spectrum of gram-positive and gram-negative aerobic and anaerobic bacteria including strains resistant to other chemotherapeutic agents. The in vivo protective effects, especially against infections caused by resistant bacteria, corresponded with the in vitro activity of TBG-MINO. (+info)
Metabolic drug interactions between angiogenic inhibitor, TNP-470 and anticancer agents in primary cultured hepatocytes and microsomes.
(3/884)
The potential metabolic drug interactions between TNP-470, a potent inhibitor of angiogenesis, and several commonly used anticancer agents, such as cyclophosphamide, taxol, and minocycline, were investigated in vitro using primary cultured hepatocytes and microsomes of rhesus monkeys. After incubation of hepatocytes with 5 microM [3H]TNP-470, rapid and extensive formation of six metabolites was observed, with M-II and M-IV being the predominant metabolites. After 30 min of incubation in the presence of 250 microM cyclophosphamide, concentrations of unchanged TNP-470 and M-IV were increased with values of 1.00 +/- 0.02 and 1.49 +/- 0.01 microM compared with control values of 0.67 +/- 0.09 (p =.02), 1.39 +/- 0. 03 microM (p <.01), respectively. In contrast, the concentration of M-II was substantially decreased from 1.69 +/- 0.86 to 1.02 +/- 0.16 microM (p =.01). Combination of taxol with TNP-470 led to a 50% decrease of M-II levels (p <.01), whereas unchanged TNP-470 and M-IV levels were increased by at least 2.5-fold compared with control (p =.08 and 0.01). Exposure of cells to TNP-470 with 250 microM minocycline had no effect on TNP-470 metabolism in monkey hepatocytes. In vitro studies with isolated monkey liver microsomes confirmed these drug-drug metabolic interactions detected at the cellular level. A detailed understanding of the potential drug interactions in TNP-470 metabolism occurring with taxol or cyclophosphamide is critical to fully elucidate the potentiation of the antitumor activity observed in vivo after coadministration of these two agents with TNP-470. (+info)
Comparative in-vitro activity of moxifloxacin, minocycline and azithromycin against Chlamydia spp.
(4/884)
The in-vitro activity of moxifloxacin, a new 8-methoxyquinolone, was compared with minocycline and azithromycin against 40 strains of Chlamydia trachomatis, Chlamydia pneumoniae and Chlamydia psittaci. Both the MIC and the MBC of moxifloxacin ranged from 0.03 to 0.125 mg/L. MICs of minocycline ranged from 0.015 to 0.06 mg/L and MBCs between 0.03 and 0.25 mg/L. MICs of azithromycin ranged from 0.03 to 0.125 mg/L and the MBCs between 0.06 and 0.5 mg/L. MBC values of moxifloxacin were the same as MICs in 32 (80%) of 40 strains tested, whereas those of minocycline and azithromycin were two to four times higher than their MICs. These data confirm those previously obtained indicating that quinolones kill chlamydial strains at concentrations equivalent to their MICs. (+info)
Differences in susceptibility of Enterobacteriaceae and penicillin-resistant Staphylococcus aureus to tetracycline and minocycline.
(5/884)
Two hundred strains of penicillin-resistant Staphylococcus aureus and 311 isolates of Enterobacteriaceae were compared for their susceptibility to tetracycline and minocycline. Thirteen and one-half percent of the staphylococcal isolates were resistant to tetracycline but susceptible to minocycline. Similarly, 24% of the enterobacterial isolates were found to be tetracycline resistant but susceptible to minocycline. Of a total of 511 recent clinical isolates, 14.5% were susceptible to minocycline but were tetracycline resistant. (+info)
Minocycline sensitivity related to the phage type of multiply resistant staphylococci.
(6/884)
Clinical isolated of multiply antibiotic-resistant strains of Staphlococcus aureus were divided into three groups by phage typing. The most prevalent type, which is usually cloxacillin resistant, was found to be moderately sensitive to minocycline. Unfortunately the degree of sensitivity is not sufficient to warrant the use of the antibiotic in severe staphlococcal infection. (+info)
Treatment of early seropositive rheumatoid arthritis with minocycline: four-year followup of a double-blind, placebo-controlled trial.
(7/884)
OBJECTIVE: Rheumatoid arthritis (RA) causes substantial morbidity and mortality, and current treatments are suboptimal. Recent studies have demonstrated the short-term efficacy of minocycline in the treatment of patients with early RA. This study was undertaken to compare patients treated with conventional therapy in the early phase of their RA and those treated with minocycline, after 4 years of followup. METHODS: Forty-six patients with seropositive RA of <1 year's duration had been enrolled in a double-blind study of minocycline (100 mg twice daily) versus placebo. After the blinded portion of the study (3-6 months, depending upon response), all patients were treated with conventional therapy. This report compares those patients randomized to receive placebo for 3 months and then conventional therapy for the duration of 4 years versus those originally randomized to receive minocycline. RESULTS: Twenty of the 23 original minocycline-treated patients and 18 of the 23 original placebo-treated patients were available for followup (mean 4 years). At followup, RA was in remission (American College of Rheumatology criteria) without disease-modifying antirheumatic drug (DMARD) or steroid therapy in 8 of the patients originally treated with minocycline compared with 1 patient in the placebo group (P = 0.02). Ten patients in the minocycline group versus 16 in the original placebo group currently require DMARD therapy (P = 0.02). CONCLUSION: Among patients with seropositive RA, remissions are more frequent and the need for DMARD therapy is less in those treated early in the disease course with minocycline compared with those treated with conventional therapy delayed by an average of only 3 months. Minocycline appears to be an effective therapy for early RA; further investigation into its mechanism of action is needed. (+info)
Efficacy of antibacterial drugs in mice with complex infection by Candida albicans and Escherichia coli.
(8/884)
We investigated the effect of seven antibacterial antibiotics: kanamycin, gentamicin, tetracycline, minocycline, ampicillin, piperacillin and cefotaxime, on survival of mice infected sequentially with a lethal dose of Candida albicans and a sublethal dose of Escherichia coli. The mortality of C. albicans-infected mice was facilitated by the superinfection with E. coli. When administered to mice with C. albicans/E. coli complex infection, aminoglycosides and tetracyclines significantly prolonged the survival period as compared with the infected and untreated controls. The recovery of viable counts of E. coli from the renal tissues was rapidly reduced by the treatment with gentamicin or minocycline, compared to the untreated control. Thus it was concluded that nullification by the treatment with aminoglycosides or tetracyclines of the enhancing effect of E. coli superinfection on the lethality of C. albicans-infected mice is due to early elimination of E. coli from the kidney. (+info)