Active substances: Doxycycline
Furthermore, L-690,330 also decreased mitochondrial load as judged by complex IV Fig. Accordingly, the IMPase inhibitory activity of lithium can account for its induction of autophagy. Mood-stabilizing drugs facilitate clearance of mutant proteins Inositol depletion is a common mechanism for mood stabilizing drugs like lithium, carbamazepine CBZ, and valproic acid VPA Williams et al.
Similar results were seen with VPA unpublished data.
Accordingly, we pretreated cells with myo-inositol and PEI before adding lithium. Treatment with the proteasome inhibitor, lactacystin, led to massive accumulation of the fluorescent substrate, whereas myo-inositol or PEI had no effect on its levels, compared with the untreated control cells Fig.
Lithium and IMPase inhibitor induce autophagy independently of mTOR inhibition We were interested if this novel means of pharmacologic regulation of autophagy was independent of the known pathway that is regulated negatively by mTOR.
Therefore, rapamycin and intracellular inositol seem to regulate autophagy independently. To demonstrate this effect clearly we chose early time points at which we do not observe obvious reductions of the levels of these proteins when the cells are treated with either of the compounds alone.
Thus, two independent pathways of inducing autophagy in mammalian cells have an additive effect, which is reflected by the greater clearance of mutant proteins because of simultaneous inhibition of mTOR and IMPase.
This provides a new direction for combinatorial treatment of neurodegenerative disorders e. These aggregate-prone proteins are distinct confirmed autophagy substrates Ravikumar et al.
Moreover, free inositol myo-inositol inhibited clearance of autophagy substrates Fig. This represents a novel pathway of mammalian autophagy regulation. It is still not clear how mTOR regulates mammalian autophagy.
Data from older controlled studies and a meta-analysis have demonstrated a beneficial effect on laboratory parameters and modest clinical effects in patients with rheumatoid arthritis RA.
Early initiation of DMARDs is beneficial at minimizing long-term disability; however, their use is associated with significant adverse reactions. Tetracyclines were first used for the treatment of RA in the 1960 s when the disease was thought to be caused by an infectious agent.
Minocycline has demonstrated anti-inflammatory properties such as down-regulation of type 2 nitric oxide synthase a mediator in collagen degradation, upregulation of interleukin-10 an inhibitory cytokine in synovial tissue, and suppressive effects on B and T cell function.
Recommendations are made for several DMARDs, depending on these patient factors, and include the following nonbiologic agents either alone or in combination: hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine.
Due to infrequent use and lack of new data since the guideline, minocycline along with other nonbiologic DMARDs azathioprine, cyclosporine, and gold were considered but not included in the guideline.
The guideline recommends initiating combination therapy or switching between DMARDs, biologic agents, and tofacitinib depending on duration and severity of disease and on whether deterioration, loss of benefit, or no improvement occurs.
The guideline recommends consideration of tapering but not discontinuing therapy when RA is in remission.
Tetracyclines included oral minocycline 100 to 200 mg daily, intravenous doxycycline 200 mg daily for days 1 through 21, then 200 mg once weekly from weeks 4 through 11, oral doxycycline 200 mg daily or 50 mg twice daily, and oral tetracycline 250 mg daily.