Sirolimus (rapamycin, Rapamune ® ) and combination therapy with cyclosporin A in the rat developing adjuvant arthritis model: Correlation with blood levels and the effects of different oral formulations

Carlson, Richard P.; Hartman, David S.; Ochalski, S. J.; Zimmerman, Janice L.; Glaser, Keith B.

doi:10.1007/s000110050339

Cited by 23 publications

(16 citation statements)

References 15 publications

(19 reference statements)

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“…This medicament has demonstrated high efficacy in experimental autoimmune uveoretinitis [21], in an experimental model of systemic lupus [23], as well as in experimental arthritis [24]. On the other hand, pioneer attempts to treat glomerular diseases in humans with RAPA have not enriched us with encouraging results, but rather stressed the functional kidney disorders caused by this drug [25].…”

Section: Discussionmentioning

confidence: 99%

Effects of Rapamycin on Active Heymann Nephritis

Naumovic¹,

Jovović²,

Basta-Jovanović³

et al. 2007

Am J Nephrol

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Background/Aim: The effects of rapamycin (RAPA) were examined in active Heymann nephritis (HN), an experimental model of human membranous nephropathy (MN). Current opinion on the therapy of MN is controversial, and medications used for its treatment have not yielded the expected results. Methods: In a two-part study, we examined the effects of RAPA (1.5 mg/kg/day) during the induction phase of HN and on the evolving disease. In both parts, control groups of immunized rats not treated with RAPA and control groups of unimmunized rats were observed and sacrificed concurrently with the treated groups. Results: During the induction phase no significant changes in proteinuria were observed in the group treated with RAPA, in comparison to those in the untreated group (p < 0.001). During the evolving disease RAPA significantly lowered proteinuria (p < 0.001). The characteristic pathohistologic changes and IgG depositions along the glomerular basement membrane were considerably diminished, and infiltration of CD8+ cells completely prevented. Conclusion: RAPA demonstrated beneficial effects on disease progression, given either in the induction phase or during evolving HN. It would be desirable to investigate the effect of RAPA on patients with MN.

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Section: Discussionmentioning

confidence: 99%

Effects of Rapamycin on Active Heymann Nephritis

Naumovic¹,

Jovović²,

Basta-Jovanović³

et al. 2007

Am J Nephrol

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“…The manufacturer of Rapamune® recommends to mix the dose with at least 60 ml of water or orange juice, but not any other liquids, to stir the emulsion vigorously, to drink it immediately followed by another 120 ml of water or orange juice. A previous study (7) investigated the impact of two different formulations of Sirolimus® on blood levels and the development of arthritis induced in rats. On the one hand, Sirolimus® was formulated as a suspension with TWEEN™ 80 (Polysorbate 80) (Croda International PLC) (polyethylene glycol sorbitan monooelate), and on the other hand as a highly waterdiluted emulsion containing PHOSAL® 50 PG and 1% TWEEN™ 80.…”

Section: Liquid and Semiliquid Systemsmentioning

confidence: 99%

“…Further examples for an improvement of the side-effect profile of active ingredients by applying phospholipids include the following substances: NSAIDs (Piroxicam, marketed under various trade names, including Feldene® (Pfizer Labs)) (49), Sudoxicam (49), Taurocholate (41), Sirolimus® (7,43) and anabolic steroids (71).…”

Section: Reduction Of Side Effectsmentioning

confidence: 99%

Phospholipids and Lipid-Based Formulations in Oral Drug Delivery

Kromp²,

et al. 2010

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Phospholipids become increasingly important as formulation excipients and as active ingredients per se. The present article summarizes particular features of commonly used phospholipids and their application spectrum within oral drug formulation and elucidates current strategies to improve bioavailability and disposition of orally administered drugs. Advantages of phospholipids formulations not only comprise enhanced bioavailability of drugs with low aqueous solubility or low membrane penetration potential, but also improvement or alteration of uptake and release of drugs, protection of sensitive active agents from degradation in the gastrointestinal tract, reduction of gastrointestinal side effects of non-steroidal anti-inflammatory drugs and even masking of bitter taste of orally applied drugs. Technological strategies to achieve these effects are highly diverse and offer various possibilities of liquid, semi-liquid and solid lipid-based formulations for drug delivery optimization.

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“…Combination studies with tacrolimus and sirolimus in established AA [16], and cyclosporin A and sirolimus in the developing AA model [91], have shown additive inhibitory effects, but not synergistic effects as observed in transplantation animal models [99]. The use of a two pronged attack (e.g.…”

Section: History Of Drug Therapy and Current Antiinflammatory And Immmentioning

confidence: 99%

“…tacrolimus inhibiting early activation at T cell receptors through the inhibition of calcineurin and the transcription of IL-2 and the expression of IL-2 receptors, and sirolimus blocking the proliferation of lymphocytes at the late Gl phase of the cell cycle by preventing the sirolimus effector protein from interacting with the p70 ribosomal S6 kinase or possibly autophosphorylation of PI3 kinase) would be a very exciting combination to try using alternate day, low-dose regimens for treating recalcitrant RA and preventing flares. Also, the prolonged efficacy of sirolimus in AA after dosing cessation may help reduce the accumulation of drug and therefore, reduce immunosuppressiverelated side-effects including infection and other compromised immune surveillance functions [16,88,91]. Overall, these animal models will help demonstrate to the clinicians a better and safer treatment for complicated autoimmune diseases like RA.…”

Section: History Of Drug Therapy and Current Antiinflammatory And Immmentioning

confidence: 99%