|Dr. Daniel Shoskes submitted a brief note and two abstracts:
|I have always had a bit of trouble with the idea that Elmiron
reconstitutes the bladder lining. Just because the bladder lining is
deficient in the GAG layer, which uses a heparin analogue as a building
block, doesn't automatically mean that sprinkling this building block
on the surface of the bladder would fix the problem. It also doesn't
explain the efficacy of Elmiron in some men (seen so far in unblinded
trials). The following recent paper suggests an alternate mechanism
which makes more sense to me. If so, it might be another mechanism
whereby the quercetin in Prosta-Q is effective.
Daniel Shoskes MD
Cleveland Clinic Florida
J Urol 2000 Dec;164(6):2119-25
Pentosanpolysulfate inhibits mast cell histamine secretion and
intracellular calcium ion levels: an alternative explanation of its
beneficial effect in interstitial cystitis.
Chiang G, Patra P, Letourneau R, Jeudy S, Boucher W, Green M, Sant GR,
Department of Pharmacology and Experimental Therapeutics, Tufts
University School of Medicine and Department of Urology, New England
Medical Center, Boston, Massachusetts.
[Medline record in process]
Mast cells are ubiquitous cells derived from the bone marrow
and are responsible for allergic reactions as they release numerous
vasodilatory, nociceptive and pro-inflammatory molecules in response to
immunoglobulin E (IgE) and specific antigen. Mast cell secretion is
also triggered by a number of peptides, such as bradykinin and
substance P, and may also be involved in the development of
|An example is interstitial cystitis, which is a
sterile painful bladder disorder that has been associated with a
defective glycosaminoglycan bladder mucosal layer and an increased
number of activated mast cells. Pentosanpolysulfate is a synthetic,
sulfated polysaccharide that has been approved for the treatment of
interstitial cystitis on the premise that it may replenish the
defective glycosaminoglycan layer.
|We hypothesize that
pentosanpolysulfate may also have an additional or alternate action on
bladder mast cells. We report that pentosanpolysulfate has a powerful
dose dependent inhibitory effect on mast cell release of histamine
induced by the mast cell secretagogue compound 48/80.
Inhibition of mast cell secretion was documented by light and
electron microscopy and extended to stimulation by substance P or IgE
The inhibition was more potent than that seen
with the clinically available mast cell stabilizer disodium
cromoglycate (cromolyn). Maximal inhibition by pentosanpolysulfate was
apparent within 1 minute, was unaffected by the length of
pre-incubation and persisted after the drug was washed off. In
contrast, the effect of cromolyn was limited by rapid tachyphylaxis. In
addition, while cromolyn has no effect on mucosal or rat basophilic
leukemia cells, pentosanpolysulfate inhibited histamine secretion from
both. Confocal microscopy using a calcium indicator dye showed that
pentosanpolysulfate decreased intracellular calcium ion levels.
Pentosanpolysulfate appears to be a potent inhibitor of
allergic and nonimmune mast cell stimulation, which is an alternative
explanation of its benefit in interstitial cystitis.
Effects of luteolin, quercetin and baicalein on immunoglobulin
E-mediated mediator release from human cultured mast cells.
Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N, Nagai H
Department of Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
Flavonoids have a variety of activities including
anti-allergic activities, and are known to inhibit histamine release
from human basophils and murine mast cells.
The effects of
luteolin, a flavone, on the immunoglobulin (Ig) E-mediated allergic
mediator release from human cultured mast cells (HCMCs) were
investigated and compared with those of baicalein and quercetin.
HCMCs were sensitized with IgE, and then treated with
flavonoids before challenge with antihuman IgE. The amount of released
mediators was determined as was mobilization of intracellular Ca2+
concentration, protein kinase C (PKC) translocation and phosphorylation
of intracellular proteins were detected after anti-IgE stimulation.
Luteolin, baicalein and quercetin inhibited the release of
histamine, leukotrienes (LTs), prostaglandin D2 (PGD2), and granulocyte
macrophage-colony stimulating factor (GM-CSF) from HCMC in a
concentration-dependent manner. Additionally, the three flavonoids
inhibited A23187-induced histamine release. As concerns Ca2+
signalling, luteolin and quercetin inhibited Ca2+ influx strongly,
although baicalein did slightly. With regard to PKC signalling,
luteolin and quercetin inhibited PKC translocation and PKC activity
strongly, although baicalein did slightly. The suppression of Ca2+ and
PKC signallings might contribute to the inhibition of mediator release.
|The activation of extracellular signal-regulated kinases (ERKs) and
c-Jun NH2-terminal kinase (JNK), that were activated just before the
release of LTs and PGD2 and GM-CSF mRNA expression in IgE-mediated
signal transduction events, were clearly suppressed by luteolin and
quercetin. In contrast, the flavonoids did not affect the activation of
p38 mitogen-activated protein kinase (p38 MAPK) pathway.
These results indicate that luteolin is a potent inhibitor of human
mast cell activation through the inhibition of Ca2+ influx and PKC
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