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TREATMENT AND PREVENTION OF LIPODERMATOSCLEROSIS
The present invention relates to the use of iron scavenging compounds
for the preparation of compositions for use in the treatment and
prevention oflipodermatosclerosis.
In the United Kingdom,10-20% of the adult population is affected by
the complications of venous disease, including deep vein thrombosis,
varicose veins,lipodermatosclerosis and venous ulceration.
Approximately 50% of all venous ulcers are present for periods greater
than nine months and two-thirds are recurrent. Venous problems are not
only limited to the elderly, since greater than 40% of patients form
venous ulcers before the age of 50. Venous disease consumes
approximately 2% of the total annual healthcare budget in the UK.
In patients with venous disease, the valves in the veins of the lower
limb become incompetent, generally due to deep vein thrombosis and/or
superficial vein incompetence, resulting in venous hypertension on
exercise and the retrograde flow of blood through the superficial
venous system (venous reflux) to the blood vessels in the skin.
Chronic venous disease often progresses from defective valves and the
appearance of varicose veins, to the development of skin changes in
the lower leg and finally to the formation of venous ulcers. Despite
the frequency of venous disease, surprisingly little is understood of
the mechanisms by which chronic venous hypertension leads to venous
ulceration.
Many patients with venous insufficiency develop skin changes in the
lower leg known aslipodermatosclerosis (LDS). LDS is also known as
hypodermitis sclerodermaformis,liposclerosis, hypodermatosclerosis
sclerodermoformis,lipomembranous change in chronic panniculitis
andsclerosing panniculitis. LDS skin is characterised by skin
induration or thickening and brown pigmentation caused by haemosiderin
deposition. These features often occur in skin before ulceration as
well as in skin surrounding an ulcer. The degree of skin thickening
(induration or fibrosis) is thought to be directly related to venous
ulcer formation and subsequently delayed healing. Removal of the
fibrotic LDS skin surrounding venous ulcers by debridement often leads
to increased ulcer healing. Treatment of this problem has for many
years relied on established principles of compression and limb
elevation and drug treatment has been of little benefit. Yet there is
clearly a role for drugs in the management of venous disease either
alone or in combination with compression therapy. It is likely to be
beneficial to intervene in the initial processes that cause the
lipodermatosclerotic skin changes leading to ulceration rather than to
modify the repair processes when an ulcer has formed.
The same processes that caused the ulcer are likely to contribute to
its perpetuation and delayed healing.
The present invention relates to the inhibition of the effects of
excess iron deposition in the skin following chronic venous
insufficiency. The present inventors have found that excess iron may
have a much larger influence on the early stages
oflipodermatosclerosis than previously thought.
During venous insufficiency, repeated damage of cutaneous blood
vessels due to venous hypertension, causes the leakage of blood
proteins and erythrocytes. The damaged erythrocytes deposited in the
interstitial tissue are thought to be cleared by dermal macrophages
and the iron derived from haemoglobin stored within the cells as
ferritin and in haemosiderin granules.
Ackermanet al., in 1988 performed x-ray spectrometry, a method based
on x-ray fluorescence analysis, for non-invasive determination of iron
levels in the skin of sixteen patients with venous ulceration. The
mean ( SEM) iron concentration in the skin around the venous ulcer was
elevated, compared with control values ofnonulcerated skin(25054 vs
12839ug) and compared with normal skin from the forearm (25054 vs142.
5, ug). This group suggested that dermal iron deposition may not be an
incidental by-product of increased venous pressure, but may actively
perpetuate tissue damage in venous ulcerations. However, attempts to
treat venous ulcers with inhibitors of the effects of excess iron have
not been overly effective. The present inventors have found that there
is little evidence of haemosiderin deposition in ulcer base tissue. It
is thought that elevated levels of iron in ulcer wound fluid may be
due to iron leaching into the wound fluid, rather than to iron
accumulation in the ulcer tissue itself.
It is known that dissolved iron in high concentrations is cytotoxic
because the iron catalyses the formation of oxygen free radicals. The
present inventors have found that even quite low concentrations of
iron below the threshold for cytotoxicity can cause increased collagen
production which may explain the fibrotic skin changes seen in LDS. It
therefore seems that low levels of dissolved iron play an important
part in the early stages of venous disease, in particular the fibrotic
stages oflipodermatosclerosis. It further appears that removal or
sequestering of dissolved iron could be an effective method to prevent
or treat the fibrotic symptoms oflipodermatosclerosis.
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Tom
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Iron scavenging compounds in venous disease 
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