Note: hyaluronic acid and hyaluronan are used
interchangeably.
Ciba Found Symp. 1989;143:41-53; discussion
53-59, 281-285.
Turnover and metabolism of hyaluronan.
Fraser JR, Laurent TC.
Department of Medicine, University of Melbourne, Parkville,
Victoria, Australia.
The highest concentrations of hyaluronan occur in synovial
fluid, vitreous body, skin and certain specialized tissues such
as umbilical cord and rooster comb, during fetal development,
and in tissue repair and regeneration. The largest amounts are
found in the intercellular matrix of skin and musculoskeletal
tissues. Turnover in the bloodstream is normally in the range of
0.3-1.0 microgram min-1/kg body weight. Circulating hyaluronan
is mostly derived from lymph. Lymph nodes may nevertheless
extract as much as 80-90% from peripheral lymph before it can
reach the bloodstream. Turnover in peripheral tissues may be
effected by degradation in situ, or by transfer into lymph by
diffusion or hydrodynamic forces. Hyaluronan is firmly bound in
specific association with cells or binding proteins but much of
it exists in freely mobilized compartments with a half-life of
two days or less, and it is metabolized after transport
elsewhere. Metabolic degradation of hyaluronan is principally
intracellular and relies on uptake by a receptor which, in
contrast with other hyaluronan-binding structures, also binds
chondroitin sulphate. It is suggested that this dual specificity
may be primarily associated with metabolic degradation of
hyaluronan. Uptake and metabolism are primarily effected in
liver and lymph node by endothelial cells lining the sinusoids
of each. Further studies indicate that in lymph nodes and in
spleen, macrophage-like cells intertwined with the endothelial
cells also take up hyaluronan. The metabolic cycle from polymer
to monosaccharides, acetate and beyond can be completed in vivo
within 10 minutes.
Drugs. 1994 Mar;47(3):536-66.
Hyaluronic acid. A review of its pharmacology and use as a
surgical aid in ophthalmology, and its therapeutic potential in
joint disease and wound healing.
Goa KL, Benfield P.
Adis International Limited, Auckland, New Zealand.
Hyaluronic acid is a naturally occurring polysaccharide with
distinct physicochemical properties which underlie its
application as a viscoelastic tool in ophthalmological surgery.
In cataract surgery the role of hyaluronic acid in facilitating
procedures and protecting the corneal endothelium is well
established. Some benefit has also been gained with the use of
hyaluronic acid in penetrating keratoplasty, trabeculectomy,
retinal reattachment and trauma surgery, although its efficacy
in these indications is less well-defined in the published
literature. In addition to its lubricating and cushioning
properties, demonstration of some in vitro anti-inflammatory
activity and a possible disease-modifying effect for hyaluronic
acid in animals has prompted its investigation as a treatment in
osteoarthritis and, to a much lesser extent, in rheumatoid
arthritis. Hyaluronic acid 20 mg, as weekly intra-articular
injections for 3 to 7 weeks, improved knee pain and joint motion
in patients with osteoarthritis. Although this occurred to a
greater degree than with placebo in most comparisons, the
effects of hyaluronic acid was similar to those of placebo in
the largest trial. In the few available comparisons with other
agents, hyaluronic acid appeared equivalent to
methylprednisolone 40 mg (for 3 weeks) and to a single injection
of triamcinolone 40 mg. Hyaluronic acid was distinguished from
other therapies by providing a sustained effect after treatment
discontinuation. Together with its very good tolerability
profile, these properties justify further study of hyaluronic
acid in patients with osteoarthritis. Some limited evidence of
improvement in patients with rheumatoid arthritis, and a
possible healing effect of hyaluronic acid on tympanic membrane
perforations, represent additional areas of interest for future
investigation. In summary, hyaluronic acid is a well-established
adjunct to cataract surgery and may prove to be a promising
option in the treatment of patients with osteoarthritis. Its
very good tolerability provides further impetus for examination
of its potential role in an extended scope of arthritic and
ophthalmological indications, and in wound healing.
Exp Lung Res. 1997 May-Jun;23(3):229-244.
Further investigation of the use of intratracheally
administered hyaluronic acid to ameliorate elastase-induced
emphysema.
Cantor JO, Cerreta JM, Armand G, Turino
GM.
Columbia University College of Physicians and Surgeons, New
York, New York, USA.
Previously, this laboratory has shown that intratracheally
administered hyaluronic acid (HA) significantly reduces
air-space enlargement in a hamster model of emphysema induced
with pancreatic elastase. Whereas HA was given immediately
following elastase in those initial studies, the current
investigation determined the effect of instilling HA up to 2 h
before or after intratracheal administration of elastase to
hamsters. Both 1 and 2 mg HA, given 2 h before pancreatic
elastase, significantly decreased (p < .05) air-space
enlargement compared to controls (as measured by the mean linear
intercept). Instillment of 2 mg HA, 1 h after pancreatic
elastase, had a similar effect (p < .05). In contrast, 1 mg HA,
given 1 or 2 h after pancreatic elastase, did not significantly
affect the mean linear intercept. Against human neutrophil
elastase, HA exhibited the same protective effect. While
neutrophil elastase induced less air-space enlargement than
pancreatic elastase, both 1 and 4 mg of HA, given 2 h prior to
the enzyme, still produced a significant reduction (p < .05) in
the mean linear intercept. HA exerted this effect despite the
fact that it initiates a transient influx of neutrophils into
the lung. Since HA does not slow the clearance of
intratracheally instilled [14C] albumin from the lung, its
mechanism of action may not involve physical interference with
the movement of elastase through the lung, but may instead
depend on interaction with elastic fibers. Evidence for an
association between these two matrix constituents was provided
by studies using fluorescein-labeled HA. Overall, these results
further suggest that HA may be useful in preventing lung injury
by elastases.
Br J Ophthalmol. 1997 Jul;81(7):533-6.
Effectiveness of hyaluronan on corneal epithelial barrier
function in dry eye.
Yokoi N, Komuro A, Nishida K, Kinoshita
S.
Department of Ophthalmology, Kyoto Prefectural University of
Medicine, Japan.
AIMS/BACKGROUND: The aim of this study was to assess
quantitatively the effectiveness of hyaluronan on corneal
disruption in patients with dry eye. Corneal epithelial barrier
function was evaluated by measuring fluorescein permeability
using a slit-lamp fluorophotometer. METHODS: 11 patients with
dry eye were assigned to this study. Hyaluronan ophthalmic
solution (0.1% hyaluronic acid) was instilled five times a day
to the right eye, in addition to the usual artificial tear
solutions. The left eye received only the artificial tear
solutions. Corneal barrier function was evaluated on the
pretreatment day, and at 2 and 4 weeks after treatment.
Fluorophotometry was used to measure fluorescein uptake at the
central and lower corneal portions. RESULTS: Two weeks after
treatment, hyaluronan treated right corneas showed significant
corneal epithelial barrier improvement in the lower portion,
compared with the pretreatment day (p < 0.025). Four weeks after
treatment, the treated corneas showed significant improvement in
the central corneal portion (p < 0.025) and improvement in the
lower portion, compared with the pretreatment day. The untreated
left corneas, on the other hand showed no improvement during the
course of the study. CONCLUSION: This study suggests that
hyaluronan is effective in the treatment of corneal epithelial
disruption in dry eye.
J Invest Dermatol. 1999 Nov;113(5):740-6.
Absorption of hyaluronan applied to the surface of intact
skin.
Brown TJ, Alcorn D, Fraser JR.
Department of Biochemistry and Molecular Biology, Monash
University, Melbourne, Victoria, Australia.
Hyaluronan has recently been introduced as a vehicle for topical
application of drugs to the skin. We sought to determine whether
hyaluronan acts solely as a hydrophilic reservoir on the surface
of intact skin or might partly penetrate it. Drug-free
hyaluronan gels were applied to the intact skin of hairless mice
and human forearm in situ, with and without [3H] hyaluronan.
[3H]hyaluronan was shown by autoradiography to disseminate
through all layers of intact skin in mouse and human, reaching
the dermis within 30 min of application in mice. Cellular uptake
of [3H]hyaluronan was observed in the deeper layers of
epidermis, dermis, and in lymphatic endothelium. Absorption
through skin was confirmed in mice by chromatographic analysis
of blood, urine, and extracts from skin and liver, which
identified 3H as intact hyaluronan and its metabolites, free
acetate and water. Hyaluronan absorption was similarly
demonstrated without polyethylene glycol, which is usually
included in the topical formulation.
[3H]hyaluronan absorption
was not restricted to its smaller polymers as demonstrated by
the recovery of polymers of (360-400 kDa) from both blood and
skin. This finding suggests that its passage through epidermis
does not rely on passive diffusion but may be facilitated by
active transport.
This study establishes that hyaluronan is
absorbed from the surface of the skin and passes rapidly through
epidermis, which may allow associated drugs to be carried in
relatively high concentration at least as far as the deeper
layers of the dermis.
Am J Orthop. 2000 Feb;29(2):80-8;
discussion 88-9.
Viscosupplementation for osteoarthritis
Wright KE, Maurer SG, Di Cesare PE.
Musculoskeletal Research Center, Department of Orthopaedic
Surgery, Hospital for Joint Diseases Orthopaedic Institute, New
York, New York, USA.
Viscosupplementation therapy can restore the elastic and viscous
properties of synovial fluid and thus recreate the intra-articular
joint homeostasis that is disrupted in the degenerative joint.
Hyaluronan (hyaluronic acid) products have been developed and
used for viscosupplementation therapy in osteoarthritis.
Viscosupplementation treatments using these products are well
tolerated. Because viscosupplementation therapy is based on the
concept of replenishing a normal physiological component of
synovial fluid and cartilaginous tissue, exogenous
administration of hyaluronic acid has the potential to have few
side effects or local or systemic reactions.
Viscosupplementation represents an
alternative treatment for patients with osteoarthritis in which
oral medications and/or surgery are not options or are
ineffective.
Clinical Study Shows Hyaluronic Acid in Biocell Collagen II®
Found To Have Significant Absorption and Bioavailability
NEWPORT BEACH,
Ca., February 3, 2004– BioCell Technology LLC, the exclusive
suppliers of the Patented BioCell Collagen II® ingredient,
released results from a double blind clinical study proving that
the naturally occurring Hyaluronic Acid (HA) in the BioCell
Collagen II® product has significant peak absorption and steady
state bioavailability in normal volunteer subjects. Dr. William
Judy, senior scientist at SIBR Research, called the study
“groundbreaking science” and noted BioCell Technology’s
revolutionary form of a reduced molecular weight HA manufactured
using patented technology, is absorbed and is therefore readily
available for use by the body. This is in contrast to previous
published studies which showed that other HA forms were not
absorbed and thus unavailable for use by the human body,
In a 36-hour
peak absorption study using a single dose, BioCell Collagen II®
HA significantly increased in the blood in four hours and peaked
at a level 7008.62% above control in twelve (12) hours
(P≤0.05). In the blood, HA was rapidly metabolized to two
metabolites 1/600th the size of the ingested HA.
In a 28-day
steady state bioavailability study using a constant daily dose,
after seven (7) days, BioCell Collagen II® HA and its
metabolites in the blood became stable, and these metabolites
remained significantly increased (p≤0.001) throughout the
balance of the study (HA at 3542.58% above control and HA
metabolite at 11890.15% above control).
“This
unprecedented study on hyaluronic acid, a key element in the
unique matrix of BioCell Collagen II® which consists of Collagen
Type II, Chondroitin Sulfate, and Hyaluronic Acid, demonstrates
a synergistic effect that allows for the impressive absorption
as indicated in these exciting and promising studies. BioCell
Technology has expanded its intellectual property profile and
has a patent pending to cover oral and topical applications of
hyaluronic acid derived from various natural sources for use in
dietary supplements and cosmetics,” said Suhail Ishaq, Vice
President of BioCell Technology, LLC.
By
determining the rate and magnitude of HA absorption and its
bioavailability, this study using the BioCell Collagen II®
product clearly demonstrates that this HA form has the physical
characteristics necessary to allow it and its metabolites to
move rapidly from the blood to the tissues. These findings
further support the previous documented efficacy of BioCell
Collagen II® in the management of joint and skin care.
Research Shows Oral Delivery of Hyaluronan Absorbs
Effectively in Joints
Findings
Could Impact Burgeoning Joint Care Supplement Category
Washington. D.C., April 18, 2004 – A consortium of scientists
released clinical research results about oral delivery of
radiolabeled Hyaluronan (HA) and its ability to be taken up by
joints. Dr. Alex Schauss, Director of AIBMR, presented the findings
at the 2004 Experimental Biology conference, conducted by the
Federation of American Societies for Experimental Biology.
Hyaluronan has been used for years in veterinary and human
medicine as an injection to replace lost joint fluid.
The study
was led by Dr. Schauss and conducted by a consortium of scientists
from the Life Sciences Division of the American Institute for
Biosocial and Medical Research Inc. in Puyallup, Washington and
the National “FJC” Research Institute for Radiobiology and
Radiohygiene, National Institute for Health in Budapest,
Hungary. The research was supported by Weider Nutrition
International.
“This is the
first time hyaluronic acid has been reported to be absorbed
orally, which paves the way for HA dietary supplements to be
introduced and deliver on anti-aging and joint health promises,”
said Dr. Luke Bucci, Ph.D., Vice President of Research for
Weider Nutrition International.
Until now,
there was no data on pharmacokinetics after oral intake and the
therapeutic use of hyaluronic acid was limited to injections or
topical applications. The results of this study, which examined
the absorption, excretion and distribution of radiolabeled HA
after a single oral administration in Wistar rats and Beagle
dogs, demonstrated that HA is absorbed and distributed to organs
and joints after a single oral administration.
An abstract with complete research details
was published in the April
issue of FASEB Journal.
