Hyaluronic Acid Clinical Studies
Hyaluronic acid: a unique topical vehicle for the localized delivery
of drugs to the skin.
J Eur Acad Dermatol Venereol. 2005 May;19(3):308-18.
Hyaluronic acid is a naturally occurring polyanionic, polysaccharide
that consists of N-acetyl-d-glucosamine and beta-glucoronic acid. It
is present in the intercellular matrix of most vertebrate connective
tissues especially skin where it has a protective, structure
stabilizing and shock-absorbing role. The unique viscoelastic nature
of Hyaluronic acid along with its biocompatibility and non-immunogenicity
has led to its use in a number of clinical applications, which
include: the supplementation of joint fluid in arthritis; as a
surgical aid in eye surgery; and to facilitate the healing and
regeneration of surgical wounds. More recently, Hyaluronic acid has
been investigated as a drug delivery agent for various routes of
administration, including ophtalmic, nasal, pulmonary, parenteral and
topical. In fact, regulatory approval in the USA, Canada and Europe
was granted recently for 3% diclofenac in 2.5% Hyaluronic acid gel,
Solaraze(R), for the topical treatment of actinic keratoses, which is
the third most common skin complaint in the USA. The gel is well
tolerated, safe and efficacious and provides an attractive,
cost-effective alternative to cryoablation, curettage or dermabrasion,
or treatment with 5-fluorouracil. The purpose of this review is to
describe briefly the physical, chemical and biological properties of
Hyaluronic acid together with some details of its medical and
pharmaceutical uses with emphasis on this more recent topical
application.
Intra-articular hyaluronic acid for the treatment of osteoarthritis
of the knee: systematic review and meta-analysis.
CMAJ. 2005 Apr 12;172(8):1039-43.
Osteoarthritis of the knee affects up to 10% of the elderly
population. The condition is frequently treated by intra-articular
injection of hyaluronic acid. We performed a systematic review and
meta-analysis of randomized controlled trials to assess the
effectiveness of this treatment. We searched MEDLINE, EMBASE, CINAHL,
BIOSIS and the Cochrane Controlled Trial Register from inception until
April 2004 using a combination of search terms for knee osteoarthritis
and hyaluronic acid and a filter for randomized controlled trials. We
extracted data on pain at rest, pain during or immediately after
movement, joint function and adverse events. Twenty-two trials that
reported usable quantitative information on any of the predefined end
points were identified and included in the systematic review. Even
though pain at rest may be improved by hyaluronic acid, the data
available from these studies did not allow an appropriate assessment
of this end point. According to the currently available evidence,
intra-articular hyaluronic acid has not been proven clinically
effective and may be associated with a greater risk of adverse events.
Large trials with clinically relevant and uniform end points are
necessary to clarify the benefit-risk ratio.
Hyaluronic acid for the treatment of knee osteoarthritis: long-term
outcomes from a naturalistic primary care experience.
Am J Phys Med Rehabil. 2005 Apr;84(4):278-83; quiz 284, 293.
Petrella RJ. Department of Family Medicine, University of Western
Ontario, Ontario, Canada.
Intraarticular hyaluronic acid is indicated for patients with
osteoarthritis of the knee. However, clinical experience, especially
efficacy and adverse events, with repeated injection series in the
long term are limited. DESIGN: Patients were referred to a large
primary care center for management of osteoarthritis of the knee. All
were naive to intraarticular hyaluronic acid therapy and met our entry
criteria, including resting visual analog scale pain of > 45 mm,
radiographic confirmation of unilateral knee grade 1-3 osteoarthritis,
and willingness to receive intraarticular therapy. Patients received a
three-intraarticular injection series with Suplasyn (10 mg/ml, 2-ml
injection) over 3 wks. CONCLUSIONS: Intraarticular hyaluronic acid
injections were highly effective in improving resting and walking pain
in patients with osteoarthritis of the knee on a first and a second
treatment series. Duration of symptom control was about 6 mos, and the
therapy was highly satisfactory to patients and was associated with
very few local adverse events and limited use of concomitant
therapeutic modalities. These data support the potential role of
intraarticular hyaluronic acid as an effective long-term therapeutic
option for patients with osteoarthritis of the knee.
A double blind, randomized, multicenter, parallel group study of
the effectiveness and tolerance of intraarticular hyaluronan in
osteoarthritis of the knee.
J Rheumatol. 2004 Apr;31(4):775-82.
To investigate the efficacy and tolerability of a course of 5
injections of hyaluronan ( HA or hyaluronic acid ) given at intervals
of one week in patients with symptomatic, mild to moderate
osteoarthritis (OA) of the knee. A double blind, randomized, parallel
group, multicenter (17 centers), saline vehicle-controlled study was
conducted over 18 weeks. Patients received either 25 mg (2.5 ml)
hyaluronic acid in a phosphate buffered solution or 2.5 ml vehicle
containing only the buffer by intraarticular injection. Five
injections were given at one week intervals and the patients were
followed for a further 13 weeks. Of 240 patients randomized for
inclusion in the study, 223 were evaluable for the modified intention
to treat analysis. The hyaluronic acid treatment and control groups
were comparable for demographic details, OA history, and previous
treatments. Scores for the pain and stiffness were modestly but
significantly lower in the hyaluronic acid -treated group overall and
the statistically significant difference from the control was not
apparent until after the series of injections was complete. The
physical function subscale did not reach statistical significance.
Tolerability of the procedure was good and there were no serious
adverse events that were considered to have a possible causal
relationship with hyaluronic acid. CONCLUSION: Intraarticular
hyaluronic acid treatment was significantly more effective than saline
vehicle in mild to moderate OA of the knee for the 13 week
postinjection period of the study.
Intra-articular hyaluranic acid compared with progressive knee
exercises in osteoarthritis of the knee: a prospective randomized
trial with long-term follow-up.
Rheumatol Int. 2005 Mar 18;
The goal
of this study was to determine whether hyaluronic acid or progressive
knee exercises (PE) can improve functional parameters in patients with
osteoarthritis (OA) of the knee. In a prospective clinical trial 200
knees (105 patients) with radiographic Kellgren Lawrence grade III OA
were randomized and received either three intra-articular injections
of hyaluronic acid (Hylan G-F 20) at one-week intervals or PE for 6
weeks. Patients were evaluated by use of the Hospital for Special
Surgery (HSS) Knee Score and followed-up for 18 months. Total HSS
score for hyaluronic acid and PE patients improved from 62.6+/-13.8 to
88.8+/-11.1 and from 65.4+/-12.3 to 88.3+/-9.1, respectively, at the
end of the trial (P<0.01). There were no statistically significant
differences between the groups. Twenty-one patients of the hyaluronic
acid group were excluded from the study because they had received
another form of therapy. All patients in the PE group completed the
trial. The patients who dropped out had also significant improvement.
This prospective randomized trial confirmed that both hyaluronic acid
injections and PE result in functional improvement. Hyaluronic acid
injections also increase the levels of satisfaction of the OA
patients.
A one-year, randomised, placebo (saline) controlled clinical trial
of 500-730 kDa sodium hyaluronate (Hyalgan, Hyaluronic acid) on the
radiological change in osteoarthritis of the knee.
Int J Clin Pract. 2003 Jul-Aug;57(6):467-74.
The primary objective of this study was to investigate structural
changes, as measured by joint space narrowing (JSN), within the knee
joint during treatment with intra-articular sodium hyaluronate (
Hyaluronic acid ) of molecular weight 500-730 kDa in patients with
osteoarthritis (OA) of the knee. Patients received a weekly intra-articular
injection of either 20 mg2/ml Hyaluronic acid or a 2 ml vehicle
placebo (saline) for three weeks. This course was repeated twice more
at four-monthly intervals. Concomitant treatment with analgesics or
NSAIDs was allowed. The primary efficacy measure was the reduction in
mean joint space width (JSW) of the medial compartment at 52 weeks. A
total of 408 patients were randomised and 319 completed the one-year
study (Hyaluronic acid: n=160, placebo: n=159); 273 of the 319 were
included in the primary analysis. Analysis of variance on these 273
patients did not show a statistically significant difference between
the two treatment groups. However, there was a significant difference
in response to treatment in terms of the baseline JSW (p=0.01),
indicating that outcome of treatment may depend on-baseline JSW.
Therefore, a subgroup analysis by baseline JSW was conducted. This
compared patients with a JSW >4.6 mm with those with a JSW <4.6
mm. In those with radiologically milder disease at baseline and
receiving Hyaluronic acid, the JSN was significantly reduced compared
with placebo (p=0.02). In patients with radiologically more severe
disease there was no difference in JSN between the two treatments.
Although, in this one-year study, no overall treatment effect was
seen, those with radiologically milder disease at baseline had less
progression of joint space narrowing when treated with Hyaluronic
acid.
Treatment of gingivitis with hyaluronan ( hyaluronic acid ).
J Clin Periodontol. 2003 Feb;30(2):159-64.
Hyaluronic acid (hyaluronan) is a glycosaminoglycan with
anti-inflammatory and antiedematous properties. It was evaluated in a
gel formulation for its effect in the treatment of plaque-induced
gingivitis. METHOD: In a randomised double-blind study, 50 male
subjects with plaque-induced gingivitis were divided into two groups
and used a verum or placebo gel twice daily additionally to oral
hygiene for a 3-week treatment period. Clinical indices (API, Turesky
index, PBI) and crevicular fluid variables (peroxidase, lysozyme) were
determined at baseline and after 4, 7, 14 and 21 days, respectively.
Significant improvements could be found for all clinical variables in
both groups. The Hyaluronic acid group showed significant improvement
in the study area for the plaque indices beginning with day 4 and the
PBI beginning with day 7in comparison with the placebo group. The
crevicular fluid variables were significantly improved in the centre
of the studied inflammation area in the Hyaluronic acid group. Here
all studied sites had significant decreases in peroxidase and lysozyme
activities after 7, 14 and 21 days, whereas in the placebo group only
one site showed a significant decrease for lysozyme after 7 and 21
days. These data suggest that a Hyaluronic acid containing gel has a
beneficial effect in the treatment of plaque-induced gingivitis.
Comparison of two hyaluronan drugs and placebo in patients with
knee osteoarthritis. A controlled, randomized, double-blind,
parallel-design multicentre study.
Rheumatology (Oxford). 2002 Nov;41(11):1240-8.
To compare the efficacy and safety of intra-articular injections of
two different hyaluronan ( hyaluronic acid ) preparations and placebo
in patients with knee osteoarthritis. In a randomized, patient- and
observer-blind, placebo-controlled and multicentre trial with parallel
groups, 210 patients, aged 60 yr or above, with knee osteoarthritis
were included in a per protocol analysis. The patients were treated
with three injections, once weekly, of either native
high-molecular-weight hyaluronan (Artzal((R))) or cross-linked
hyaluronan (Synvisc) or with placebo and were followed for 52 weeks.
The primary efficacy measures were weight-bearing pain during study
weeks 0-26 and the duration of clinical benefit measured with
Kaplan-Meier survival analysis for weeks 0-52. The secondary outcome
measures were resting and maximum pain, Lequesne index, WOMAC (Western
Ontario and McMaster University Osteoarthritis Index) and SF-36
(Medical Outcomes Study Short Form Health Survey) scores. RESULTS: The
intra-articular injections produced a significant reduction in
weight-bearing pain, resting pain, maximum pain and Lequesne and WOMAC
scores after 26 weeks. There were no significant differences in
outcome between any of the three study groups during the first 26
weeks. In direct comparison against placebo for weeks 0-52, neither
hyaluronan treatment (Artzal or Synvisc) showed a significantly longer
duration of clinical benefit than placebo. However, when data for the
two hyaluronan-treated groups were pooled, treatment with hyaluronan
had a significantly longer duration of benefit compared with placebo
(P = 0.047). CONCLUSION: Patients with knee osteoarthritis who were
treated by injection into the knee of either of two hyaluronan
preparations or placebo showed clinical improvement during the first
26 weeks of treatment, though neither hyaluronan preparation gave a
longer duration of clinical benefit than placebo. However, when data
for the two hyaluronan treatments were pooled, there was a
significantly longer duration of clinical benefit for hyaluronan
treatment than for placebo.
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