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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 endothe-lium 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 20mg, 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 40mg (for 3 weeks) and to a single injection of triamcinolone 40mg. 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.
Physical and Pharmacodynamic Properties, and Rationale for Clinical Use
Hyaluronic acid is a naturally occurring glycosaminoglycan which, by virtue of its viscosity, elasticity and other rheological properties, acts as a lubricating and shock absorbing fluid in joints and as an ocular lubricant. The compound also exerts some mediatory effects on cellular activity (see below). Hyaluronic acid is available in formulations of various molecular weight and concentration.
The physicochemical properties of high molecular weight hyaluronic acid provide the rationale for its use as an adjunct in ophthalmic surgery, in preventing collapse of the anterior chamber and facilitating manipulation of ocular tissues. Additionally, in animal models of cataract surgery invitro and in vivo, hyaluronic acid 1 to 3% protected corneal endothelium from cell damage caused by synthetic lenses. Although in animal studies hyaluronic acid was both more and less effective than hydroxypropylmethylcellulose 2%, and tended to be less effective than the combination product hyaluronic acid 3%/chondroitin sulphate 4%, in clinical trials hyaluronic acid showed a protective effect at least comparable to these agents. Exogenous hyaluronic acid binds to specific sites on corneal endothelium and inhibits free radical formation after surgical damage, suggesting several mechanisms are responsible for its protective effect on the cornea.
Inflammatory reactions and increases in intraocular pressure following instillation of hyaluronic acid in animals have also occurred in humans undergoing ophthalmological surgery (see Clinical Use and Tolerability).
The rationale for investigating hyaluronic acid as a therapy in patients with rheumatoid or Osteoarthritis rests partly on the premise that supplementation of synovial fluid with exogenous product (viscosupplementation) augments the diminished lubricating and cushioning properties of endogenous substance seen in these diseases. This is supported by significant increases in synovial fluid viscosity and hyaluronic acid concentration or molecular weight seen in some arthritic patients injected with intra-articular hyaluronic acid 1%. Importantly, some anti-inflammatory activity is also apparent for high molecular weight hyaluronic acid (< 5 x 105D), as demonstrated by its inhibitory effects on cellular mediators of inflammation in vitro, and by preliminary evidence of reduced synovial membrane inflammation in a few patients with Osteoarthritis after intra-articular hyaluronic acid 20mg for 5 weeks. Modification of cellular migration by hyaluronic acid may also contribute to its apparent beneficial effects on wound healing and tympanic membrane perforation in animals and humans.
Of great interest is the finding that high molecular weight hyaluronic acid (7.5 to 20 x 105D) appears to have some ability to repair or protect cartilage from the pathophysiological processes of arthritis in animal models, and there is limited evidence suggesting such an effect in small numbers of patients with Osteoarthritis. Whether hyaluronic acid exerts a true disease-modifying effect in humans and animals is controversial and awaits confirmation.
The pharmacokinetics of exogenously administered hyaluronic acid are poorly characterised in humans. Normal circulating serum hyaluronic acid levels are in the range 10 to 100 μg/L. Values are increased several-fold in patients with rheumatoid or Osteoarthritis in whom they correlate with clinical inflammatory signs. Hyaluronic acid is rapidly cleared from the systemic circulation, primarily through uptake by receptors on liver endothelium, and degraded to monosaccharides and their oxidation products. It is not catabolised in the eye to any significant extent, but is biotransformed by the liver after diffusion from the eye into plasma.
The elimination half-life (t1/2β) of hyaluronic acid has been calculated as 2.5 to 5.5 minutes in human plasma. As demonstrated in rabbits, the t1/2β in the eye is correlated with the volume of the formulation, but its relationship to molecular weight is equivocal. The contribution of urinary excretion to the elimination of hyaluronic acid in humans is low (μ1% of total clearance).
Application of hyaluronic acid 1% as a viscoelastic adjunct in cataract surgery is of proven value. Hyaluronic acid 1% permits manipulation of ocular tissues, maintains the anterior chamber and protects corneal endothelium from damage. In the published literature, comparisons of hyaluronic acid formulations have not identified clear differences between products for effects on intraocular pressure or endothelial cell loss, and similar results for these parameters were found for hyaluronic acid 1% when compared with hydroxypropylmethylcellulose 2%. All viscoelastic substances produce transient elevations in intraocular pressure peaking within 6 to 12 hours of injection and tending to normalise within 24 hours. It is generally agreed that these elevations are lessened by postoperative aspiration of the product.
Hyaluronic acid has been of some benefit in facilitating corneal transplantation, and in limited investigations was superior to balanced saline solution. When used as internal tamponade during retinal reattachment, particularly in patients without proliferative retinopathy, hyaluronic acid has yielded a success rate of about 50%; however, this decreases over time. Based on available studies, efficacy of hyaluronic acid is equivocal in preventing collapse of the anterior chamber or choroidal detachment in patients with glaucoma undergoing trabeculectomy. The only prospective trial in such patients demonstrated that hyaluronic acid 1% significantly increased bleb formation and decreased the need for timolol eye drops, compared with no treatment. In trauma surgery, use of hyaluronic acid 1% has improved outcome and facilitated removal of traumatic hyphaema. Additionally, hyaluronic acid has shown some promise in other ophthalmological indications such as dry eye and as a drug delivery vehicle.
In patients with Osteoarthritis, knee pain and joint motion were improved with hyaluronic acid 20mg injected intra-articularly weekly for up to 7 weeks. Benefits were generally greater than with placebo; however, 1 large trial reported as an abstract showed no differences between hyaluronic acid 20mg and placebo. In limited comparisons, efficacy of hyaluronic acid 20mg was similar to that of intra-articular methylprednisolone 40mg weekly for 3 weeks and triamcinolone 40mg as a single dose.
The interesting and consistent finding that improvements seen with hyaluronic acid persisted throughout follow-up periods of 2 months to 1 year after discontinuation of treatment, is potentially advantageous and merits further investigation. Other aspects of the clinical profile of hyaluronic acid worthy of pursuit are the possible additive effects of hyaluronic acid with corti-costeroids in patients with Osteoarthritis, and preliminary evidence of efficacy in a few patients with rheumatoid arthritis. Healing rates of about 50% in patients with tympanic membrane perforations treated with hyaluronic acid otically also require confirmation.
The tolerability of hyaluronic acid 1 % as a viscoelastic tool in ophthalmological surgery is very good. Hyaluronic acid is nonimmunogenic; a mild or moderate inflammatory response occurring in virtually all patients after intraocular injection is likely provoked to some extent by the surgical procedure rather than being solely attributable to the product. Transient elevations in intraocular pressure remain within clinically acceptable levels in the majority of patients. Tolerability profiles appear similar for various formulations of hyaluronic acid and in comparison with hydroxypropylmethylcellulose.
Although less experience has been gained with hyaluronic acid in patients with Osteoarthritis, present evidence indicates the agent is also well tolerated in this population. Pain and/or swelling after intra-articular injection have occurred in up to 37% of patients in clinical trials, but resolved spontaneously. In one well-designed trial the incidence of such local reactions was similar for hyaluronic acid 20mg (37% of patients) and placebo (39%). Long term investigations of up to 1 year have shown no unwanted systemic effects or alterations in standard laboratory tests. Local inflammatory reactions have been observed in about 15 to 20% of patients with ruptured tympanic membranes receiving otic hyaluronic acid formulations.
Dosage and Administration
Hyaluronic acid is administered as an ocular injection in concentrations of 1% or greater. Total volume used is less than 1ml during cataract and other anterior segment surgery, and 2 to 4ml during posterior segment procedures. To minimise risk of postoperative elevated intraocular pressure, aspiration of the product is recommended following the procedure. Patients with rheumatoid or Osteoarthritis have received intra-articular hyaluronic acid 20mg weekly for up to 7 weeks in clinical trials. For healing of tympanic membrane perforations, hyaluronic acid 1% (0.1 to 0.3ml) has been instilled daily for an average of 10 days.
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