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K. Dean Reeves, M.D. Clinical Associate Professor Physical Medicine and Rehabilitation
Emphasis on Research in Use of Prolotherapy (Also called Regenerative Injection Therapy) ReevesOffice @ gmail.com Office Email DeanReevesMD @ gmail.com Personal email
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Dear Study Participants, Thank you very much to those who participated in the "Oral Hyaluronic Acid Knee Arthritis Study" at a dosage level of 2 mg per day. In summary, the two month data showed improvement in pain of 17% and 6 month data showed an improvement in pain of 28%. The 6 month data is encouraging in that a placebo typically does not improve pain that much. After the 6 month data was gathered, I approached my human subjects committee for approval for a dosage escalation study. Unfortunately the human subjects committee requested drug absorption studies which only formal drug companies can afford so I could not proceed at this time. I would also like to thank the sponsoring company which allowed this study to be conducted from my viewpoint in an unbiased fashion. Meanwhile the literature continues to grow on the importance of hyaluronic acid in growth and repair. I will certainly encourage more research on this important structure as I truly feel that at optimum dosage and time frame (both needing more study) that oral hyaluronic acid will be superior to glucosamine/ chrondroitin and able to affect more locations in the body than injectable hyaluronic acid. The liquid formulation has logical advantages in terms of absorption that need to be further studied as well. For those interested in obtaining hyaluronic acid I cannot ethically promote any particular product and much more research needs to be done. However, as a matter of record, the company that believed in their product enough to provide it for study is Hyalogic. Their web site is www.hyalogic.com and their number is 1-866-318-8484. Best regards, Dr. Reeves
Layman's Explanation Synthovial 7 is hyaluronic acid. Hyaluronic acid is a special protein that is the normal lubricant in human joints. When present in a joint, even a joint with minimal or no cartilage, it can provide a cushion effect. Hyaluronic acid in our joints is a long and complex molecule, and makes a ball shape which resists compression. However, with inflammation or other conditions the complex hyaluronic acid molecule breaks down to smaller pieces and is not effective in keeping a ball shape. Therefore it cannot provide a cushion of protection in the joint. Hyaluronic acid is also found in all connecting tissues of the body such as ligaments and tendons where it performs special functions of lubrication and helps orient ligament and tendon fibers. Synthovial 7 is classified as an oral supplement, not a drug, since it is exactly the same molecule found naturally throughout the body. Hyaluronic acid taken orally is usually degraded by stomach acid. A method of altering hyaluronic acid to prevent degradation in the stomach without altering its basic structure has been devised. Clinical benefit in patients with knee arthritis has been noted by informal observations. Hyaluronic acid as an oral supplement has substantial differences from glucosamine which is in common use. First, glucosamine is a modified simple sugar. Hyaluronic acid is a complex molecule with joint protective capability and a number of other properties that relate to its complexity. Although hyaluronic acid is complex, it is also 50% glucosamine, so that when it breaks down glucosamine is provided. Since Synthovial 7 is an oral supplement, it is not subject to FDA and safety data are not available. However, elimination studies indicate that the kidney and liver remove excess efficiently. Approximately 1500 humans and 3000 animals (horses, dogs) have received this particular oral hyaluronic acid. The longest anyone has taken oral hyaluronic acid up until now is 18 months. Benefit is usually noted within 1 week, and in some cases is delayed up to a month. Dosage comes as a liquid, and a dropper is used to place 10 drops per day (for study patients) into a cool beverage. The temperature of the beverage should not be more than 100 degrees. The product is clear and completely tasteless. No definite side effects have been observed, but both this and the amount of benefit to be expected from Synthovial 7 are reasons for the current study.
More Detail From Current Literature Hyaluronic acid is a large high molecular weight molecule that is critical, among other things, as a lubricant for joints. It is made up of a repetitive sequence of two modified simple sugars. Both simple sugars are modified glucose. One glucose has an acid group substituted on a carbon atom, and it is called glucuronic acid. The second glucose has an N acetyl group substituted on a carbon atom. It is called N acetyl glucosamine. Some of hyaluronic acid’s properties come from the negative charges of the repetitive glucuronic acids. These negative charges repel each other, causing the long molecule to stretch out. Molecules that are long and stretched out give a high viscosity (lubrication) effect even in dilute solution. Hyaluronic is a glycosaminoglycan, a name given to two simple sugars with a nitrogen-containing group on at least one of the sugars. (Zubay 1998) HA is an important glycosaminoglycan (GAG) present in all connective tissues. (Morales et al, 1997) Hyaluronic acid injection in knee osteoarthritis has been studied a number of times in double blind fashion. Only two studies have shown no clear benefit over placebo. One of these studies was short in duration (Henderson et al, 1994) and the other was long but used a low molecular weight hyaluronic acid. (Dahlberg et al, 1994) The remainder of studies showed statistically significant advantage of hyaluronic acid injection over placebo injection. (Grecomoro et al, 1987; Dixon et al, 1988; Dougados et al, 1993; Graf et al, 1993; Jones et al, 1995; Lohmander et al, 1996, Wu et al, 1997; Altman and Moskowtiz, 1998; Wobig et al, 1998; Huskisson et al, 1999.) Hyaluronic acid appears to have disease-modifying ability in osteoarthritis with injection. For example, a biopsy study in osteoarthritic knees injected with hyaluronic acid demonstrated reconstitution of the superficial layer of cartilage in areas and an improvement in density of cartilage cells. (Guidolin et al, 2001), and Frizziero also demonstrated improvement in cartilage lesions per biopsy. (Frizziero et al, 1998) In addition, an anti-inflammatory effect of hyaluronic acid injection has been demonstrated, with a decrease in inflammatory cells 6 months after a series of 5 interarticular injections. (Frizziero et al, 1998; Pasquali-Ronchetti et al, 2001) A reduction also occurs in interarticular levels of anti-cytokines such as leukotrienes and interleukin 1 beta and prostaglandin F2 alpha. (Hirota 1998) inflammatory type arthritis has also responded favorably to hyaluronic acid injection. (Emlen et al, 1996; Matsuno et al, 1999) Hyaluronic acid has been injected in other joints such as TMJ joints, with apparent clinical benefit. (Aplaslan et al, 2001) Hyaluronic acid is degraded when taken orally and so until recently must bypass the stomach in an injectable form. The hyaluronic acid type to be evaluated in this study represents a hyaluronic acid modification that allows it to avoid degradation/destruction in the stomach. The potential significance of oral hyaluronic acid is considerable:
The articular studies related to hyaluronic acid are referenced above. It is of interest, in terms of conveying safety of hyaluronic acid in human application, that non-articular applications of hyaluronic acid are showing up in diverse Medline literature. For example, several controlled studies have demonstrated that irrigation of the abdominal cavity with hyaluronic acid or placement of a bioabsorbable hyaluronic acid based membrane during open abdominal or pelvic surgery or laparoscopic surgery markedly reduces post-operative development of adhesions. (Becker, 1996; Beck, 1997; Diamond, 1998) Application of a hyaluronan-based biomembrane has also been shown to improve the healing of the mastoid cavity following "open" tympanoplasty. (Martini et al, 2000) In particular, re-epithelialization was significantly faster after the application of the biomembrane. Hyaluronic acid containing nasal cream is significantly better than cream vehicle alone in healing nasal sinus mucosa after sinus surgery. (Soldati et al, 1999) Hyaluronic acid based eye drops have been used in dry eyes and are significantly better than saline drops. (Condon, 1999; Papa, 2001) Although non-blinded, instillation of hyaluronic acid inside bladders with intractable interstitial cystitis, is receiving some attention. (Morales et al, 1997) There is even evidence that hyaluronic acid may stimulate neutrophil function and help to decrease the incidence of bacterial infection in bronchitis, and it has been given subcutaneously in such an endeavor, and found to be better than placebo in an initial study. (Venge, 1996) Hyaluronic Acid varies in its molecular weight and this is clinically significant with studies showing more benefit from higher molecular weight hyaluronic acid. (Wobig, 1999) This may be important in future study designs.The hyaluronic acid utilized in this study is a high molecular weight hyaluronic acid (HHA). This is an oral supplement that is being promoted on the Internet and is being taken by an increasingly large number of people. No formal studies have been performed. Thus the reason for this present study. Alpaslan GH, Alpaslan C. Efficacy of temporomandibular joint arthrocentesis with and without injection of sodium hyaluronate in treatment of internal derangements. J Oral Maxillofac Surg 2001 Jun;59(6):613-8; discussion 618-9. Altman RD, Moskowitz R.Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial. Hyalgan Study Group.J Rheumatol 1998 Nov;25(11):2203-12 Beck DE.The role of Seprafilm bioresorbable membrane in adhesion prevention.Eur J Surg Suppl 1997;(577):49-55 Becker JM, Dayton MT, Fazio VW, Beck DE, Stryker SJ, Wexner SD, Wolff BG, Roberts PL, Smith LE, Sweeney SA, Moore M.Prevention of postoperative abdominal adhesions by a sodium hyaluronate-based bioresorbable membrane: a prospective, randomized, double-blind multicenter study.J Am Coll Surg 1996 Oct;183(4):297-306 Condon PI, McEwen CG, Wright M, Mackintosh G, Prescott RJ, McDonald C. Double blind, randomised, placebo controlled, crossover, multicentre study to determine the efficacy of a 0.1% (w/v) sodium hyaluronate solution (Fermavisc) in the treatment of dry eye syndrome.Br J Ophthalmol 1999 Oct;83(10):1121-4 Dahlberg L, Lohmander LS, Ryd L. Intraarticular injections of hyaluronan in patients with cartilage abnormalities and knee pain. A one-year double-blind, placebo-controlled study.Arthritis Rheum 1994 Apr;37(4):521-8, Diamond MP.Reduction of de novo postsurgical adhesions by intraoperative precoating with Sepracoat (HAL-C) solution: a prospective, randomized, blinded, placebo-controlled multicenter study. The Sepracoat Adhesion Study Group.Fertil Steril 1998 Jun;69(6):1067-74 Dixon AS, Jacoby RK, Berry H, Hamilton EB. Clinical trial of intra-articular injection of sodium hyaluronate in patients with osteoarthritis of the knee. Curr Med Res Opin 1988;11(4):205-13 Dougados M; Nguyen M; Listrat V; Amor B High molecular weight sodium hyaluronate (hyalectin) in osteoarthritis of the knee: a 1 year placebo-controlled trial. Osteoarthritis Cartilage (England), Apr 1993, 1(2) p97-103 Emlen W, Niebur J, Flanders G, Rutledge J. Measurement of serum hyaluronic acid in patients with rheumatoid arthritis: correlation with disease activity.J Rheumatol 1996 Jun;23(6):974-8 Frizziero L, Govoni E, Bacchini P. Intra-articular hyaluronic acid in the treatment of osteoarthritis of the knee: clinical and morphological study.Clin Exp Rh eumatol 1998 Jul-Aug;16(4):441-9 Graf J, Neusel E, Schneider E, Niethard FU Intra-articular treatment with hyaluronic acid in osteoarthritis of the knee joint: a controlled clinical trial versus mucopolysaccharide polysulfuric acid ester.Clin Exp Rheumatol 1993 Jul-Aug;11(4):367-72 Grecomoro G, Martorana U, Di Marco C. Intra-articular treatment with sodium hyaluronate in gonarthrosis: a controlled clinical trial versus placebo.Pharmatherapeutica 1987;5(2):137-41 Guidolin DD, Ronchetti IP, Lini E, Guerra D, Frizziero L.Morphological analysis of articular cartilage biopsies from a randomized, clinical study comparing the effects of 500-730 kDa sodium hyaluronate (Hyalgan) and methylprednisolone acetate on primary osteoarthritis of the knee.Osteoarthritis Cartilage 2001 May;9(4):371-81 Henderson EB, Smith EC, Pegley F, Blake DR. Intra-articular injections of 750 kD hyaluronan in the treatment of osteoarthritis: a randomised single centre double-blind placebo-controlled trial of 91 patients demonstrating lack of efficacy.Ann Rheum Dis 1994 Aug;53(8):529-34 Hirota W. Intra-articular injection of hyaluronic acid reduces total amounts of leukotriene C4, 6-keto-prostaglandin F1alpha, prostaglandin F2alpha and interleukin-1beta in synovial fluid of patients with internal derangement in disorders of the temporomandibular joint.Br J Oral Maxillofac Surg 1998 Feb;36(1):35-8 Huskisson EC, Donnelly S. Hyaluronic acid in the treatment of osteoarthritis of the knee.Rheumatology (Oxford) 1999 Jul;38(7):602-7 Jones AC, Pattrick M, Doherty S, Doherty M. Intra-articular hyaluronic acid compared to intra-articular triamcinolone hexacetonide in inflammatory knee osteoarthritis.Osteoarthritis Cartilage 1995 Dec;3(4):269-73 Lohmander LS, Dalen N, Englund G, Hamalainen M, Jensen EM, Karlsson K, Odensten M, Ryd L, Sernbo I, Suomalainen O, Tegnander A. Intra-articular hyaluronan injections in the treatment of osteoarthritis of the knee: a randomised, double blind, placebo controlled multicentre trial. Hyaluronan Multicentre Trial Group. Ann Rheum Dis 1996 Jul;55(7):424-31 Martini A, Morra B, Aimoni C, Radice M. Use of a hyaluronan-based biomembrane in the treatment of chronic cholesteatomatous otitis media.Am J Otol 2000 Jul;21(4):468-73. Matsuno H, Yudoh K, Kondo M, Goto M, Kimura T. Biochemical effect of intra-articular injections of high molecular weight hyaluronate in rheumatoid arthritis patients.Inflamm Res 1999 Mar;48(3):154-9 Morales A, Emerson L, Nickel JC. Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. Urology 1997 May;49(5A Suppl):111-3 Papa V, Aragona P, Russo S, Di Bella A, Russo P, Milazzo G Comparison of hypotonic and isotonic solutions containing sodium hyaluronate on the symptomatic treatment of dry eye patients.Ophthalmologica 2001 Mar-Apr;215(2):124-7 Pasquali Ronchetti I, Guerra D, Taparelli F, Boraldi F, Bergamini G, Mori G, Zizzi F, Frizziero Morphological analysis of knee synovial membrane biopsies from a randomized controlled clinical study comparing the effects of sodium hyaluronate (Hyalgan) and methylprednisolone acetate (Depomedrol) in osteoarthritis. Rheumatology (Oxford) 2001 Feb;40(2):158-69 Soldati D, Rahm F, Pasche P. Mucosal wound healing after nasal surgery. A controlled clinical trial on the efficacy of hyaluronic acid containing cream. Drugs Exp Clin Res 1999;25(6):253-61 Venge P, Pedersen B, Hakansson L, Hallgren R, Lindblad G, Dahl R. Subcutaneous administration of hyaluronan reduces the number of infectious exacerbations in patients with chronic bronchitis.Am J Respir Crit Care Med 1996 Jan;153(1):312-6 Wobig M, Dickhut A, Maier R, Vetter G. Viscosupplementation with hylan G-F 20: a 26-week controlled trial of efficacy and safety in the osteoarthritic kneeClin Ther 1998 May-Jun;20(3):410-23 Wobig M, Bach G, Beks P, Dickhut A, Runzheimer J, Schwieger G, Vetter G, Balazs E. The role of elastoviscosity in the efficacy of viscosupplementation for osteoarthritis of the knee: a comparison of hylan G-F 20 and a lower-molecular-weight hyaluronan. Clin Ther 1999 Sep;21(9):1549-62 Wu JJ, Shih LY, Hsu HC, Chen TH. The double-blind test of sodium hyaluronate (ARTZ) on osteoarthritis knee.Chung Hua I Hsueh Tsa Chih (Taipei) 1997 Feb;59(2):99-106 Zubay G. Biochemistry 4th Edition 1998 William C Brown Dubuque IA 402-411
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