Clinical Research Using DONA®
Dona® is the original Crystalline Glucosamine Sulfate that has been shown effective in clinical studies to help maintain the normal function of cartilage, while supporting healthy joint function, mobility, and flexibility. It is supported by product-specific clinical data and has been evaluated in over 7,000 patients with joint discomfort in over 25 clinical trials.
Dona® is not your everyday Glucosamine Sulfate. It is different than what you may find in stores or online today. Dona® contains a specific type of glucosamine sulfate developed and sold in more than 60 countries around the world. Dona® is a stable form of glucosamine which is able to reach the joints in the right concentration. Dona® is also the only glucosamine endorsed by the Cochrane Review 2009 and is recommended by the ESCEO algorithm for joint health management.
Crystalline Glucosamine Sulfate is a formulation invented and patented by RottaPharm. It presents a method to stabilize glucosamine sulfate, through a chemical process of co-precipitation with sodium chloride, thus obtaining Crystalline Glucosamine Sulfate.
Below are some of the major scientific publications using Dona®.
Glucosamine Sulfate Use and Delay
of Progression of Knee Osteoarthritis
Conventional symptomatic treatments for osteoarthritis do not favorably affect disease progression. The aim of this randomized, placebo-controlled trial was to determine whether long-term (3-year) treatment with glucosamine sulfate can modify the progression of joint structure and symptom changes in knee osteoar- thritis, as previously suggested.
Two hundred two patients with knee osteoarthritis (using American College of Rheumatology criteria) were randomized to receive oral glucosamine sulfate, 1500 mg once a day, or placebo. Changes in radiographic minimum joint space width were measured in the medial compartment of the tibiofemoral joint, and symptoms were assessed using the algo-functional in- dexes of Lequesne and WOMAC (Western Ontario and McMaster Universities).
Osteoarthritis was of mild to moderate severity at enrollment, with average joint space widths of slightly less than 4 mm and a Lequesne index score of less than 9 points. Progressive joint space narrowing with placebo use was −0.19 mm (95% confidence interval, −0.29 to −0.09 mm) after 3 years.
Osteoarthritis was of mild to moderate severity at enrollment, with average joint space widths of slightly less than 4 mm and a Lequesne index score of less than 9 points. Progressive joint space narrowing with placebo use was −0.19 mm (95% confidence interval, −0.29 to −0.09 mm) after 3 years. Conversely, there was no average change with glucosamine sulfate use (0.04 mm; 95% confidence interval, −0.06 to 0.14 mm), with a significant difference between groups (P=.001). Fewer patients treated with glucosamine sulfate experienced predefined severe narrowings (>0.5 mm): 5% vs 14% (P =.05). Symptoms im- proved modestly with placebo use but as much as 20% to 25% with glucosamine sulfate use, with significant final dif- ferences on the Lequesne index and the WOMAC total index and pain, function, and stiffnetss subscales. Safety was good and without differences between groups.
Figure 2. Joint space narrowing in patients completing each year of the study. The number of evaluable patients in the placebo and glucosamine sulfate groups, respectively, was 84 and 83 at year 1, 57 and 68 at year 2, and 55 and 65 at year 3. Error bars represent SEM. Asterisk indicates P≤.05 vs placebo; dagger, P < .01 vs placebo.
Figure 7. Intent-to-treat Lequesne index score mean change at clinic visits throughout the study. Analysis of variance for repeated measures: P =.004 between treatments. Error bars represent SEM.
Long-term treatment with glucosamine sulfate retarded the progression of knee osteoarthritis, possibly determining disease modification.
Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: evidence from two 3-year studies
To investigate the effect of glucosamine sulfate on long-term symptoms and structure progression in postmenopausal women with knee osteoarthritis (OA).
This study consisted of a preplanned combination of two three-year, randomized, placebo-controlled, prospective, independent studies evaluating the effect of glucosamine sulfate on symptoms and structure modification in OA and post-hoc analysis of the results obtained in post- menopausal women with knee OA. Minimal joint space width was assessed at baseline and after 3 years from standing anteroposterior knee radiographs. Symptoms were scored by the algo- functional WOMAC index at baseline and after 3 years. All primary statistical analyses were per- formed in intention-to-treat, comparing joint space width and WOMAC changes between groups by ANOVA.
Of 414 participants randomized in the two studies, 319 were postmenopausal women. At baseline, glucosamine sulfate and placebo groups were comparable for demographic and disease characteristics, both in the general population and in the postmenopausal women subset. After 3 years, postmenopausal participants in the glucosamine sulfate group showed no joint space nar- rowing [joint space change of +0.003 mm (95% CI, −0.09 to 0.11)], whereas participants in the placebo group experienced a narrowing of −0.33 mm (95% CI, −0.44 to −0.22; P < 0.0001 between the two groups). Percent changes after 3 years in the WOMAC index showed an improvement in the glucosamine sulfate group [−14.1% (95%, −22.2 to −5.9)] and a trend for worsening in the placebo group (5.4% (95% CI, −4.9 to 15.7) (P = 0.003 between the two groups).
This analysis, focusing on a large cohort of postmenopausal women, demonstrated for the first time that a pharmacological intervention for OA has a disease-modifying effect in this particular population, the most frequently affected by knee OA.
Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial
Treatment of osteoarthritis is usually limited to short-term symptom control. We assessed the effects of the specific drug glucosamine sulphate on the long-term progression of osteoarthritis joint structure changes and symptoms.
We did a randomised, double-blind placebo controlled trial, in which 212 patients with knee osteoarthritis were randomly assigned 1500 mg sulphate oral glucosamine or placebo once daily for 3 years. Weightbearing, anteroposterior radiographs of each knee in full extension were taken at enrolment and after 1 and 3 years. Mean joint-space width of the medial compartment of the tibiofemoral joint was assessed by digital image analysis, whereas minimum joint-space width—ie, at the narrowest point—was measured by visual inspection with a magnifying lens. Symptoms were scored by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index.
The 106 patients on placebo had a progressive joint-space narrowing, with a mean joint-space loss after 3 years of —0 .31 mm (95% CI —0.48 to —0.13). There was no significant joint-space loss in the 106 patients on glucosamine sulphate: —0.06 mm (—0.22 to 0.09). Similar results were reported with minimum joint-space narrowing. As assessed by WOMAC scores, symptoms worsened slightly in patients on placebo compared with the improvement observed after treatment with glucosamine sulphate. There were no differences in safety or reasons for early withdrawal between the treatment and placebo groups.
Figure 2: Intention-to-treat mean (SE) sum of VAS change subscales after 3 years Upper: WOMAC pain Lower: WOMAC physical function. *p=0•047; †p=0•020. VAS=visual analogue scale.
Table 3: Average (95% CI) joint-space narrowing after 3 years
The Efficacy and Tolerability of Glucosamine Sulfate in the Treatment of Knee Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled Trial
Osteoarthritis (OA) is the most common form of arthritis and is often associated with disability and impaired quality of life.
The aim of the study was to assess the efficacy and tolerability of glucosamine sulfate (GS) in the treatment of knee OA.
Consecutive outpatients affected by primary monolateral or bilateral knee OA were enrolled in this double-blind, double-dummy, prospective, randomized, placebo-controlled trial. One group received GS 1500 mg QD for 12 weeks, and the other group received placebo QD for 12 weeks. The treatment period was followed by a 12-week treatment-free observation phase. Each patient was examined at baseline and at weeks 4, 8, 12, 16, 20, and 24. The primary efficacy criteria were pain at rest and dur- ing movement, assessed on a visual analog scale (VAS) of 0 to 100 mm. The secondary criteria included the Western Ontario and McMaster Universities (WOMAC) index for total pain score (W-TPS), total stiffness score (W-TSS), and total physical function score (W-TPFS). VAS, W-TPS, W-TSS, and W-TPFS were evaluated at baseline and at weeks 4, 8, 12, 16, 20, and 24. Analgesic drug consumption (ie, acetaminophen or NSAIDs) was also assessed.
Patient demographics were similar in the GS and placebo groups. Of 60 randomized patients (30 per group), 56 completed the study (28 treated with GS and 28 who received placebo). Statistically significant improvements in symptomatic knee OA were observed, as measured by differences in resting pain at weeks 8, 12, and 16 (all, P < 0.05 vs placebo) and in pain during movement at weeks 12 and 16 (both, P < 0.05). W-TPS was lower with GS than placebo at weeks 8, 12, and 16 (all, P < 0.01), and at week 20 (P < 0.05). W-TSS was also lower with GS than placebo at weeks 8, 12, 16, and 20 (all, P < 0.05). W-TPFS was lower with GS than placebo at weeks 8 (P < 0.05), 12 (P < 0.01), 16 (P < 0.05), and 20 (P < 0.05). Drug consumption was lower in the GS group than the placebo group at weeks 8, 12, 16, and 20 (all, P < 0.05). The incidence of adverse events was 36.7% with GS and 40.0% with placebo.
GS 1500 mg QD PO for 12 weeks was associated with statisti- cally significant reductions in pain and improvements in functioning, with decreased analgesic consumption, compared with baseline and placebo in these patients with knee OA. A carryover effect was detected after treatment ended. (Curr Ther Res Clin Exp. 2009;70:185–196) © 2009 Excerpta Medica Inc.
Synovial and plasma glucosamine concentrations in osteoarthritic patients following oral crystalline glucosamine sulphate at therapeutic dose
We investigated the synovial and plasma glucosamine concentrations in osteoarthritic patients following oral administration of crystalline glucosamine sulphate at the therapeutic dose of 1500 mg once-a-day for 14 days.
Twelve osteoarthritic patients (six males and six females) received 14 consecutive once-daily oral administrations of crystalline glu- cosamine sulphate soluble powder (1500 mg), in an open fashion. Plasma and synovial ﬂuid were collected simultaneously from the same patient, at baseline and, at steady state (3 h after the last dose). Glucosamine was determined in plasma and synovial ﬂuid by liquid chroma- tographyetandem mass spectrometry.
Median endogenous glucosamine concentrations in plasma and synovial ﬂuid were 52.0 ng/ml (0.29 mM) and 36.5 ng/ml (0.21 mM), respectively (P 0.001), and varied substantially among patients (41e121 ng/ml and < 10e67 ng/ml, respectively). Three hours after the last dose, glucosamine concentrations resulted increased from baseline in all patients with median increases of 20.5 and 21.5 folds in plasma and synovial ﬂuid, respectively, the difference being not statistically signiﬁcant (P 0.11). In plasma, the median post-treatment value was 1282 ng/ml (7.17 mM) and ranged from 600 to 4061 ng/ml (3.35e22.7 mM). The median post-treatment synovial glucosamine concentration was 777 ng/ml (4.34 mM), i.e., signiﬁcantly lower than in plasma (P 0.001), and ranged from 577 to 3248 ng/ml (3.22e18.1 mM). Plasma and synovial glucosamine concentrations were highly correlated and were in the 10 mM range.
Glucosamine is bioavailable both systemically and at the site of action (the joint) after oral administration of crystalline glucos- amine sulphate in ostaeoarthritis patients. Steady state glucosamine concentrations in plasma and synovial ﬂuid were correlated and in line with those effective in selected in vitro studies.
Crystalline glucosamine sulfate in the management of knee osteoarthritis: efficacy, safety, and pharmacokinetic properties
Glucosamine is an amino monosaccharide and a natural constituent of glycosaminoglycans in articular cartilage. When administered exogenously, it is used for the treatment of osteoarthritis as a prescription drug or a dietary supplement.
The latter use is mainly supported by its perception as a cartilage building block, but it actually exerts specific pharmacologic effects, mainly decreasing interleukin 1-induced gene expression by inhibiting the cytokine intracellular signaling cascade in general and nuclear factor-kappa B (NF-kB) activation in particular. As a whole, the use of glucosamine in the management of osteoarthritis is supported by the clinical trials performed with the original prescription product, that is, crystalline glucosamine sulfate. This is the stabilized form of glucosamine sulfate, while other formulations or different glucosamine salts (e.g. hydrochloride) have never been shown to be effective. In particular, long-term pivotal trials of crystalline glucosamine sulfate 1500 mg once daily have shown significant and clinically relevant improvement of pain and function limitation (symptom-modifying effect) in knee osteoarthritis. Continuous administration for up to 3 years resulted in significant reduction in the progression of joint structure changes compared with placebo as assessed by measuring radiologic joint space narrowing (structure-modifying effect).
The two effects combined may suggest a disease-modifying effect that was postulated based on an observed decrease in the risk of undergoing total joint replacement in the follow up of patients receiving the product for at least 12 months in the pivotal trials. The safety of the drug was good in clinical trials and in the postmarketing surveillance. Crystalline glucosamine sulfate 1500 mg once daily is therefore recommended in the majority of clinical practice guidelines and was found to be cost effective in pharmacoeconomic analyses. Compared with other glucosamine formulations, salts, or dosage forms, the prescription product achieves higher plasma and synovial fluid concentrations that are above the threshold for a pharmacologically relevant effect, and may therefore justify its distinct therapeutic characteristics.
Glucosamine oral bioavailability and plasma pharmacokinetics after increasing doses of crystalline glucosamine sulfate in man
Pharmacokinetic data on glucosamine are scant, limiting the understanding of glucosamine sulfate mechanism of action in support of its treatment effects in osteoarthritis. This study investigated the oral pharmacokinetics and dose-proportionality of glucosamine after administration of the patented crystalline glucosamine sulfate in man.
Twelve healthy volunteers received three consecutive once-daily oral administrations of glucosamine sulfate soluble powder at the doses of 750, 1500, and 3000 mg, in an open, randomised, cross-over fashion. Glucosamine was determined in plasma collected up to 48 h after the last dose by a validated Liquid Chromatography method with Mass Spectrometry detection. Pharmacokinetic parameters were calculated at steady state.
Endogenous plasma levels of glucosamine were detected (10.4e204 ng/ml, with low intra-subject variability). Glucosamine was rapidly absorbed after oral administration and its pharmacokinetics were linear in the dose range 750e1500 mg, but not at 3000 mg, where the plasma concentrationetime proﬁles were less than expected based on dose-proportionality. Plasma levels increased over 30-folds from baseline and peaked at about 10 mM with the standard 1500 mg once-daily dosage. Glucosamine distributed to extravascular compartments and its plasma concentrations were still above baseline up to the last collection time. Glucosamine elimination half-life was only tentatively estimated to average 15 h.
Glucosamine is bioavailable after oral administration of crystalline glucosamine sulfate, persists in circulation, and its pharmacokinetics support once-daily dosage. Steady state peak concentrations at the therapeutic dose of 1500 mg were in line with those found to be effective in selected in vitro mechanistic studies. This is the only glucosamine formulation for which pharmacokinetic, efﬁcacy and safety data are now available.
Fig. 1. Mean glucosamine plasma concentration vs time profiles at steady state after repeated once-daily doses of glucosamine sulfate 750, 1500 and 3000 mg (n Z 12 for each dose level). Concentrations are baseline-subtracted and expressed as ng/ml (panel A) or mM (panel B). Bars represent standard deviations.
Glucosamine prevents in vitro collagen degradation in chondrocytes by inhibiting advanced lipoxidation reactions and protein oxidation
Osteoarthritis (OA) affects a large segment of the aging population and is a major cause of pain and disability. At present, there is no specific treatment available to prevent or retard the cartilage destruction that occurs in OA. Recently, glucosamine sulfate has received attention as a putative agent that may retard cartilage degradation in OA. The precise mechanism of action of glucosamine is not known. We investigated the effect of glucosamine in an in vitro model of cartilage collagen degradation in which collagen degradation induced by activated chondrocytes is mediated by lipid peroxidation reaction. Lipid peroxidation in chondrocytes was measured by conjugated diene formation. Protein oxidation and ldehydic adduct formation were studied by immunoblot assays. Antioxidant effect of glucosamine was also tested on malondialdehyde (thiobarbituric acid-reactive substances [TBARS]) formation on purified lipoprotein oxidation for comparison.
Glucosamine sulfate and glucosamine hydrochloride in millimolar (0.1 to 50) concentrations specifically and significantly inhibited collagen degradation induced by calcium ionophore-activated chondrocytes. Glucosamine hydrochloride did not inhibit lipid peroxidation reaction in either activated chondrocytes or in copper-induced oxidation of purified lipoproteins as measured by conjugated diene formation. Glucosamine hydrochloride, in a dosedependent manner, inhibited malondialdehyde (TBARS) formation by oxidized lipoproteins. Moreover, we show that glucosamine hydrochloride prevents lipoprotein protein oxidation and inhibits malondialdehyde adduct formation inchondrocyte cell matrix, suggesting that it inhibits advanced lipoxidation reactions. Together, the data suggest that the mechanism of decreasing collagen degradation in this in vitro model system by glucosamine may be mediated by the inhibition of advanced lipoxidation reaction, preventing the oxidation and loss of collagen matrix from labeled chondrocyte matrix. Further studies are needed to relate these in vitro findings to the retardation of cartilage degradation reported in OA trials investigating glucosamine.
A review of glucosamine for knee osteoarthritis: why patented crystalline glucosamine sulfate should be differentiated from other glucosamines to maximize clinical outcomes
The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm for knee osteoarthritis (OA) recommends symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) first line for the medium to long term management of OA, due to their ability to control pain, improve function, and delay joint structural changes. Among SYSADOAs, glucosamine is probably the most widely used intervention. In the present review of glucosamine for knee OA, we have investigated whether the evidence is greater for the patented crystalline glucosamine sulfate (pCGS) preparation (Rottapharm/Meda) than for other glucosamine formulations. Glucosamine is actually widely available in many forms, as the prescription-grade pCGS preparation, generic and over-the-counter formulations of glucosamine sulfate (GS) and food supplements containing glucosamine hydrochloride (GH), which vary substantially in molecular form, pharmaceutical formulation and dose regimens.
Only pCGS is given as a highly bioavailable once daily dose (1500 mg) with a proven pharmacological effect. pCGS consistently reaches the plasma levels of around 10 lM required to inhibit interleukin-1 induced expression of genes involved in the pathophysiology of joint inflammation and tissue destruc- tion, compared with sub-therapeutic levels achieved with GH. It is evident, from careful consideration of the evidence base, that only the pCGS formulation of glucosamine reliably provides an effect size on pain that is higher than that of paracetamol and equivalent to that provided by non-steroidal anti- inflammatory drugs.
Figure 4. Effect of prior patented crystalline glucosamine sulfate formulation on cumulative incidence of total joint replacement surgery for up to 5 years following treatment. Reproduced from Bruye`re et al. 200843, with permission. CGS, crystalline glucosamine sulfate.
In comparison, the effect size on pain of non-crystalline GS preparations and GH from randomized controlled trials is repeatedly demonstrated to be zero. In addition, there is evidence that chronic administration of pCGS has disease-modifying effects, with a reduction in the need for total joint replacement surgery lasting for at least 5 years after treatment cessation. Consequently, the pCGS preparation (Rottapharm/Meda) is the logical choice, with demonstrated medium-term control of pain and lasting impact on disease progression.