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Role of collagen hydrolysate in bone and joint disease

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Abstract

To review the current status of collagen hydrolysate in the treatment of osteoarthritis and osteoporosis. Review of past and current literature relative to collagen hydrolysate metabolism, and assessment of clinical investigations of therapeutic trials in osteoarthritis and osteoporosis. Hydrolyzed gelatin products have long been used in pharmaceuticals and foods; these products are generally recognized as safe food products by regulatory agencies. Pharmaceutical-grade collagen hydrolysate (PCH) is obtained by hydrolysis of pharmaceutical gelatin. Clinical studies suggest that the ingestion of 10 g PCH daily reduces pain in patients with osteoarthritis of the knee or hip; blood concentration of hydroxyproline is increased. Clinical use is associated with minimal adverse effects, mainly gastrointestinal, characterized by fullness or unpleasant taste. In a multicenter, randomized, doubleblind, placebo-controlled trial performed in clinics in the United States, United Kingdom, and Germany, results showed no statistically significant differences for the total study group (all sites) for differences of mean pain score for pain. There was, however, a significant treatment advantage of PCH over placebo in German sites. In addition, increased efficacy for PCH as compared to placebo was observed in the overall study population amongst patients with more severe symptomatology at study onset. Preferential accumulation of 14C-labeled gelatin hydrolysate in cartilage as compared with administration of 14C-labeled proline has been reported. This preferential uptake by cartilage suggests that PCH may have a salutary effect on cartilage metabolism. Given the important role for collagen in bone structure, the effect of PCH on bone metabolism in osteoporotic persons has been evaluated. Studies of the effects of calcitonin with and without a collagen hydrolysate-rich diet suggested that calcitonin plus PCH had a greater effect in inhibiting bone collagen breakdown than calcitonin alone, as characterized by a fall in levels of urinary pyridinoline cross-links. PCH appeared to have an additive effect relative to use of calcitonin alone. Collagen hydrolysate is of interest as a therapeutic agent of potential utility in the treatment of osteoarthritis and osteoporosis. Its high level of safety makes it attractive as an agent for long-term use in these chronic disorders.

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... Moreover, IL-1β stimulates the inflammatory response via overexpression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (Cox)-2 (Gupta et al., 2008). The expression of type X collagen (Col 10) is one of the major characteristics of chondrocyte hypertrophy, which is followed by cartilage matrix degradation and vascular invasion (Moskowitz, 2000), and Col 10 might be a neoepitope biomarker of knee OA . Agents that antagonize IL-1β-associated OA-related factors might have a considerable efficacy for OA treatment. ...
... During the progression of OA, MMPs (MMP3 and MMP13) and ADAMTS5 are the major enzymes involved in catabolic dysregulation, while Col 2 is involved in anabolism (Cui et al., 2017). The expression of Col 10 is one of the major characteristics of chondrocyte hypertrophy, which is followed by cartilage matrix degradation and vascular invasion (Moskowitz, 2000). In this study, cells were stimulated with IL-1β after pretreatment with or without SA for 24 h. ...
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Osteoarthritis (OA) is a major cause of cartilage pain and limited mobility in middle-aged and elderly individuals. The degeneration of cartilage induced by inflammation and cartilage anabolic and catabolic disorder plays a key role in OA. Shikimic acid (SA), a natural ingredient extracted from Illicium verum, has been shown to exert notable anti-inflammatory effects in previous studies, suggesting its potential effects in the treatment of OA. In this study, we revealed that the pretreatment of SW1353 human chondrocytes with SA before interleukin 1β (IL-1β) stimulation effectively decreased the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (Cox)-2, matrix metalloproteinases (MMPs; MMP3 and MMP13), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5, type X collagen, and p62; increased the expression of type II collagen, ATG7, Beclin-1, and LC3; and increased the autophagic flux. Mechanistically, we found that SA suppressed the IL-1β-induced activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) pathways. Furthermore, the results of safranin O staining and toluidine blue staining of primary rat cartilage chondrocytes and a trauma-induced rat model of OA showed that SA alleviated progression of OA in vivo. Collectively, our research enhances understanding of the mechanism of protective effect of SA against the progression of OA, which involves amelioration of cartilage degeneration, thereby providing new evidence for the use of SA as a therapy to prevent the development of OA.
... That is why it is digested in the human body more efficiently. Besides, this type of collagen has absorbent and regenerating properties, so it is widely used as a component of various pharmaceutical and cosmetic products [4,5]. Another reason for the increased interest in fish collagen is the high prevalence rate of bovine rabies, which makes it impossible to use the resulting collagen in food. ...
... Series: Earth and Environmental Science 421 (2020) 062030 IOP Publishing doi:10.1088/1755-1315/421/6/062030 5 ...
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The research is devoted to the use of a cod skin hydrolysate as a component of citrus fruit beverages. It is demonstrated that the addition of a hydrolysate increases the content of protein in the beverage, slightly increases the viscosity of the beverage, and does not adversely affect its sensory characteristics. Hydrolysate is produced by enzymatic treatment of cod skin. The processing parameters allowing achieving the desired degree of destruction are determined. Physico-chemical parameters and sensory analyses of the obtained hydrolysate and its amino acid composition were analyzed. The influence of collagen hydrolysate on the physical and chemical composition of beverages, their structural and mechanical characteristics (pH and viscosity) and sensory analyses are estimated.
... Actually, a variety of supplements based on collagen-derived peptides have been patented and are commercialized in Europe, Japan and the USA, indicating great interest in the nutraceutical industry of these products. Furthermore, the hydrolysed gelatine derivatives recently received the GRAS status, "generally recognized as safe", by the FDA (Moskowitz 2000). In particular the use of marine-discarded sources for the preparation of gelatine hydrolysates is constantly increasing, due to the absence of risk for transmission of bovine spongiform encephalopathy and to fulfil certain religious food requirements in Muslim and Jewish markets. ...
... Collagen hydrolysates show very interesting properties such as the resistance of certain collagen-derived peptides containing hydroxyproline to protein digestion, revealing that, after oral administration and absorption by the digestive tract in human or animal models they show significant biological activities (Moskowitz 2000). ...
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Collagens are a large family of structural proteins present in the extracellular matrix of metazoans where they are involved in the formation of a fibril network providing the structural integrity of tissues. The main sources of marine collagen are the waste of the fishing industry, as well as some marine invertebrates particularly abundant in the environment and rich in collagen, such as jellyfishes or sponges. In vertebrates, the collagen family is extremely heterogeneous as its members can vary considerably in size, function, distribution and structural organization. The main source of marine collagen and gelatin for biotechnology applications is fish processing waste in the food industry. The polymeric nature of collagen, as well as its low level of immunogenicity, provides an excellent material for tissue engineering applications. The polymers used for scaffold preparation are mainly of biological origin as cellulose, chitosan, silk fibroin, hyaluronic acid, collagen and gelatin.
... Calcium in bones is deposited by hydroxyapatite and fixed by bone collagen. Therefore, it is beneficial to bone metabolism that the amino acids or oligopeptides necessary for the synthesis of collagen are supplemented (Moskowitz, 2000). ...
... in which X and Y positions are often proline and hydroxyproline, and they are the most abundant content among various amino acids accounting for about 25%. However, collagen has no tryptophan and seldom cysteine (Moskowitz, 2000). In present study, we extracted flesh and skin peptides and compared their amino acid composition. ...
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Fish processing produces a lot of by‐products highly containing large amount of proteins which mainly consist of collagen, implying great potential value for application as nutraceutical ingredients. In present study, two kinds of sharks, Chiloscyllium plagiosum and Mustelus griseus, were used as raw material to gain three kinds of “compound peptides” (CPs) by enzymolysis, FCP (CPs from the flesh of C. plagiosum), SCP (CPs from the skin of C. plagiosum), and SMG (CPs from the skin of M. griseus). According to a series of constituent analysis, the molecule weights of FCP, SCP, and SMG were under 800 Da; amino acids composition analysis of FCP, SCP, and SMG showed that there were high glycine, proline, and hydroxyproline and low cysteine contents in SCP and SMG, which is the characteristic of collagen peptides; their total protein contents were 87.500%, 91.875%, and 95.625%, respectively; and heavy metal contents of CPs were all beneath national standards. After three kinds of CPs were administrated intragastrically to C57BL/6 mice at a total dosage of 15 g/kg, bone‐strengthening effects of SCP and SMG were manifested by osteoblasts activity promotion, bone mineral density (BMD) increase, and marrow adipocyte number decrease, yet nonsignificant effects were shown in FCP group. No index showed toxicity of SCP and SMG in subacute toxicology trial, indicating their safety as functional foods. Herein, industrial application foundation of the skins from these two sharks was explored but more efforts should subsequently be implemented for further exploitation. Our research showed that the skin of two kinds of sharks Chiloscyllium plagiosum and Mustelus griseus might have a novel application as extractive raw materials of functional food—a hydrolysate which we named compound peptides. They are easy to produce and possess bone‐strengthening effects and nontoxic, laying a foundation for industrial production.
... Collagen preparations are currently widely used in dietary supplements intended for a wide demographic, and can prevent and treat osteoarticular diseases in athletes burdened by heavy physical exertion and cosmetic preparations. Collagen can also keep blood vessels, skin, hair and nails in a good condition [29]. Inulin is a water-soluble fiber with prebiotic properties that are well documented in the scientific literature. ...
... Our designed fruit-based drinks differed from currently manufactured drinks in their contents of hydrolyzed collagen proteins, which are easily digestible in nutritionally significant amounts (approx. 9 g per a 300 g serving of the drink), the equivalent to daily recommended intakes in dietary supplements (up to 10 g per day) [29]. These drinks were also distinguishable in their contents of fiber (approx. ...
Article
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High levels of osmolalities have been found in manufactured carbohydrate-based functional drinks that occasionally include added protein; however, fruit components rich in bioactive ingredients have been absent. It has proved difficult to obtain recovery drinks based on natural fruit components that deliver calories and nutrients to the body whilst simultaneously ensuring that the body is adequately hydrated after physical exertion; the problem being that it is difficult to ensure the drinks’ stability at low pH levels and maintain an appropriate sensory quality. This study aims to develop drinks based on natural fruit components that contain added electrolytes, carbohydrates, prebiotic fiber and protein; an improved water and electrolyte balance; the calories needed after intense physical exertion; a high content of nutrients; and a favorable sensory quality. Furthermore, the relationships between regressive osmolalities of beverage components are herein investigated. The study materials were raspberry powders (prepared via fluidized-bed jet milling, drying, freeze-drying and spray-drying) as well as citrated sodium, potassium, magnesium salts, isomaltulose, hydrolyzed collagen, whey protein isolate and prebiotic fiber. The drinks’ polyphenols and antioxidant properties were measured spectrophotometrically, whilst vitamin C content was determined using high-pressure liquid chromatography. The sensory qualities of each drink were assessed according to a scaling method. Six test versions of recovery drinks were prepared in which osmolalities ranged from 388 to 607 mOsm/kg water, total polyphenol content was 27–49 mg GAE/100 mL and vitamin C level was 8.1–20.6 mg/100 mL, following compositions defined by the study results. It is thus possible to obtain fruit-based recovery drinks of the recommended osmolality that contain added protein, prebiotics and fiber, as well as defined amounts of electrolytes and carbohydrates. All drinks were found to have a satisfactorily sensory quality. The design of appropriate recovery drink compositions was also greatly helped by investigating the relationships among the regressive osmolalities of beverage components (i.e., electrolytes, carbohydrates, fruit powders and protein).
... Since collagen is insoluble in cold water, collagen hydrolysates prepared by enzymatic degradation of gelatin, namely collagen peptides (CPs), are used instead in food supplements and pharmaceutical preparations. Many studies have reported that oral administration of CPs has benefi cial effects on bone metabolism and against joint disorders (1)(2)(3)(4)(5)(6). We previously reported that administration of CPs derived from chicken cartilage could partially suppress the rheumatoid arthritis score and levels of plasma infl ammatory cytokines in SKG mice (7). ...
... We previously reported that administration of CPs derived from chicken cartilage could partially suppress the rheumatoid arthritis score and levels of plasma infl ammatory cytokines in SKG mice (7). Clinical trials suggested that CP supplementation may have positive therapeutic effects against osteoarthritis and other joint disorders (4)(5)(6). ...
Article
Collagen peptides (CPs) are bioactive molecules that have beneficial effects on bone metabolism and against joint disorders. In the present study, we investigated the effect of CP supplementation on visceral fat mass and plasma lipid concentrations in high-fat diet (HFD)-induced obese mice. Male ddY mice were fed a normal diet or HFD for 3 wk, and assigned to N or NCP groups and to F or FCP groups, respectively. The NCP and FCP group mice were administered experimental diets containing 25 mg/g CPs for 3 wk further. During the experimental period, CP supplementation affected neither the food consumption nor the body weight of the mice. No significant differences in the plasma triglyceride, non-esterified fatty acid, and cholesterol concentrations were observed among all the groups. In contrast, the weight of testicular fat mass was significantly decreased in the FCP group as compared with that in the F group. The expression levels of leptin and tumor necrosis factor (TNF)-α genes in the adipose tissue correlated with the visceral fat mass, although these differences were not significant. These findings indicate that CPs may have a reducing effect on visceral fat content but are less effective in reducing body weight.
... Bioactive peptides-such as the collagen hydrolysates obtained by the enzymatic hydrolysis of collagen-rich materials such as skin, bone and fish scales-are among the most used ingredients for the development of nutraceuticals. Consumption of collagen hydrolysates has been known to exert beneficial effects on joints [33], bones [33,34], skin [17,19] and blood vessels [35], which contain collagen. A metabolism study of collagen hydrolysate suggests that collagen-derived di-or tripeptides in the blood torrent increase significantly after oral ingestion and are incorporated into the skin, bone and joint tissue [36][37][38]. ...
... Bioactive peptides-such as the collagen hydrolysates obtained by the enzymatic hydrolysis of collagen-rich materials such as skin, bone and fish scales-are among the most used ingredients for the development of nutraceuticals. Consumption of collagen hydrolysates has been known to exert beneficial effects on joints [33], bones [33,34], skin [17,19] and blood vessels [35], which contain collagen. A metabolism study of collagen hydrolysate suggests that collagen-derived di-or tripeptides in the blood torrent increase significantly after oral ingestion and are incorporated into the skin, bone and joint tissue [36][37][38]. ...
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Cortisol is an endogenous glucocorticoid (GC) and primary stress hormone that regulates a wide range of stress responses in humans. The adverse effects of cortisol on the skin have been extensively documented but the underlying mechanism of cortisol-induced signaling is still unclear. In the present study, we investigate the effect of cortisol on collagen type I expression and the effect of AP collagen peptides, collagen tripeptide-rich hydrolysates containing 3% glycine-proline- hydroxyproline (Gly-Pro-Hyp, GPH) from the fish skin, on the cortisol-mediated inhibition of collagen type I and the cortisol-induced signaling that regulates collagen type I production in human dermal fibroblasts (HDFs). We determine that cortisol downregulates the expression of collagen type I. AP collagen peptides or GC receptor (GR) inhibitors recover the cortisol-mediated inhibition of collagen type I and GR activation. AP collagen peptides or GR inhibitors also prevent the cortisol-dependent inhibition of transforming growth factor (TGF)-β signaling. AP collagen peptides or GR inhibitors are effective in the prevention of collagen type I inhibition mediated by cortisol in senescent HDFs and reconstituted human skin models. Taken together, GR signaling might be responsible for the cortisol-mediated inhibition of TGF-β. AP collagen peptides act as GR-mediated signaling blockers, preventing the cortisol-dependent inhibition of collagen type I. Therefore, AP collagen peptides have the potential to improve skin health.
... This result was similar to reports from other areas, such as northern Pakistan [10] and Spain [69]. The muscular pain category was a dominant MSD category, and many communities around the world have used many medicinal plants to treat it [70]. Famers have used many medicinal plants to treat muscle pain caused by laborious work in the fields [71]. ...
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Millions of people suffer from Musculoskeletal System Disorders (MSDs), including Karen people who work hard in the fields for their subsistence and have done so for generations. This has forced the Karen to use many medicinal plants to treat MSDs. We gathered data from 15 original references covering 27 Karen communities and we document 461 reports of the use of 175 species for treating MSDs among the Karen people in Thailand. The data were analyzed by calculating use values (UV), relative frequency of citation (RFC) and informant consensus factor (ICF). Many use reports and species were from Leguminosae and Zingiberaceae. Roots and leaves were the most used parts, while the preferred preparation methods were decoction and burning. Oral ingestion was the most common form of administration. The most common ailment was muscle pain. Sambucus javanica and Plantago major were the most important species because they had the highest and second-highest values for both UV and RFC, respectively. This study revealed that the Karen people in Thailand use various medicinal plants to treat MSDs. These are the main resources for the further development of inexpensive treatments of MSDs that would benefit not only the Karen, but all people who suffer from MSD.
... The relationship between consumption of n-3 dietary (PUFA) and treatment of arthritis has been deeply studied (James and Cleland, 1997;Hurst et al., 2010). Other than that, a clinical study proposes that intake of collagen hydrolysates that are isolated from fish waste can reduce pain in patients with osteoarthritis (Moskowitz, 2000). ...
... -08, 2008. With that, the content of collagen in a single serving of the product, i.e., 200 ml of the drink, should be 200 % of the daily need, which is 5 g (Matsumoto et al., 2006;Moskowitz, 2000). The content of dry matter in the ingredients of the starch drink formulation (FI) is shown in Table 1, and its nutritional value in Table 2. (1) Based on the information matrix (Table 1), Table 3 shows a system of linear balance equations and limitations. ...
... Subsequently, peptides could be transported by the intestine in the form of free amino acids and di-or tripeptides, which results in poor assimilation. However, HC plays an important role because collagen in its hydrolyzed form can be easily assimilated by the body due to previous digestion with enzymes [83][84][85][86]. In addition, the presence of hydroxyproline promotes the major assimilation of HC because this amino acid along with proline can be absorbed in the gastrointestinal tract after ingestion [82]. ...
Article
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In this study, the preparation of a milk whey-based beverage with the addition of different concentrations of hydrolyzed collagen (0.3%, 0.5%, 0.75%, and 1%) was carried out. The control was considered at a concentration of 0%. Physicochemical properties, viscosity, antioxidant activity, and microbiological parameters were evaluated. The 1% collagen treatment showed the highest protein content (9.75 ± 0.20 g/L), as well as radical inhibition for ATBS (48.30%) and DPPH (30.06%). There were no significant differences (p ≥ 0.05) in the fat and lactose parameters. However, the pH in the control treatment was lower compared to beverages treated with hydrolyzed collagen. Fourier transform-infrared spectroscopy showed spectra characteristic of lactose and collagen amides. The viscosity increased significantly as the concentration of hydrolyzed collagen increased. The addition of hydrolyzed collagen increased the bioavailability, nutritional value, and the antioxidant activity of the beverage. Hydrolyzed collagen acted as an antimicrobial agent, as there was no presence of microorganism pathogens observed in the treated beverages.
... Collagen Supplements and Osteoarthritis Pain: How Persuasive is the Evidence? 34 As outlined in 2000 by Moskowitz [32], a form of oral collagen known as collagen hydrolysate is of particular interest as a therapeutic agent in efforts to treat osteoarthritis more effectively due to its high safety level, even when used for long periods. Although disputed by Bongers., et al. [37] who found collagen peptide did not reduce pain in active middle aged to healthy subjects with knee pain complaints, Bakilan., et al. [28] found collagen added to acetaminophen to improve the efficacy of this painkiller in a similar sample. ...
Article
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This mini review aimed to examine support for the alternate hypothesis that collagen supplements can help to ameliorate osteoarthritis pain significantly and effectively.
... Similar to isoflavone, fsCH containing collagen peptides of GPH, GP, and PH was effective in counteracting estrogen loss-induced uterus atrophy and osteoclastic bone loss. This study revealed that fsCH enhanced the formation of trabecular bones and collagenous matrix in the metaphysis and diaphysis of OVX mice through reducing expression of the osteoclastic biomarkers of CAII, V-ATPase, and cathepsin K. Other investigations have shown that collagen hydrolysates have a beneficial effect on osteoarthritis and osteoporosis [31,32]. However, the action mechanisms of fsCH on bone health in the postmenopausal state have not yet been defined. ...
Article
Osteoporosis manifest in postmenopausal women is an osteolytic disease characterized by bone loss, leading to increased susceptibility to bone fractures and frailty. The use of complementary therapies to alleviate postmenopausal osteoporosis is fairly widespread among women. The current study examined that Pangasius hypophthalmus fish skin collagen hydrolysates (fsCH) inhibited ovariectomy (OVX)-induced bone loss by conducting inter-comparative experiments for anti-osteoporotic activity among 206-618 mg/kg fsCH, 2 mg/kg isoflavone, 15 mg/kg glycine-proline-hydroxyproline (GPH) tripeptide, and calcium lactate. Surgical estrogen loss of mice for 8 weeks reduced serum 17β-estradiol levels with uterus atrophy, which was ameliorated by orally administering fsCH or isoflavone to mice. Similar to isoflavone, fsCH containing GPH-enhanced bone mineral density reduced levels of cathepsin K and proton-handling proteins, and elevated collagen 1 level in OVX bones. The treatment with fsCH and isoflavone enhanced the serum levels of collagen synthesis-related procollagen type 1 carboxy/amino-terminal propeptides reduced by OVX, whereas serum levels of osteocalcin and alkaline phosphatase, as well as collagen breakdown-related carboxy/amino-terminal telopeptides of type 1 collagen were reduced in OVX mice treated with fsCH, isoflavone, and calcium lactate. The trabecular bones were newly formed in OVX bones treated with isoflavone and fsCH, but not with calcium lactate. However, a low-dose combination of fsCH and calcium lactate had a beneficial synergy effect on postmenopausal osteoporosis. Furthermore, similar to isoflavone, 15-70 μg/mL fsCH, with its constituents of GPH and dipeptides of glycine-proline and proline-hydroxyproline, enhanced osteogenesis through stimulating differentiation, matrix mineralization, and calcium deposition of MC3T3-E1 osteoblasts. Accordingly, the presence of fsCH may encumber estrogen deficiency-induced bone loss through enhancing osteoclastogenic differentiation and matrix collagen synthesis. Therefore, fsCH may be a natural compound retarding postmenopausal osteoporosis and pathological osteoresorptive disorders.
... Collagen hydrolysates are usually obtained by enzymatic hydrolysis of collagen. Collagen hydrolysates could provide benefits for the skeleton [8]. Collagen hydrolysates used as food supplements improve the compositional and biodynamic characteristics of vertebrae in ovariectomized rats [9]. ...
Article
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Bovine bone collagen hydrolysates promote bone formation through regulating bone growth. However, the peptide sequences within these isolates have not been characterized. In this study, twenty-nine peptides from bovine bone collagen hydrolysates were purified and identified using nano-HPLC-MS-MS and Peak Studio analysis. HHGDQGAPGAVGPAGPRGPAGPSGPAGKDGR (Deamidation) and GPAGANGDRGEAGPAGPAGPAGPR (Deamidation) enhanced cell viability, inhibited apoptosis, and significantly altered the cell cycle of MC3T3-E1 osteoblast cells. These peptides were selected to perform molecular docking analysis to examine the mechanism underlying these bioactivities. Molecular docking analysis showed that these two peptides formed hydrophobic interactions and hydrogen bonds with epidermal growth factor receptor (EGFR) to activate the EGFR-signaling pathway, which may explain their bioactivity. These findings indicate that these and other similar peptides might be candidates for the treatment of osteoporosis.
... However their activities are based on their amino acid composition and sequence (Pihlanto-Leppälä 2000; Kim and Wijesekara 2010). It has already been shown that bioactive peptides isolated from fi sh protein hydrolysates, algal fucans, and galactans possess anticoagulant, anticancer, hypocholesterolemic (Moskowitz 2000) and antioxidative properties (Jun et al. 2004;Rajapakse et al. 2005). In addition, purifi ed peptides extracted from Chlorella vulgaris have shown protective effects against cellular damage (Sheih et al. 2009). ...
Chapter
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Emerging research evidence regarding the impact of diet on human health beyond the basic nutrition has aroused the curiosity of consumers. Marine based bioactive compounds, in particular, are believed to provide a number of health benefits. The marine ecosystem covers more than 70% of the earth’s surface but represents 95% of the biosphere with phenomenal biodiversity (Faulkner 1995). Therefore, marine bioactive compounds can be derived from a number of sources including marine plants, microorganisms and by-products of the fish industry. Many marine organisms live in complex, competitive and aggressive habitats exposed to extreme conditions and in adapting to new environmental surroundings, they produce a wide variety of biologically active secondary metabolites which cannot be found in other organisms. While the effect of these compounds on the human body may be very small over relatively short periods, they could contribute significantly to health when they are consumed throughout one’s life as a part of the daily diet (Biesalski et al. 2009).
... In particular, pharmaceutical-grade collagen hydrolysate (PCH) and undenatured type II collagen (UC-II) have been shown to improve the symptoms of OA by stimulating joint collagen. 55,56 On the other hand, nerve growth factor (NGF) (a neurotrophin) is necessary for the normal development of the sympathetic nervous system and sensory neurons. For individuals with musculoskeletal pain, treatment with NGF inhibitors such as tanezumab, fulranumab, and fasinumab can produce significant improvements in joint pain and physical function, which may be a potent analgesic for patients with C3-subtype OA. 57 For patients in the C4 subgroup, the primary approach is the application of antiinflammatory agents. ...
Article
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The limited molecular classifications and disease signatures of osteoarthritis (OA) impede the development of prediagnosis and targeted therapeutics for OA patients. To classify and understand the subtypes of OA, we collected three types of tissue including cartilage, subchondral bone, and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients. By applying unsupervised clustering analysis to the cartilage transcriptome, OA patients were classified into four subtypes with distinct molecular signatures: a glycosaminoglycan metabolic disorder subtype (C1), a collagen metabolic disorder subtype (C2), an activated sensory neuron subtype (C3), and an inflammation subtype (C4). Through ligand-receptor crosstalk analysis of the three knee tissue types, we linked molecular functions with the clinical symptoms of different OA subtypes. For example, the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4, which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients. Based on the marker genes of the four OA subtypes identified in this study, we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification. The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients, which may allow for precise diagnosis and treatment of OA.
... After absorption, they travel throughout the body, repairing, rebuilding, and providing energy [3]. Hydrolysed collagen used in skin-care products enhances the appearance of dry or damaged skin by reducing flaking and restoring suppleness [4]. Besides a few studies are reported on the collagen hydrolysis by using some proteases, no more reports are available on the collagen hydrolysis by using bromelain from pineapple stem. ...
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The present study involves investigations on the collagen peptides obtained through bromelain hydrolysis. The collagen produced from Nitta Gelatin India Limited-Gelatin-H 1303080 was hydrolysed with bromelain extracted from pineapple stem. Collagen is the most important structural protein in the body, which gives the strength to build our body. Full length collagen molecules are broken down to form hydrolysed collagen. It is fat free, cholesterol free, easily digestible, and high in essential amino acids, hence used in medical field to help from sore joint recovery, cancer recovery, and post-surgery treatments. Initially, extracted bromelain was purified by ammonium sulfate precipitation, dialysis, and ion-exchange chromatography using DEAE cellulose column. SDS PAGE analysis showed the molecular weight of purified bromelain to be 30kDa. To separate bromelain from hydrolysed collagen, SEC method was employed. Homogeneity of these peptides was screened by using SDS PAGE. This led to the finding of 11 fractions of low molecular weight collagen peptides. The preliminary studies of hydrolysed collagen obtained through enzymatic hydrolysis were investigated. This study reveals that extracted stem bromelain was efficient for collagen hydrolysis.
... The mainstay of treatment of osteopenia and osteoporosis includes dietary changes, regular weight-bearing exercises, calcium and vitamin D supplementation and pharmacologic treatment mainly with antiresorptive or anabolic agents 2 . Collagen peptides (CPs), also called collagen hydrolysates produced by hydrolysis of collagen, have also been shown to have high oral bioavailability and could have a place as a treatment option [3][4][5][6][7][8][9] . ...
Article
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Objectives: Collagen peptides (CPs) seem to exert beneficial effects on bone and may have a role as a treatment option. In the present randomized prospective study, we aimed to examine the efficacy, as expressed by changes in P1NP and CTX, and the tolerability of 3-month supplementation of calcium, vitamin D with or without bioactive CPs in postmenopausal women with osteopenia. Methods: Fifty-one female, postmenopausal women with osteopenia were allocated to two groups: Group A received a sachet containing 5 g CPs, 3.6 g calcium lactate (equivalent to 500 mg of elemental calcium) and 400 IU vitamin D3 and group B received a chewable tablet containing 1.25 g calcium carbonate (equivalent to 500 mg of elemental calcium) and 400 IU vitamin D3 daily. Results: In group A, the P1NP levels significantly decreased by 13.1% (p<0.001) and CTX levels decreased by 11.4% (p=0.058) within 3 months of supplementation. In group B, P1NP and CTX did not change. Group A presented better compliance in comparison to group B and no adverse events contrary to group B. Conclusions: These findings may reflect the reduction of the increased bone turnover in postmenopausal women with the use of calcium, vitamin D and CPs supplements. The addition of CPs in a calcium and vitamin D supplement may enhance its already known positive effect on bone metabolism. Clinical Trial ID: NCT03999775.
... Research on the health benefits of 4-hydroxyproine has focused on its role in improving joint, skin and bone health (Moskowitz 2000;Zhang et al. 2011a) and in preventing gut inflammation in animal models. For example, Pro-Hyp stimulates the growth and migration of fibroblasts in the mouse skin (Shigemura et al. 2009) and, therefore, would have important implication for maintaining dermal hydration and accelerating wound healing (Li and Wu 2018). ...
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Taurine (a sulfur-containing β-amino acid), creatine (a metabolite of arginine, glycine and methionine), carnosine (a dipeptide; β-alanyl-l-histidine), and 4-hydroxyproline (an imino acid; also often referred to as an amino acid) were discovered in cattle, and the discovery of anserine (a methylated product of carnosine; β-alanyl-1-methyl-l-histidine) also originated with cattle. These five nutrients are highly abundant in beef, and have important physiological roles in anti-oxidative and anti-inflammatory reactions, as well as neurological, muscular, retinal, immunological and cardiovascular function. Of particular note, taurine, carnosine, anserine, and creatine are absent from plants, and hydroxyproline is negligible in many plant-source foods. Consumption of 30 g dry beef can fully meet daily physiological needs of the healthy 70-kg adult human for taurine and carnosine, and can also provide large amounts of creatine, anserine and 4-hydroxyproline to improve human nutrition and health, including metabolic, retinal, immunological, muscular, cartilage, neurological, and cardiovascular health. The present review provides the public with the much-needed knowledge of nutritionally and physiologically significant amino acids, dipeptides and creatine in animal-source foods (including beef). Dietary taurine, creatine, carnosine, anserine and 4-hydroxyproline are beneficial for preventing and treating obesity, cardiovascular dysfunction, and ageing-related disorders, as well as inhibiting tumorigenesis, improving skin and bone health, ameliorating neurological abnormalities, and promoting well being in infants, children and adults. Furthermore, these nutrients may promote the immunological defense of humans against infections by bacteria, fungi, parasites, and viruses (including coronavirus) through enhancing the metabolism and functions of monocytes, macrophages, and other cells of the immune system. Red meat (including beef) is a functional food for optimizing human growth, development and health.
... The use of protein materials (collagen) to obtain new auxiliaries for leather processing is an important component of research in the field [3][4][5][6][7][8][9][10][11][12][13]. Figure 1 schematically shows the experimental model for obtaining collagen hydrolysates from chrome-free tanned (wetwhite) leather waste. The physical-chemical characteristics of the obtained collagen material (marked R 0 ) are presented in Table 2 ...
... In 2000, Moskowitz was one of the first to describe the potential beneficial effects of collagen peptides (CPs), also known as collagen hydrolysate, as a treatment for osteoarthritis and osteoporosis (Moskowitz 2000). Subsequently, a study by Oesser and Seifert was the first demonstrating that CPs are able to stimulate the biosynthesis of the extracellular matrix (ECM) of cartilage (Oesser and Seifert 2003), but this finding was not confirmed in preclinical studies (Schadow et al. 2013(Schadow et al. , 2017. ...
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The purpose of this study was to examine the effects of 12 weeks collagen peptide (CP) supplementation on knee pain and function in individuals with self-reported knee pain. Healthy physically active individuals (n = 167; aged 63 [interquartile range = 56–68] years) with self-reported knee pain received 10 g/day of CP or placebo for 12 weeks. Knee pain and function were measured with the Visual Analog Scale (VAS), the Lysholm questionnaire, and the Knee injury and Osteoarthritis Outcome Score (KOOS). Furthermore, we assessed changes in inflammatory, cartilage, and bone (bio)markers. Measurements were conducted at baseline and after 12 weeks of supplementation. Baseline VAS did not differ between CP and placebo (4.7 [2.5–6.1] vs. 4.7 [2.8–6.2], p = 0.50), whereas a similar decrease in VAS was observed after supplementation (−1.6 ± 2.4 vs. −1.9 ± 2.6, p = 0.42). The KOOS and Lysholm scores increased after supplementation in both groups (p values < 0.001), whereas the increase in the KOOS and Lysholm scores did not differ between groups (p = 0.28 and p = 0.76, respectively). Furthermore, CP did not impact inflammatory, cartilage, and bone (bio)markers (p values > 0.05). A reduced knee pain and improved knee function were observed following supplementation, but changes were similar between groups. This suggests that CP supplementation over a 12-week period does not reduce knee pain in healthy, active, middle-aged to elderly individuals. Novelty CP supplementation over a 12-week period does not reduce knee pain in healthy, active, middle-aged to elderly individuals. CP supplementation over a 12-week period does not impact on inflammatory, cartilage, and bone (bio)markers in healthy, active, middle-aged to elderly individuals.
... Clinical studies suggest that the ingestion of 10g collagen hydrolysates daily reduces pain in patients with osteoarthritis of the knee or hip while blood concentration of hydroxyproline is increased. Clinical use was associated with minimal adverse effects, mainly gastrointestinal, characterized by fullness or unpleasant taste [23]. ...
Article
Background Potential effects of different doses of specific fish collagen peptides (Naticol®) on the signs of skin ageing were firstly assessed in double-blind, randomised and placebo controlled clinical studies. The studies showed benefits of fish collagen peptides (Naticol®) on skin firmness, skin hydration and wrinkle appearance. In addition to these benefits, some animal experiments have suggested that ingestion of specific fish collagen peptides (Naticol®) might also have beneficial effects on joint health such as osteoarthritis. Aim This pilot clinical trial study was designed to assess the safety and tolerability of daily oral doses of specific fish collagen peptides (Naticol®) in healthy subjects with knee osteoarthritis. Methods In a double-blinded, placebo controlled pilot clinical study, 30 adults (20 active; 10 placebo) consumed a 10g sachet of the investigational product (Naticol®; specific fish collagen peptides) and a comparator product (maltodextrin) daily in 20cl of cold liquid (fruit juice, milk or cold tea) 15 minutes before breakfast, for 8 weeks. Potential pain reduction was tested using the Western Ontario McMaster Universities (WOMAC) scores; Quality of Life (QOL) using the Participant Global Assessment (SF-36v2 questionnaire) and Physical performance using the Short Physical Performance Battery (SPPB) at both baseline and after 8 weeks. Results From effect size statistics (Cohen’s d), subjects in the active group experienced more of an improvement across the majority of measurements than subjects in the placebo group over the 8 weeks of the study. From the WOMAC Physical Function sub-score the placebo group experienced a small improvement (d = 0.68) against the active group’s large improvement (d = 1.08). While for the WOMAC Composite score the active group experienced a large improvement (d = 1.07). In terms of the SF-36v2 Social Functioning and Pain sub scores, there was no change in score for the placebo group (d = 0.00), while the active group noticed an improvement by small (d = -0.34) and medium (d = -0.50) amounts, respectively. While for the SF-36v2 Emotional Well-Being and General Healthy Issues sub-scores, the placebo based subjects dis-improved over the 8 weeks (d = 0.07 and 0.15, respectively), while the subjects in the active group improved in both cases (d = -0.18) and -0.09, respectively). In terms of the SPPB, active group experienced an improvement in the Chair test and Total score. (d = -0.47 and d = -0.33, respectively). There was no difference in adverse events between groups (p > 0.05). Conclusion The results demonstrated that daily oral doses of specific fish collagen peptides (Naticol®) in healthy subjects with knee osteoarthritis has the potential to reduce pain, improve quality of life and lower body function. Further studies with a higher dosage of product for subjects with a body weight greater than 70 kg should be performed. Keywords Clinical study; Effect size; Fish collagen peptides; Naticol®; Osteoarthritis.
... 159 A 24-week multinational double-blind randomized controlled trial of patients with knee osteoarthritis indicated that treatment with 10 g/day of collagen hydrolysate elicited no significant changes in the WOMAC index. 160,161 Though collagen hydrolysate appears to demonstrate equivocal efficacy in reducing osteoarthritis-associated pain, its use is accepted in the treatment of osteoarthritis. 160 Collagen hydrolysates are considered highly safe, with minimal adverse effects such as gastrointestinal fullness and unpleasant taste. ...
Article
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Naringin is a naturally occurring flavonoid found in plants of the Citrus genus that has historically been used in traditional Chinese medical regimens for the treatment of osteoporosis. Naringin modulates signaling through numerous molecular pathways critical to musculoskeletal development, cellular differentiation, and inflammation. Administration of naringin increases in vitro expression of bone morphogenetic proteins (BMPs) and activation of the Wnt/β-catenin and extracellular signal-related kinase (Erk) pathways, thereby promoting osteoblastic proliferation and differentiation from stem cell precursors for bone formation. Naringin also inhibits osteoclastogenesis by both modifying RANK/RANKL interactions and inducing apoptosis in osteoclasts in vitro. In addition, naringin acts on the estrogen receptor in bone to mimic the native bone-preserving effects of estrogen, with few systemic side effects on other estrogen-sensitive tissues. The efficacy of naringin therapy in reducing the osteolysis characteristic of common musculoskeletal pathologies such as osteoporosis, degenerative joint disease, and osteomyelitis, as well as inflammatory conditions affecting bone such as diabetes mellitus, has been extensively demonstrated in vitro and in animal models. Naringin thus represents a naturally abundant, cost-efficient agent whose potential for use in novel musculoskeletal biotherapies warrants re-visiting and further exploration through human studies. Here, we review the cellular mechanisms of action that have been elucidated regarding the action of naringin on bone resident cells and the bone microenvironment, in vivo evidence of naringin’s osteostimulative and chondroprotective properties in the setting of osteolytic bone disease, and current limitations in the development of naringin-containing translational therapies for common musculoskeletal conditions.
... The measured fluorescence (λ ex = 295 nm and λ em = 340 nm) is characteristic for the tryptophan residues in OVA (Lakowicz, 1999;Onda and Hirose, 2003). This method was selective for OVA with no interference from gelatin (at the tested concentrations), as gelatin lacks tryptophan in its structure (Moskowitz, 2000). Other analysis methods have been used for quantitation of the protein loading in gelatin nanoparticles; for example OVA loading in gelatin nanoparticles was evaluated semi-quantitatively by SDS-PAGE electrophoresis and Coomasie-Blue staining (Zwiorek, 2006), and bovine serum albumin (BSA) loading in gelatin nanoparticles has been detected using HPLC method (Baseer et al., 2019). ...
Article
Multifunctional gelatin nanoparticles modified by NIR-emitting gold/silver alloy nanoclusters loaded with ovalbumin (OVA) as a model antigen were developed. Two different designs of nanoparticles were introduced; positively charged NPs with OVA displayed over the surface (S-NPs) versus OVA encapsulated in the NPs’ matrix and surface functionalized by dextran (Dex-NPs) for dendritic cells targeting. The nanoparticles showed average particle sizes of 210 and 305 nm and zeta potentials of +25.6 and -23.9 mV, for S-NPs and Dex-NPs, respectively. Both types of NPs succeeded to induce maturation of murine bone marrow-derived dendritic cells (BMDCs) as indicated by the upregulated surface expression of MHC-II and co-stimulatory molecules CD86, CD80 and CD40. Dex-NPs induced no cytotoxicity in BMDC, in contrast to S-NPs. Functionalization of NPs with dextran increased their uptake by BMDCs, enhanced secretion of immune stimulatory chemokines, and boosted their T cell stimulation capacity. Co-culture of NP loaded BMDCs with OVA-specific CD4 or CD8 T cells, induced enhanced T cell proliferation and release of IL-2 from both CD8 and CD4 cells and IFN- γ from CD8 T cells. This highlights the potential of the developed NPs as vaccines for inducing T helper 1 type CD4 as well as CD8 responses, such as vaccines for cancer or viral infections.
... 15,16 In addition to these preclinical studies, open-label or placebo-controlled randomized clinical trials have been conducted. Several data showed the bene cial effects of CH on joint health in different populations particularly comprising individuals with OA. 17,18,19,20,21,22 The daily administration of CH for 3 months improved joint health or function. That is, there was a decrease in pain 11,12,14 and dependency on pain relievers 14 and improvement in leg strength. ...
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Background Knee osteoarthritis (OA) is a leading cause of disability among elderly individuals. Medical and surgical treatments are expensive and have side effects. The current study aimed to investigate the efficacy and safety of FlexC-II ® , a type II collagen hydrolysate, and BRAND'S Essence of Chicken with FlexC-II ® (BEC-FlexC-II ® ) on joint, muscle, and bone functions among elderly adults with OA.Methods Patients (n = 160) with grade 1–3 knee OA based on the Kellgren–Lawrence classification system, joint pain for ≥3 months, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score of >6 were considered eligible in this study. The participants were randomized into four groups (BEC-FlexC-II ® , FlexC-II ® , glucosamine hydrochloride [HCl], and placebo) and were instructed to perform resistance training for 24 weeks. The outcomes included WOMAC score, visual analogue scale (VAS) score, hand grip strength, fat-free mass (FFM), bone mass, and 36-Item Short-form Survey score. ResultsThe WOMAC scores of all groups improved after 24 weeks. However, the results did not significantly differ. Meanwhile, there was a remarkable difference in the VAS score between groups (P = 0.039). The FlexC-II ® group had a greater reduction in pain than the placebo group (mean ± standard error: −1.3 ± 0.45, P = 0.021). In the FlexC-II ® group, the VAS score significantly reduced by 0.9 ± 1.89 (P = 0.034) after 14 days. In the adjusted analyses, the BEC-FlexC-II ® group had a significantly higher FFM than the glucosamine HCl (P = 0.02) and placebo (P = 0.017) groups and hand grip strength than the glucosamine HCl group (P = 0.002). Further, on the basis of a subgroup analysis, participants with poor training compliance in the BEC-FlexC-II ® group had a significantly higher left hip bone mass than those in the placebo (P = 0.01) and glucosamine HCl (P = 0.049) groups.Conclusions FlexC-II ® relieves OA-associated pain within 14 days, and BEC-FlexC-II ® increases muscle mass and strength after 24 weeks. Thus, BEC-Flex-CII ® is a promising novel, holistic supplement that can improve mobility by promoting joint, muscle, and bone functions among elderly individuals. However, full-scale studies should be conducted in the future to validate these findings.Trial registrationThis clinical trial was retrospectively registered in ClinicalTrials.gov with the ID NCT04483024 on July 20, 2020. URL: https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0008FK4&selectaction=Edit&uid=U0004BM2&ts=2&cx=-5y1oh4
... Collagen has been widely processed as products in food, cosmetic, biomedical, and pharmaceutical industries. For examples, oral consumption of collagen peptides as a food supplement may improve low bone mineral density in people in malnutrition and people suffering from degenerative joint diseases [20] . Fish scale is another good source of gelatin which has a rheological property of thermo-reversible transformation between sols and gel thus widely utilized in food, pharmaceutical, and photographic industries especially in the culinary area. ...
Article
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Fish scale, the chief waste materials generated during fish processing is however a promising and cost efficacious source of different important nutrients but unfortunately it has not received much attention. This consideration stresses to explore the proximate composition and minerals contents of fish scales from 12 different fish species collected from three different fish market in Dhaka city to evaluate their usage as potential bioactive compounds. The average carbohydrate, lipid, protein, moisture and ash contents were recorded within a range of 0.35± 0.24 to 2.18 ±0.68 %, 0.27±0.21 to 1.60± 0.08 %, 40.28 ±1.02 to 71.57± 0.64 %, 7.87± 0.57 to 20.53±0.48 % and 19.06± 0.6 to 39.55± 0.94 % respectively. The research reveals that all the twelve species of fish's scales contained reasonable amount of micronutrients more notably calcium (3246.93±18.98 to 7930.42±60.02 mg/100g), iron (24.15±1.74 to 1360.60±10.43 mg/100g), magnesium (151.13 ±18.5 to 236.56 ±25.61 mg/100g) and phosphorous (230.40 ±5.11 to 2031. 09 ±25.01 mg/100 g).
... Studies have indicated that UC-II supplementation protects from joint damage, improves the daily activities performance, with mobility and physical capacity being important components. Therefore, it is suggested that there was a consequent improvement in the quality of life of patients who received this treatment [13,25,26]. Another test used to assess functionality in such patients is TUG. ...
Article
Background: Knee osteoarthritis (OA) is characterized by a progressive degeneration of cartilage and menisci, leading to pain and locomotor disability. Here, we aimed to assess the effect of an exercise protocol and the oral use of non-hydrolyzed collagen (UC-II) on the functionality and quality of life of women with knee OA. Material and methods: Individuals were divided into three groups (CG [control group]; MG [medication group]; EG [exercise group]). In the CG there was no intervention, while MG received an oral dose (1 capsule/day) of UC-II and the EG held 12 sessions of an exercise protocol. Results: In the functionality tests (6-min walk test, 6MWT and timed up and go test [TUG]) the EG (p < 0.001/p = 0.020) and MG (p = 0.010/p = 0.010) revealed a significant improvement when compared to the CG. In the analysis of quality of life by WOMAC, a significant improvement was found only in the EG (p = 0.030) when compared to the CG; the same happened in the stiffness domain (EG, p = 0.010), despite in the pain domain, both the EG (p < 0.001) and the MG (p = 0.060) were better than the CG. Conclusion: Data obtained here reveal that an exercise protocol and UC-II have similar effects for functionality, despite exercise being superior in promoting the quality of life score.
... The chemical composition of gelatin is in many respects, similar to that of collagen. Gelatin gels generally have melting temperature 35°C that is below human body temperature, which makes gelatin unique in terms of its sensory aspects, especially flavor release which is particularly desired for some food applications [10]. Gelatin samples were prepared by thermal denaturation of the collagen fibrils at 70°C for 6-10 hours in water. ...
Article
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During the conversion of raw hides or skins into leather involves generation of enormous amount of solid waste which has been major concern for environment and cause detrimental effect on it. In leather industry solid wastes can be generated almost from all operations including pre-tanning, tanning, and even post tanning operation. Solid wastes are mainly raw trimmings, fleshing, chrome shaving, buffing dust, keratin, finished scraps etc. The economic development of a country depends on the utilization of indigenous raw materials and their by-products. This paper focuses on utilization of raw trimmings into useful product like non edible gelatin those demand is going up day by day due to its versatile application in various fields. Raw trimmings are mainly originated during sorting of leather before actual tanning process happens and best for non- edible gelatin production as it does not contain any harmful chemicals. This study will also describe the chemical properties of gelatin, gelatin manufacturing process, manufacturing parameters from the leather wastes like raw trimmings. Optimum extraction of non-edible gelatin from raw trimmings found at 75-85?C for 12 hours in slightly basic condition. This study found that huge amount of raw trimmings which generally thrown directly to environment can serve as potential raw materials for the manufacture of non-edible as well as edible gelatin.
... Different clinical studies have investigated the protective effects of collagen on joints [88,89]. It has been suggested that supplementation with 4.5-10 g/day of collagen peptides, at least for 2 months, relieves knee and hip joint pain in people with OA [90]. In a RCT involving 147 athletes, 10 g collagen/day for 24 weeks reduced activity-related joint pain [91]. ...
Article
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Osteoarthritis (OA) is a degenerative inflammatory condition of the joint cartilage that currently affects approximately 58 million adults in the world. It is characterized by pain, stiffness, and a reduced range of motion with regard to the arthritic joints. These symptoms can cause in the long term a greater risk of overweight/obesity, diabetes mellitus, and falls and fractures. Although the current guidelines for the treatment of OA suggest, as the gold standard for this condition, pharmacological treatment characterized by non-steroidal anti-inflammatory drugs (NSAID), opioids, and cyclooxygenase (COX)-2-specific drugs, a great interest has been applied to nutraceutical supplements, which include a heterogeneous class of molecules with great potential to reduce inflammation, oxidative stress, pain, and joint stiffness and improve cartilage formation. The purpose of this review is to describe the potential application of nutraceuticals in OA, highlighting its molecular mechanisms of actions and data of efficacy and safety (when available).
... Native collagen is resistant to peptide cleavage by digestive enzymes, resulting in poor absorption (as low as 10%) into the circulation. 100 Production into gelatin increases digestion and absorption, though perhaps not to the extent of other dietary proteins. For instance, work using rodent models has shown that relatively more nitrogen is recovered from the intestine of rats Figure 2 Graphical representation of the industrial sources of dietary collagen, the extraction procedures used to produce hydrolyzed collagen, and the proposed applications of collagen peptide ingestion in humans. ...
Article
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Collagen is the central structural component of extracellular connective tissue, which provides elastic qualities to tissues. For skeletal muscle, extracellular connective tissue transmits contractile force to the tendons and bones. Connective tissue proteins are in a constant state of remodeling and have been shown to express a high level of plasticity. Dietary-protein ingestion increases muscle protein synthesis rates. High-quality, rapidly digestible proteins are generally considered the preferred protein source to maximally stimulate myofibrillar (contractile) protein synthesis rates. In contrast, recent evidence demonstrates that protein ingestion does not increase muscle connective tissue protein synthesis. The absence of an increase in muscle connective tissue protein synthesis after protein ingestion may be explained by insufficient provision of glycine and/or proline. Dietary collagen contains large amounts of glycine and proline and, therefore, has been proposed to provide the precursors required to facilitate connective tissue protein synthesis. This literature review provides a comprehensive evaluation of the current knowledge on the proposed benefits of dietary collagen consumption to stimulate connective tissue remodeling to improve health and functional performance.
... Even though findings are equivocal, there is compelling evidence that COL inhibits bone collagen breakdown and alleviates painful symptoms associated with degenerative joint conditions (García-Coronado et al. 2019). As a result, two review papers (Moskowitz 2000;Bello and Oesser 2006) concluded that COL could be used as a safe, therapeutic supplement in helping to manage symptoms associated with osteoarthritis and osteoporosis. ...
Article
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Collagen peptide supplementation (COL), in conjunction with exercise, may be beneficial for the management of degenerative bone and joint disorders. This is likely due to stimulatory effects of COL and exercise on the extracellular matrix of connective tissues, improving structure and load-bearing capabilities. This systematic review aims to evaluate the current literature available on the combined impact of COL and exercise. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a literature search of three electronic databases-PubMed, Web of Science and CINAHL-was conducted in June 2020. Fifteen randomised controlled trials were selected after screening 856 articles. The study populations included 12 studies in recreational athletes, 2 studies in elderly participants and 1 in untrained pre-menopausal women. Study outcomes were categorised into four topics: (i) joint pain and recovery from joint injuries, (ii) body composition, (iii) muscle soreness and recovery from exercise, and (iv) muscle protein synthesis (MPS) and collagen synthesis. The results indicated that COL is most beneficial in improving joint functionality and reducing joint pain. Certain improvements in body composition, strength and muscle recovery were present. Collagen synthesis rates were elevated with 15 g/day COL but did not have a significant impact on MPS when compared to isonitrogenous higher quality protein sources. Exact mechanisms for these adaptations are unclear, with future research using larger sample sizes, elite athletes, female participants and more precise outcome measures such as muscle biopsies and magnetic imagery.
... Given that collagen peptides have been demonstrated to influence microcirculation positively [52,53], this may result in greater effects in enhancing growth of muscle in comparison to other protein sources. Furthermore, since collagen peptides have been demonstrated to reduce both osteoarthritis pain significantly, as well as relieve functional joint pain [54,55], this could result in those supplemented with them experiencing less pain whilst performing resistance exercises, and hence be more responsive to training. ...
Article
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The increasing commercial necessity to valorise commodities such as gelatine has led to significant developments in its processing and the outcome of these refinements has resulted in new applications in fields such as pharmaceuticals, medical devices, cosmetics, food and nutraceuticals. This in turn has led to the investigation of alternative sources of compounds with collagen-like properties, other than the conventionally used raw materials from mammalian species. Moreover, the current desire to seek natural, rather than synthetic compounds-especially regarding oral consumption and/or topical application-combined with the ability of gelatine derived products to form gels with varying degrees of flexibility and hydroplasticity has also accelerated research into previously unexplored applications. In the food sector, these include:- use of gelatine derivatives as an encapsulating agent (including the development of micro-beads as carriers of active compounds) foaming agents, emulsifiers, biodegradable films, colloid stabilizers and as nutraceuticals. The latter sector has especially benefitted from developments in enzymatic hydrolysis processes, where specific and highly characterised bioactive peptides often containing the amino acid hydroxyproline are end-products which have been identified to be orally bioavailable and metabolised and hence likely to deliver potential clinical benefits. This review examines manufacturing processes employed to typically produce hydrolysed collagen, evaluates studies examining bioavailability, metabolism and likely health benefits as well as potential clinical applications as a nutraceutical.
... Some studies have shown that etoxib has a positive effect on OA inflammation, and shows good tolerance and low incidence of side effects (17). Collagen hydrolysate is a potential therapeutic agent for OA and osteoporosis (18). However, these drugs can only improve mild OA and have no good effect on serious diseases requiring surgical treatment. ...
Article
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Osteoarthritis (OA) is the most common motor system disease in the elderly, with a high incidence and a huge social and economic burden. Therefore, it is urgent to study its potential pathogenesis to improve the therapeutic effect of the disease. In this study, we constructed a number of regulator-mediated OA dysfunction modules, and carried out in-depth analysis in order to examine the disease development process. Differential expression analysis, co-expression analysis and enrichment analysis were combined to screen genes related to disease progression. Subsequently, key regulatory factors in the process of OA were identified based on the pivotal regulators that may manipulate important parts of the module subnetwork. A total of 16 OA dysfunction modules were obtained, involving the aggregation of 3,239 module genes. Then, enrichment analysis showed that module genes were significantly involved in apoptosis, inflammation-related functions and signaling pathways. Finally, we revealed a series of regulators, including 842 ncRNA (miR-132-3p, miR-130a-3p and miR-590-3p), 59 transcription factors (NFKB1, RELA and STAT3). We consider that STAT3 is the core transcription factor and promotes the development of OA through the signal of NF-κB. Overall, our results provide biologists and pharmacists with a new way of thinking to reveal the disease process of OA, and provide a wider range of candidate targets for follow-up research.
... In a series of clinical studies, pain and joint function in osteoarthritic patients were clearly improved by the daily administration of collagen peptides over a period of three to six months, whereas in other trials the effect on pain and joint mobility was less pronounced or limited to a subgroup [31][32][33][34][35][36][37]. Since a short-term increase in degradation can be assumed during or immediately after exercise [5], the positive effect of collagen peptides was also tested in activity-related joint complaints involving non-diseased subjects. ...
Article
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First evidence indicates that the supplementation of specific collagen peptides is associated with a significant reduction in activity-related joint pain in young adults. The purpose of the current investigation was to confirm the efficacy of the same collagen peptides in a comparable study population. In total, 180 active men and women aged between 18 and 30 years with exercise-related knee pain but no diagnosed joint disease completed the trial over a period of 12 weeks. Participants were randomly assigned to the group receiving 5 g of specific collagen peptides (CP-G) or to the placebo group (P-G). For the primary outcome, changes in pain during or after exercise from pre- to post-intervention were assessed by the participants using the Visual Analog Scale (VAS). These changes were additionally evaluated by the examining physician by means of anamnesis and physical examination of the affected knee joint. As secondary outcomes, pain under resting conditions and after 20 squats were compared between the study groups. In addition, the mobility of the knee joint and the use of alternative therapies (e.g., ointments or physiotherapy) were recorded. The supplementation of specific collagen peptides derived from type I collagen with a mean molecular weight of 3 kDa led to a significantly (p = 0.024) higher reduction of exercise-induced knee pain (−21.9 ± 18.3 mm) compared with the placebo group (−15.6 ± 18.5 mm). These findings were consistent with the physician’s evaluation (−23.0 ± 19.2 mm vs. −14.6 ± 17.9 mm, p = 0.003). The decrease in pain under resting conditions and after squats did not significantly differ between the groups, as only a small number of participants suffered from pain under these conditions. Due to the clinically unremarkable baseline values, the mobility of the knee joint did not change significantly after the intervention. In conclusion, the current investigation confirmed that the oral intake of bioactive collagen peptides used in the current investigation led to a statistically significant reduction of activity-related joint pain in young active adults suffering from knee joint discomfort.
... Gelatin, also referred to collagen hydrolysate, is an irreversibly hydrolyzed form of collagen present in the bones, skin, and other connective tissues [16,17]. Gelatin has been used for treating osteoarthritis, rheumatoid arthritis, and osteoporosis, as well as for recovery after sports-related injury [18][19][20]. However, it is not known if gelatin has an effect on OC differentiation and bone resorbing functions. ...
Article
Here, we assessed the effects of varying concentrations of gelatin coating on Receptor Activator of Nuclear Factor κ-B Ligand (RANKL)-induced RAW264.7 murine macrophage differentiation into osteoclast (OC) via osteoclastogenesis. The microstructures of coating surfaces with different concentrations of gelatin were examined by scanning electron microscopy and atomic force microscopy. Increased gelatin coating concentrations led to decreased gel rigidity but increased surface adhesion force attenuated OC differentiation and the decreased actin ring formation in RANKL-induced osteoclastogenesis. The decreased actin ring formation is associated with decreased lysosomal-associated membrane protein 1 (LAMP1) activity and bone resorption in the differentiated OCs with different gelatin coating concentrations as compared to the cells differentiated without gelatin coatings. In addition, increasing concentrations of gelatin coating attenuated the medium TGF-β1 protein levels and the expression levels of TGF-β and type-I (R1) and type-II (R2) TGF-β receptors in OCs, suggesting the gelatin-induced suppression of TGF-β signaling for the regulation of RNAKL-induced OC differentiation. Taken together, these findings showed that changes in gelatin coating concentrations, which were associated with altered gel thickness and substrate rigidity, might attenuate TGF-β signaling events to modulate OC differentiation and concomitant actin ring formation and bone matrix resorption in RANKL-induced osteoclastogenesis.
... Collagen hydrolysates belong to one of the most interesting class of nutraceuticals to improve OA condition or delay its outcomes, especially through the downregulation of the inflammation and degradation molecules [28]. The use of collagen hydrolysates in vivo dates back to a 2000 study that reported that collagen hydrolysates were able to reduce pain in patients with knee or hip OA, and increase the blood concentration of hydroxyproline [43]. Since then, different sources of collagens have been studied. ...
Article
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Articular cartilage experiences mechanical constraints leading to chondral defects that inevitably evolve into osteoarthritis (OA), because cartilage has poor intrinsic repair capacity. Although OA is an incurable degenerative disease, several dietary supplements may help improve OA outcomes. In this study, we investigated the effects of Dielen® hydrolyzed fish collagens from skin (Promerim®30 and Promerim®60) and cartilage (Promerim®40) to analyze the phenotype and metabolism of equine articular chondrocytes (eACs) cultured as organoids. Here, our findings demonstrated the absence of cytotoxicity and the beneficial effect of Promerim® hydrolysates on eAC metabolic activity under physioxia; further, Promerim®30 also delayed eAC senescence. To assess the effect of Promerim® in a cartilage-like tissue, eACs were cultured as organoids under hypoxia with or without BMP-2 and/or IL-1β. In some instances, alone or in the presence of IL-1β, Promerim®30 and Promerim®40 increased protein synthesis of collagen types I and II, while decreasing transcript levels of proteases involved in OA pathogenesis, namely Htra1, and the metalloproteinases Mmp1-3, Adamts5, and Cox2. Both Promerim® hydrolysates also decreased Htra1 protein amounts, particularly in inflammatory conditions. The effect of Promerim® was enhanced under inflammatory conditions, possibly due to a decrease in the synthesis of inflammation-associated molecules. Finally, Promerim® favored in vitro repair in a scratch wound assay through an increase in cell proliferation or migration. Altogether, these data show that Promerim®30 and 40 hold promise as dietary supplements to relieve OA symptoms in patients and to delay OA progression.
Article
This work brings a relevant contribution to the development of functional beverages by investigating the effect of protein hydrocolloids on the particle size distribution, flow behaviour and friction profile of low-fat chocolate-flavoured milk (Choc-FM_(SMP)). Three proteins were tested: gelatin, collagen hydrolysate (ColHdr) and microparticulate whey (MWhey). Our results revealed that the flow consistency coefficient (K) increased by the addition of the protein hydrocolloids without significantly affecting the particle size distribution (the majority of the particles did not exceed 40 μm). At the highest concentration level (1.5% w/w), ColHdr and MWhey presented K ∼ 10 mPa sⁿ. This represented a 4-fold increase in the K value obtained for Choc-FM_(SMP) (without hydrocolloid). Gelatin, however, reached a maximum K ∼ 6 mPa sⁿ for the upper-limit concentration tested (0.5% w/w). The magnitude of the coefficient of friction (CoF ∼ 0.4 to 0.5) was not significantly affected by the type or concentration of proteins used. The friction trend (regimes), however, was mainly influenced by the protein type. The gelatin-based system was characterized by a prolonged mixed-regime. For ColHdr and MWhey systems, there was evidence that the cocoa particles promoted abrasive wear which, in turn, was assigned with a decaying trend of CoF and friction hysteresis at the dry-contact zone (sliding speed < 1mm s⁻¹). In both sensory and rheological measurements, the increase in thickness promoted by the hydrocolloids can be ordered, from high to low, as ColHdr∼MWhey > gelatin. Creaminess and oiliness were ranked slightly higher for ColHdr than the gelatin-based sample.
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In this study, the effect of hydrolyzed type-II collagen supplementation on Y balance performance investigated in patients with stage 2-3 osteoarthritis according to Kellgren Lawrence radiological staging. A total of 20 female patients that consists of 10 experimental groups with a average age of 38.7 ± 2.70 and 10 control groups with a average age of 38.3 ± 1.99 were included in the study. Tthe experimental group patients received paracetamol treatment with 1500 mg/day for three months orally hydrolyzed type-II collagen treatment on an empty stomach 10 g/day in the morning. The patients in the control group received only 1500 mg/day paracetamol treatment for three months. As a result of the statistical analysis that is performed at the end of the study, it is found that there are statistically significant differences in the Y balance's pre-test and post-test performance values of the experimental group (p <0.05). However, there is no significant difference in the pre-test and post-test performance values of the control group (p> 0.05). As a result, it can be said that type-II collagen supplementation, which is one of the building blocks of joint cartilage in the body, can provide positive effects on the balance performance of female patients with knee osteoarthritis.
Article
Marine biodiversity provides a range of diverse biological resources, including seafoods that are rich in protein and a well-balanced amino acid composition. Previous studies have shown that peptides can improve bone formation and/or inhibit bone resorption, suggesting the potential for seafood bioactive peptides (SBPs) in development of food and pharmaceuticals for management of osteoporosis. In this review, we provided an up-to-date overview of the anti-osteoporosis activity of SBPs and describe their underlying molecular mechanisms. We focus on SBPs’ development, broadening the scope and depth of research, as well as strengthening in vivo and clinical research. In vitro cell cultures and in vivo animal osteoporosis models have demonstrated the potential for seafood-derived SBPs, including fish, mollusks, crustaceans, seaweed and microalgae, in preventing osteoporosis. These peptides may act by activating the signaling pathways, such as BMP/Smads, MAPK, OPG/RANKL/RANK, and NF-κB, which are associated with modulation bone health.
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This study showed that gelatin ingestion significantly increased prolyl-hydroxyproline (Pro-Hyp) levels in plasma of 9 subjects, with maximum concentrations of 15.5 ± 3.0 nmol/mL 2 h post-ingestion. Hydroxyprolyl-glycine (Hyp-Gly) concentrations were significantly increased and reached a maximal level of 2.3 ± 0.5 nmol/mL 1 h post-ingestion of gelatin. A low molecular weight gelatin hydrolysate (LMW-GH) significantly enhanced concentrations of both peptides, while gelatin hydrolysate ingestion did not significantly enhance the maximum concentration and area under the plasma concentration-time curve (AUC) of Hyp-Gly relative to gelatin. The absorption of free Hyp following gelatin ingestion (94.4 ± 16.4 nmol/mL) was significantly lower relative to GH (150.9 ± 15.3 nmol/mL) and LMW-GH (169.1 ± 32.5 nmol/mL). The present study is the first report demonstrating that Hyp-containing peptides are elevated to μM levels in human plasma after gelatin ingestion. These results suggested that gelatin is useful as a functional food as effectively as GH.
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Gelatins are important and frequently-used food additives, but the quality control of gelatins is always an intractable problem in routine analysis. In this work, a new strategy for simultaneously rapid identification and quantification of gelatins from various species using ultrasound assisted digestion-UPLC-MS/MS was described. Fourteen peptide markers were used for authenticity of gelatins by the presence or absence of these species-specific peptides. In the meantime, adulteration ratios could be calculated based on the peak area of different species peptide markers. With 10 g/L trypsin and ultrasound application, digestion time could be decreased from >12h (traditional method) to 5 min, and the determination of animal gelatins could be achieved in 20 min with a single analysis run. Twenty-five commercial gelatin samples were screened, among which two deer-hide gelatin samples were adulterated with 900 g/kg and 265 g/kg cattle-hide gelatin (CHG); two donkey-hide gelatin (ACC) samples were adulterated with 66 g/kg and 381 g/kg horse-hide gelatin; and one ACC sample was adulterated with 786 g/kg CHG. This strategy provides an efficient and sensitive authentication and traceability of gelatin-containing products, and could also be applied to processed meat or protein food.
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The marine environment has a tremendous biodiversity and is the source of a biologically active molecules with huge potential in pharmaceutical and biotechnological applications. The health benefits of seafood consumption have primarily been associated with protective effects against cardiovascular diseases (CVD). However, intake of seafood has also been associated with improved faetal and infant development, as well as several other diseases and medical conditions. The health promoting effects have been chiefly attributed to the long-chain n-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In addition, the general fatty acid profile is considered favourable. On the other hand, recent and emerging research on seafood proteins and other seafood derived components suggest that these nutritional components contribute to the health effects. In this review the nutritional characteristics and health benefits of marine foods, and discuss some current and future trends in marine food consumption.
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To assess the effects of intra-articular injections of hyaluronan on symptoms of knee osteoarthritis (OA). Two hundred and forty patients with symptomatic, radiological knee OA were randomly assigned to treatment with weekly injections for five weeks with either 25 mg of high molecular weight hyaluronan or vehicle. Results were evaluated at weeks 1, 2, 3, 4, 5, 13, and 20 by visual analogue scales (pain, function, motion, activity), algofunctional index, and global evaluation by patient and investigator. Analysis was by "intention to treat', "per protocol', and area under the curve principles on unstratified patient groups and for patients stratified into four groups of equal size by age and baseline algofunctional index. No serious side effects were reported. At 20 weeks both treatment groups were improved compared with baseline, with no difference between unstratified groups treated with placebo or hyaluronan. Comparison of treatment groups stratified by age and baseline algofunctional index revealed a significant difference in favour of hyaluronan over placebo (pain, activity, algofunctional index, global evaluations by patient and investigator) for patients older than 60 years and with a baseline algofunctional index greater than 10. There was no clinically relevant difference between the two treatments for the other three stratified subgroups of younger age or fewer symptoms. Similar results were obtained by area under the curve, intention to treat, and per protocol analysis. Patients older than 60 years with knee osteoarthritis and with significant symptoms corresponding to an index of severity of knee disease of 10 or more, comprise the group most likely to benefit from treatment with intra-articular hyaluronan injections.
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Glucosamine and chondroitin preparations are widely touted in the lay press as remedies for osteoarthritis (OA), but uncertainty about their efficacy exists among the medical community. To evaluate benefit of glucosamine and chondroitin preparations for OA symptoms using meta-analysis combined with systematic quality assessment of clinical trials of these preparations in knee and/or hip OA. We searched for human clinical trials in MEDLINE (1966 to June 1999) and the Cochrane Controlled Trials Register using the terms osteoarthritis, osteoarthrosis, degenerative arthritis, glucosamine, chondroitin, and glycosaminoglycans. We also manually searched review articles, manuscripts, and supplements from rheumatology and OA journals and sought unpublished data by contacting content experts, study authors, and manufacturers of glucosamine or chondroitin. Studies were included if they were published or unpublished double-blind, randomized, placebo-controlled trials of 4 or more weeks' duration that tested glucosamine or chondroitin for knee or hip OA and reported extractable data on the effect of treatment on symptoms. Fifteen of 37 studies were included in the analysis. Reviewers performed data extraction and scored each trial using a quality assessment instrument. We computed an effect size from the intergroup difference in mean outcome values at trial end, divided by the SD of the outcome value in the placebo group (0.2, small effect; 0.5, moderate; 0.8, large), and applied a correction factor to reduce bias. We tested for trial heterogeneity and publication bias and stratified for trial quality and size. We pooled effect sizes using a random effects model. Quality scores ranged from 12.3% to 55.4% of the maximum, with a mean (SD) of 35.5% (12%). Only 1 study described adequate allocation concealment and 2 reported an intent-to-treat analysis. Most were supported or performed by a manufacturer. Funnel plots showed significant asymmetry (P< or =.01) compatible with publication bias. Tests for heterogeneity were nonsignificant after removing 1 outlier trial. The aggregated effect sizes were 0.44 (95% confidence interval [CI], 0.24-0.64) for glucosamine and 0.78 (95% CI, 0.60-0.95) for chondroitin, but they were diminished when only high-quality or large trials were considered. The effect sizes were relatively consistent for pain and functional outcomes. Trials of glucosamine and chondroitin preparations for OA symptoms demonstrate moderate to large effects, but quality issues and likely publication bias suggest that these effects are exaggerated. Nevertheless, some degree of efficacy appears probable for these preparations.
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The effect of daily gelatine ingestion on human scalp hair was studied in a normal adult population. The most dramatic effect of supplementing the normal diet with 14 grams of gelatine daily was an increase in hair diameter averaging 9.3% in the first study and 11.3% in the second study. Approximately seventy percent of the subjects in both studies showed increases in hair diameter ranging from 5% to 45%. It is postulated that this increase constitutes an improvement in the mechanical properties of the hair. Further, it was shown that the increase in hair diameter was generally inversely proportional to the initial, predosing value. Within 6 months after cessation of gelatine dosing, hair diameter reversed back its original level. The increase was therefore directly attributable to gelatine ingestion. Yield point and yield extension increased with increases in hair diameter. Furthermore, yield stress values indicated that strength changes in the hair fibers were due mainly to increases in diameter and not to changes in hair structure. Gelatine ingestion did not affect linear hair growth. Increases in hair diameter was not affected by age of subjects or diet quality. Generally, male subjects exhibited smaller increases than females, possibly as a consequence of greater initial hair thickness. A proposed mechanism of action for the effect of gelatine on scalp hair is discussed.
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Introduction Recently two of us reported on the treatment of the brittle nail with gelatin.1 This study raised several questions requiring further investigation. Among these were the following: (1) the duration of the effect after ingestion of gelatin has been stopped; (2) which clinical conditions and pathological states of the nails respond to gelatin intake; (3) the mechanism of the effect of gelatin on nails. It was felt also that an attempt should be made to correlate other physiological changes in pathological nails. Specifically, the concept that blood levels of calcium, phosphorus, and/or the basal metabolic rate in pathological nails are disturbed, was challenged. This idea seems to have established itself firmly on the medical mind, in spite of the work of Kile2 and others. A recent query on brittleness in nails was answered by giving calcium deficiency3 as the usual cause. The
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Although gratifying approaches to the management of osteoarthritis (OA) are available as a result of improved knowledge about disease pathophysiology (see below), responses are limited in many patients by less than optimal responses to available modalities or by intolerance or toxicity to currently available medications. Accordingly, the search continues for agents that are characterized by greater symptomatic relief, less overall toxicity and, optimally, agents that may have a beneficial effect on the basis of disease structural modification. A veritable explosion of new agents considered to have potential efficacy in the treatment of OA has taken place. Carefully performed clinical studies, using designs of sufficient precision and power to avoid errors in conclusions and interpretation, are essential to support the use of these agents in treatment of OA. Current treatment of osteoarthritis includes: Non-Pharmacologic Therapy Patient education Programmed exercises Weight loss Joint protection Thermal modalities Pharmacologic Therapy Nonopioid analgesics (e.g., acetaminophen) Topical analgesics (e.g., capsaicin) Nonsteroidal anti-inflammatory drugs Intra-articular steroids Intra-articular hyaluronate Opioid analgesics Surgical Approaches Arthroscopic debridement Osteotomy Total joint arthroplasty Glucosamine and chondroitin sulfate, agents marketed as nutritional supplements in the United States, have been purported to be effective in the treatment of OA in various studies over the past 3 to 4 decades. 4,5,6,7,8,9,10,14,15,16,17,19,20,32,33,35,36 Interest relative to their role in the treatment of OA and other arthritides was markedly accentuated in 1997 with the publication of The Arthritis Cure 28 and a subsequent volume, Maximizing the Arthritis Cure, 29 by Jason Theodasakis, MD, who described them as effective drugs for treatment of symptoms of OA and the potential to reduce structural damage in OA cartilage. Subsequently, the intake of these agents in the United States market has increased considerably, and at present, they are widely used by patients. A parallel increase in their use for the treatment of arthritis has been noted in veterinary medicine. A review of the literature reveals that a number of short-term studies, particularly studies in Europe and Asia, suggests that these agents have efficacy equal to that of currently used nonsteroidal anti-inflammatory agents (NSAIDs), although their onset of action is slower. The widespread use of these agents, in addition to short-term trials suggestive of efficacy, has prompted initiation of a larger trial by the Office of Alternative Medicine of the National Institutes of Health comparing their efficacy relative to placebo. This article defines current knowledge of glucosamine, chondroitin sulfate, and collagen hydrolysate to provide a perspective of the current status of these agents in the treatment of osteoarthritis.
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For the purposes of classification, it should be specified whether osteoarthritis (OA) of the knee is of unknown origin (idiopathic, primary) or is related to a known medical condition or event (secondary). Clinical criteria for the classification of idiopathic OA of the knee were developed through a multicenter study group. Comparison diagnoses included rheumatoid arthritis and other painful conditions of the knee, exclusive of referred or paraarticular pain. Variables from the medical history, physical examination, laboratory tests, and radiographs were used to develop sets of criteria that serve different investigative purposes. In contrast to prior criteria, these proposed criteria utilize classification trees, or algorithms.
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The efficacy and tolerability of 20 mg of hyaluronic acid were compared in an open, randomized trial with that of 40 mg of 6-methylprednisolone acetate, administering them both by an intra-articular route once a week for 3 weeks to patients suffering from inflammatory knee osteoarthritis. The results of the study showed that for up to one week after the end of treatment hyaluronic acid's analgesic activity was comparable to that of the steroid, while at the end of the follow-up (45 days after the end of treatment) all the pain monitoring parameters presented significant differences in favour of the HA-treated group. Both treatments were well tolerated, since no local or systemic adverse reactions were observed.
Article
Clinical criteria for the classification of patients with hip pain associated with osteoarthritis (OA) were developed through a multicenter study. Data from 201 patients who had experienced hip pain for most days of the prior month were analyzed. The comparison group of patients had other causes of hip pain, such as rheumatoid arthritis or spondylarthropathy. Variables from the medical history, physical examination, laboratory tests, and radiographs were used to develop different sets of criteria to serve different investigative purposes. Multivariate methods included the traditional "number of criteria present" format and "classification tree" techniques. Clinical criteria: A classification tree was developed, without radiographs, for clinical and laboratory criteria or for clinical criteria alone. A patient was classified as having hip OA if pain was present in combination with either 1) hip internal rotation greater than or equal to 15 degrees, pain present on internal rotation of the hip, morning stiffness of the hip for less than or equal to 60 minutes, and age greater than 50 years, or 2) hip internal rotation less than 15 degrees and an erythrocyte sedimentation rate (ESR) less than or equal to 45 mm/hour; if no ESR was obtained, hip flexion less than or equal to 115 degrees was substituted (sensitivity 86%; specificity 75%). Clinical plus radiographic criteria: The traditional format combined pain with at least 2 of the following 3 criteria: osteophytes (femoral or acetabular), joint space narrowing (superior, axial, and/or medial), and ESR less than 20 mm/hour (sensitivity 89%; specificity 91%). The radiographic presence of osteophytes best separated OA patients and controls by the classification tree method (sensitivity 89%; specificity 91%). The "number of criteria present" format yielded criteria and levels of sensitivity and specificity similar to those of the classification tree for the combined clinical and radiographic criteria set. For the clinical criteria set, the classification tree provided much greater specificity. The value of the radiographic presence of an osteophyte in separating patients with OA of the hip from those with hip pain of other causes is emphasized.
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A multi-centre randomized, double-blind, parallel-group clinical trial was carried out in 63 patients with osteoarthritis of the knee to compare the efficacy and tolerability of a course of intra-articular injections of 20 mg sodium hyaluronate with a similar course of injections of placebo. Treatment consisted of up to 11 injections over a 23-week period. Evaluation was by means of subjective symptom and activity assessments, serially during the course of treatment and also 25 weeks thereafter. Ten patients (5 of 30 on active treatment; 5 of 33 on placebo) were withdrawn prematurely. Pain on movement, assessed by visual analogue scale (VAS) showed statistically significant (p less than 0.05 to p less than 0.0001) reductions in mean scores throughout the first 11 weeks of treatment with sodium hyaluronate but smaller, non-significant, reductions with placebo treatment. The difference between treatments was significant (p less than 0.05) at 5 weeks. Pain at rest, also assessed by VAS, showed little change in mean scores with placebo but with sodium hyaluronate there was a progressive reduction which was significant (p less than 0.01) throughout the period from 5 to 23 weeks. The difference between sodium hyaluronate and placebo was significant (p less than 0.05 to p less than 0.002) at Weeks 5, 11, 15, 19 and 23. 'Activities of daily living' were assessed using a standard scale. There were small improvements with both treatments, significant at some assessments and somewhat greater with sodium hyaluronate than placebo, but there were no statistically significant differences between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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Within the context of a double blind randomized controlled parallel trial of 2 nonsteroidal antiinflammatory drugs, we validated WOMAC, a new multidimensional, self-administered health status instrument for patients with osteoarthritis of the hip or knee. The pain, stiffness and physical function subscales fulfil conventional criteria for face, content and construct validity, reliability, responsiveness and relative efficiency. WOMAC is a disease-specific purpose built high performance instrument for evaluative research in osteoarthritis clinical trials.
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The efficacy and tolerance of oral glucosamine sulphate were tested against placebo in a prospective double-blind trial in 20 out-patients with established osteoarthrosis. Two capsules of either glucosaminene sulphate (250 mg) or placebo were administered 3-times daily over a period of 6 to 8 weeks. Articular pain, joint tenderness and restricted movement were semi-quantitatively scored 1 to 4 every 3 days, and individually averaged over the treatment period (overall composite score). Possible side-reactions were similarly scored upon positive questioning of the patients. Haematology, erythrocyte sedimentation rate, urine analysis and X-rays were recorded before and after treatment. Significant alleviation of symptoms was associated with the use of the active drug at the prescribed dose. Similarly, patients given glucosamine sulphate experienced earlier alleviation of symptoms compared with those who had placebo. The use of glucosamine sulphate also resulted in a significantly larger proportion of patients who experienced lessening or disappearance of symptoms within the trial period. No adverse reactions were reported by the patients treated with glucosamine, and no variation in laboratory tests was recorded.
Article
A new preparation of pure glucosamine sulphate, in injectable and oral form, was investigated in a controlled clinical trial in patients with osteoarthrosis. Two groups of 15 in-patients received either 400 mg glucosamine sulphate daily (12by the intramuscular and 3 by the intra-articular route) for 7 days, followed by 2 weeks at 1.5 g daily of oral glucosamine sulphate in 3 divided doses, or an intramuscular injection daily of a piperazine/chlorbutanol combination for 7 days, followed by oral placebo during the following 2 weeks. Semi-quantitative scoring of pain at rest and during active and passive movements, of restricted function and, where possible, of walking time over 20 metres, were taken as therapeutic activity indices, and tested before and after 1 and 3 weeks of treatment. Patients were positively questioned daily for possible intolerance symptoms. Laboratory tests were recorded before and after treatment. With both initial parenteral treatments, each symptom significantly improved, with a trend for faster and greater recovery with glucosamine, mainly in restricted function. During the maintenance period, a further significant improvement was recorded in the group receiving glucosamine, whereas with placebo the symptom scores rose to almost the pre-treatment levels. A similar pattern was shown in the measurement of walking speed. Clinical and biological tolerance were excellent with both treatments. No drug-related complaints were recorded, nor signs of interference in other illnesses or interactions with other drug treatments. It is suggested that injectable and/or oral treatment with pure glucosamine sulphate should be considered for the basic therapy of primary or secondary osteoarthrosis, mainly because it restores articular function to a certain extent.
Article
Calcitonin has an important role in the treatment of post-menopausal osteoporosis. The authors investigated the effect of calcitonin administration or calcitonin administration supplement with a diet rich in collagen proteins on markers of bone metabolism. A group of 108 patients with postmenopausal osteoporosis (BMD lower than 80% of the BMD in premenopausal women) was treated with Calsynar (Rhoune Poulenc-Rorer), 100 u., i.m. twice a week for 24 weeks. Forty-nine of these women took an oral collagen hydrolysate, 10 g per day, for the same period of time. Before and after termination of treatment clinical and laboratory tests were made, X-ray examination of the LS spine and the right forearm, single-photon osteometry of the right forearm and urinary excretion of pyridinoline (UPD), deoxypyridinoline (UDPD) and hydroxyproline (Uhyp) was assessed. As a result of treatment the BMD values increased only insignificantly (by 1.8%) the UPD values declined (to 62.51%) and those of UDPD (to 70.4%), as compared with basal values. The statistical significance is at the 1% level. When collagen proteins were administered concurrently, the decline was more marked (to 56.22% and 56.1% resp.), and as compared with the calcitonin treated group (to 67.73% and 82.30% resp.); the difference is significant at the 5% level. The decline of UPD and UDPD values persisted also three months after discontinued treatment; in patients on the diet with collagen hydrolysate practically no rise of these indicators occurred (54.02% and 56.66% resp.). a) administration of 100 u. calcitonin twice a week for 24 weeks led to a decline of excretion indicators of bone collagen breakdown products, b) the effect of treatment must be monitored using these indicators, c) oral administration of collagen proteins enhanced and prolonged the effect of calcitonin.
Article
Hyaluronic acid is a natural component of cartilage and is considered not only as a lubricant in joints but also as playing a physiological role in the trophic status of cartilage. Hyalectin, a selected fraction of hyaluronic acid extracted from cocks' combs, has exhibited efficacy in animal models of osteoarthritis. To assess the efficacy and tolerability of intra-articular injections of hyalectin, we conducted a prospective, randomized, placebo-controlled trial of 1 years' duration in 110 patients with painful hydarthrodial osteoarthritis of the knee. At entry and once a week for 3 weeks, aspiration of the knee effusion and intra-articular injections of either hyalectin 20 mg (H) or its vehicle (C) were performed. The vehicle acted as the control treatment. Four weeks after the last injection, the improvement was greater in the H group compared with the C group (pain: -35.5 +/- 26.4 mm vs -25.8 +/- 21.4, P = 0.03, Lequesne's functional index: -3.8 +/- 4.3 vs -2.3 +/- 3.3, P = 0.03). During the 1 year follow-up, the need to perform supplementary local therapies (joint fluid aspiration because of painful hydarthrodial episodes and/or local corticosteroid injections) was more frequent in group C (44% vs 30%, P = 0.03). Moreover, at the final visit, the physician's overall assessment of efficacy was in favor of H (77% vs 54%, P = 0.01) and the improvement in the functional index was greater in group H (-4.4 +/- 5.1 vs -2.7 +/- 4.1, P = 0.05). This study suggests that intra-articular injections of hyalectin may (1) improve clinical condition and (2) have a long-term beneficial effect in patients with osteoarthritis of the knee.
Article
Several reported studies suggest that repeated intra-articular injections of hyaluronan result in sustained relief from pain and functional disability in patients with knee osteoarthritis. Several in vivo data suggest that hyaluronan might have a beneficial structural effect in osteoarthritis. The objective of the study was to evaluate the potential structure-modifying effects of Hyalgan (500-730 kDa molecular weight), a highly-purified sodium hyaluronate. Patients with painful knee osteoarthritis (ACR criteria) were enrolled in a prospective, controlled study of 1-year duration. After randomization, either conventional therapy or three cycles (every 3 months) of three intra-articular injections of Hyalgan (once a week during 2 weeks) were given. Clinical outcome was added using pain visual analog score (VAS), functional impairment: Lequesne's index, quality of life: arthritis impact measurement scale (AIMS2) and structural outcome using X-rays: joint space narrowing and arthroscopy: global assessment using VAS, SFA scoring and grading systems. Of the 39 recruited patients, 36 completed the 1-year trial (19 in the Hyalgan group and 17 in the control group). There was no difference between groups at entry. Between-group comparison for changes in clinical parameters reached statistical significance for the quality of life index (AIMS2: -0.4 +/- 0.7 vs 0.2 +/- 0.9 in the Hyalgan and control groups respectively, P < 0.05). Deterioration in the structural parameters was less in the Hyalgan group, with a statistically significant difference for two of the three evaluated parameters (overall assessment of chondropathy: +5.1 +/- 12.7 vs 16.7 +/- 18.3, P = 0.016; SFA scoring system: +3.7 +/- 7.3 vs +9.0 +/- 11.5, P = 0.05) in the Hyalgan and control groups, respectively. This study supports existing data concerning the favorable symptomatic effect of intra-articular injections of Hyalgan in osteoarthritis of the knee and suggests that repeated intra-articular injections of Hyalgan might delay the structural progression of the disease. Other studies are required to confirm these results and to determine the long-term monitoring of osteoarthritic patients using such local therapy.
Article
To determine efficacy and safety of intraarticular (IA) hyaluronic acid (HA; Hyalgan) versus placebo and a nonsteroidal antiinflammatory drug for osteoarthritis (OA) of the knee. A series of 5 weekly IA injections of HA (20 mg each) was compared to placebo or oral naproxen in a 26 week, double blind, masked observer, multicenter trial of 495 patients with idiopathic OA. Acetaminophen was permitted for escape analgesia. The primary measurement was pain experienced on a 50 foot walk test for those completing the study (completers) as measured on a 10 cm visual analog scale (VAS). Also measured were the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index (pain, stiffness, function) and categorical assessments of pain. Patients receiving HA improved more with respect to pain on the 50 foot walk compared to placebo at Week 26 (HA vs placebo difference 8.8 mm; p < 0.005); 56% of HA treated patients compared to 41 % of placebo treated patients had > or = 20 mm reduction in the VAS from Week 5 continuously through Week 26 (p=0.031). At 26 weeks, more HA treated patients (47.6%) had slight pain or were pain-free in contrast to placebo treated (33.1%; p=0.039) or naproxen treated (36.9%; p=0.22) [corrected] patients. Improvement in secondary outcome variables was generally superior in the HA group compared to those receiving placebo and was significantly better at Week 26 with respect to the WOMAC pain (p=0.041) and WOMAC physical function (p=0.047) subscales. The HA group also tended to have better results relative to the naproxen group in both primary and secondary assessments. For all randomized patients, there was a > or = 20 mm improvement in pain experienced on the 50 foot walk in 28% [corrected] of placebo treated patients vs 36% [corrected] of the HA treated patients (p=0.127; 67% of patients completed the trial). Injection site pain, more commonly reported in the HA group (38/164=23%) than in the placebo group (22/168=13%; p < 0.001), resulted in withdrawal in 6 patients (4%). One withdrawal was associated with the HA injection (< 1%). Gastrointestinal adverse events were significantly more common in the naproxen group than the HA or the placebo groups and 14 naproxen treated patients (8.3%) discontinued prematurely due to these events. This large, controlled randomized clinical trial confirms that 5 weekly IA injections of HA (Hyalgan) in patients with OA of the knee are generally well tolerated, provide sustained relief of pain and improved patient function, and were at least as effective with fewer adverse reactions as continuous treatment with naproxen for 26 weeks.
Article
There are a sufficient number of short-term studies with these agents suggesting efficacy equal to that seen in the symptomatic treatment of OA using NSAIDs. Two recent meta-analyses by McAlindon and colleagues and Towheed et al reviewed clinical trials of glucosamine and chondroitin in the treatment of osteoarthritis. The study by McAlindon and co-workers included all double-blind placebo-controlled trials of greater than 4 weeks' duration, testing oral or parenteral glucosamine or chondroitin for treatment of hip or knee osteoarthritis. Thirteen trials (six with glucosamine, seven with chondroitin) met eligibility criteria. The authors used global pain score or the Lequesne index in the index joint as the primary outcome measure and considered the trial positive if improvement in the treatment group was equal to or greater than 25% compared with the placebo group, and was significant (P < or = .05). All 13 studies reviewed were classified as positive, demonstrating large effects, compared with placebo (39.5% [S.D. 21.9] for glucosamine, 40.2% [S.D. 6.4] for chondroitin). The authors concluded that clinical trials of these two agents showed substantial benefit in the treatment of osteoarthritis but provided insufficient information about study design and conduct to allow definitive evaluation. Towheed and colleagues reviewed nine randomized, controlled trials of glucosamine sulfate in osteoarthritis. In seven of the randomized controlled trials, in which they compared glucosamine with placebo, glucosamine was always superior. In two randomized controlled trials comparing glucosamine to ibuprofen, glucosamine was superior in one and equivalent in one. Methodologic problems, including lack of standardized case definition of osteoarthritis and lack of standardized outcome assessment led the authors to conclude that further studies are needed to determine if route of administration is important and whether the therapeutic effect is site specific. A meta-analysis of chondroitin sulfate trials has also been published. Of the 12 published trials, 4 randomized double-blind placebo or NSAID-controlled trials with 227 patients on chondroitin sulfate were entered into the analysis. All four studies showed chondroitin sulfate to be superior to placebo, with respect to Lequesne index, visual analog scale for pain and medication consumption. Significant changes (P < or = .05) were seen in those treated from day 60 to the study endpoints (150 to 180 days). Pooled data demonstrated at least 50% improvement in the study variables in the chondroitin treated group. Discrepancies in some of the study findings reported in the literature may relate to the composition of the nutritional supplements used. Studies in the United States have revealed that a number of preparations claiming to contain certain doses of glucosamine or chondroitin sulfate have significantly less (or none) of the dosages described. Accordingly, it is essential that studies performed with these agents use preparations that are carefully defined in manufacture. The amounts generally administered are glucosamine, 1500 mg, and chondroitin sulfate, 1200 mg, daily. Although glucosamine has been described as effective when used alone, it is probably reasonable to use the combination pending further studies. The average cost is approximately $30 to $45 per month. In the interim, what should physicians tell their patients when they ask whether these agents are effective, or whether they should or should not take them? The authors emphasize that these agents are not FDA-evaluated or recommended for the treatment of OA. They are available as health food supplements, and the number of studies of toxicity, particularly with respect to long-term evaluations, is limited. The pros and cons of these agents and the published data are described so that patients can make a reasonably informed decision as to whether they wish to proceed with use of these agents in therapy. (ABSTRACT TRUNCATED)
Article
Several investigations showed a positive influence of orally administered gelatin on degenerative diseases of the musculo-skeletal system. Both the therapeutic mechanism and the absorption dynamics, however, remain unclear. Therefore, this study investigated the time course of gelatin hydrolysate absorption and its subsequent distribution in various tissues in mice (C57/BL). Absorption of (14)C labeled gelatin hydrolysate was compared to control mice administered (14)C labeled proline following intragastric application. Plasma and tissue radioactivity was measured over 192 h. Additional "gut sac" experiments were conducted to quantify the MW distribution of the absorbed gelatin using SDS-electrophoresis and HPLC. Ninety-five percent of enterally applied gelatin hydrolysate was absorbed within the first 12 h. The distribution of the labeled gelatin in the various tissues was similar to that of labeled proline with the exception of cartilage, where a pronounced and long-lasting accumulation of gelatin hydrolysate was observed. In cartilage, measured radioactivity was more than twice as high following gelatin administration compared to the control group. The absorption of gelatin hydrolysate in its high molecular form, with peptides of 2.5-15kD, was detected following intestinal passage. These results demonstrate intestinal absorption and cartilage tissue accumulation of gelatin hydrolysate and suggest a potential mechanism for previously observed clinical benefits of orally administered gelatin.
Article
To determine the efficacy and safety of the cyclooxygenase 2 (COX-2) specific inhibitor, rofecoxib in patients with osteoarthritis (OA) of the knee. Rofecoxib, 25 mg or 125 mg once daily, was compared with placebo in a 6 week, double blind, parallel group, randomized, multicenter study of 219 patients with knee OA. Both doses of rofecoxib produced clinically significant improvement as assessed by primary (e.g., WOMAC Pain Subscale 0-100 mm, decrease from baseline: placebo: 7.1 mm; rofecoxib 25 mg: 28.1 mm, rofecoxib 125 mg: 28.0 mm; p < 0.001 rofecoxib vs placebo) and secondary efficacy (p < 0.05) criteria compared with placebo. Clinical improvement with the 25 mg dose was similar to that with the 125 mg dose. Both rofecoxib doses were generally well tolerated. Specific inhibition of COX-2 by 25 and 125 mg rofecoxib, administered once daily, resulted in clinically meaningful improvements in patients with OA. This study confirms that COX-2 derived prostanoids are important clinical mediators of pain and other symptoms of knee OA and that inhibition of COX-1 is not required to provide clinical benefit.
Article
Glucosamine products have been used extensively for the management of pain in osteoarthritis (OA). We investigated the efficacy of the hydrochloride salt of glucosamine on pain and disability in knee OA. At Week -2, subjects were examined, randomized, and instructed to take only prescribed acetaminophen for pain. At Week 0 patients were examined, prescribed acetaminophen, and either placebo or glucosamine hydrochloride (glucosamine). At Week 4 the prescriptions for acetaminophen and placebo or glucosamine were renewed. At Weeks 4 and 8, patients returned diaries and unused medications, and were examined. The WOMAC questionnaire was administered at Weeks -2, 0, and 8. After completing the randomized 8 week trial, subjects were offered known glucosamine hydrochloride capsules in an 8 week open label trial, with followup telephone survey after the 8 week open label trial. The primary endpoint (statistically significant difference in WOMAC pain score between Week 0 and Week 8) was not met. However, positive trends were noted for the glucosamine group in 23 of 24 WOMAC questions. A significant difference was noted from Week 5 through Week 8 in the knee examination (p = 0.026) and in the response to a daily diary pain question (p = 0.018). However, responding to the question, "Are you better than at the start of the trial?", 40% of placebo and only 49% of glucosamine subjects answered in the affirmative (p = 0.58). At the end of the randomized trial, 34% of placebo and 47% of glucosamine subjects believed that they had been given glucosamine. After the end of the 8 week open label trial, 77% of the subjects were still taking glucosamine, although now obliged to pay for commercially available products. There was no significant difference in pain reduction between the glucosamine hydrochloride and placebo groups as measured by WOMAC. However, the secondary endpoints of cumulative pain reduction as measured by daily diary and knee examination were favorable, suggesting that glucosamine hydrochloride benefits some patients with knee OA.
Article
To compare the efficacy and safety of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, with those of naproxen, a nonsteroidal anti-inflammatory drug (NSAID), and placebo in the treatment of osteoarthritis of the knee. In this multicenter, randomized, double-blind, placebo-controlled trial, 1003 patients with symptomatic osteoarthritis of the knee were randomly assigned to receive celecoxib at doses of 50, 100, or 200 mg twice a day; naproxen, 500 mg twice a day; or placebo for 12 weeks. Patients were evaluated with standard measures of efficacy 2 to 7 days after discontinuing previous NSAID or analgesic therapy and after 2, 6, and 12 weeks of treatment with the study drug. Celecoxib treatment led to significant improvement in the signs and symptoms of osteoarthritis as determined by all efficacy measures. Significant pain relief occurred within 2 days of the initiation of treatment, and maximum anti-inflammatory and analgesic activity, evident within 2 weeks, was sustained throughout the 12-week study. All celecoxib doses were efficacious compared with placebo, although the 50-mg twice-daily dosage regimen was minimally effective. The higher doses of celecoxib (100 and 200 mg twice a day) were similarly efficacious, and the magnitude of improvement observed with these dosing regimens was comparable to that seen with naproxen at a dose of 500 mg twice a day. All doses of celecoxib and naproxen were well tolerated. COX-2 inhibition with celecoxib is an effective approach for the treatment of osteoarthritis, as seen by clinical improvement in signs and symptoms comparable to treatment with naproxen.
A one-year randomized double-blind, placebo-controlled study with oral chondroitin sulfate in patients with knee osteoarthritis
  • Fleish
Fleish AM, Merlin C, Imhoff A., Holder J, Kissling R. A one-year randomized double-blind, placebo-controlled study with oral chondroitin sulfate in patients with knee osteoarthritis. Osteoarthritis Cartilage (Supplement A) 1997;5:70.
Glucosamine and chondroitin treatment for osteoarthritis of the knee or hip: Meta-analysis and quality assessment of clinical trials
  • Mcalindon Te
  • J Gulin
  • Felson
  • Dt
McAlindon TE, Gulin J, Felson DT. Glucosamine and chondroitin treatment for osteoarthritis of the knee or hip: Meta-analysis and quality assessment of clinical trials. Arthritis Rheum 1998;41:A198.
Can a mixture of gelatin and L-cystine stimulate proteoglycan synthesis?
  • Seeligmuller
Seeligmuller K, Happel HK. Can a mixture of gelatin and L-cystine stimulate proteoglycan synthesis? Therapiewoche 1989;39:3153-57.
On supportive therapy for osteo-and chondropathies
  • Krug
Krug E. On supportive therapy for osteo-and chondrop-athies. Ztschr F Erfahrungsheilkunde 1989;11:930-8.
Scientific literature reviews on gener-ally recognized as safe (GRAS) food ingredients, gelatin. FDA contract no
  • Informatics
  • Inc
Informatics, Inc. Scientific literature reviews on gener-ally recognized as safe (GRAS) food ingredients, gelatin. FDA contract no. 1975;223-75-2004.
Individuelle Arthrosetherapie ist moglich (Individual arthrosis therapy is possible)
  • Oberschelp
Chondropathia patellae
  • Gotz
The effect of gelatin on fragile finger nails
  • Tyson
Multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy and tolerability of pharmaceutical collagen hydrolysate in patients with osteoarthritis of the knee
  • Dgf Stoess
Therapie Der Osteoarthrose—Welche Wirkung Haben Gelantineparaprate?
  • Adam
Scientific literature reviews on generally recognized as safe (GRAS) food ingredients, gelatin
  • Informatics, Inc