Article

Short-Term Treatment of Painful Osteoarthritis of the Knee with Oral Enzymes: A Randomised, Double-Blind Study versus Diclofenac

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Abstract

Objective: To compare the short-term efficacy and tolerability of an oral enzyme therapy with the NSAID diclofenac in patients with symptomatic osteoarthritis of the knee (gonarthritis). Methods: In a double-blind clinical trial, 73 patients with painful gonarthritis were randomised to receive 3 weeks of treatment with an oral enzyme preparation (Phlogenzym®) containing bromelain, trypsin and rutin (n = 36), or the NSAID diclofenac (n = 37). Efficacy was primarily evaluated using the Lequesne index (measuring pain and function of the affected knee). Other investigations included assessment of pain symptoms using a visual analogue scale (VAS), global assessment of efficacy and tolerability (by both patients and one physician), and various laboratory parameters. Patients were evaluated at baseline, at weekly intervals throughout the 3-week treatment period, and at 7 weeks (i.e. 4 weeks after discontinuing therapy). Results: The Lequesne index improved continuously in both groups: from 13.56 at baseline to 3.10 after 3 weeks (end of therapy) to 2.05 at 7 weeks (follow-up) in the enzyme group, and from 14.04 to 3.50 to 2.24, respectively, in the diclofenac group. Statistical evaluation showed the treatment groups to be equivalent; the lower bound of the 95% confidence interval of the Mann-Whitney estimator was above 0.44 (the limit for equivalence) at all time points. Global assessment of efficacy and tolerability of the drugs was ‘very good’ or ‘good’ for the majority patients. Conclusions: Short-term evaluation indicates that oral enzymes may be considered an effective and safe alternative to NSAIDs such as diclofenac in the treatment of painful gonarthritis.

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... Overall, six trials were identified that fulfilled the selection criteria mentioned and for which raw IPD were made available (see Table 1). [19][20][21][22][23][24] ...
... Written informed consent was obtained from each patient prior to study enrolment following an oral and written explanation about the aim and the potential risks of the study. 25 DIC dosage varied between studies: three had a reference-dose regimen of 150 mg DIC (one tablet, three times daily) in the first week, followed by 100 mg DIC (one tablet, twice daily) in the remaining treatment period; 19,21,22 two studies administered 100 mg DIC (one tablet, twice daily) during the whole treatment period; 20,23 and in one study 150 mg DIC (two tablets, three times daily) was administered throughout the whole treatment period. 24 Only one study contained a pure placebo group in addition to OEC and DIC; 24 the other five trials were solely actively controlled. ...
... When necessary, patients were allowed to self-medicate with acetaminophen (500 mg per tablet, up to 2,000 mg per day); however, they had to stop this rescue medication 24 hours prior to each scheduled examination. Treatments were given daily for a planned duration of 3 weeks in three studies, 19,21,22 6 weeks in two, 20,23 and 12 weeks in one study. 24 ...
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Objective To compare efficacy, safety, and tolerability of an oral enzyme combination (OEC) containing proteolytic enzymes and bioflavonoid vs diclofenac (DIC), a nonselective nonsteroidal anti-inflammatory drug in the treatment of osteoarthritis of the knee. Materials and methods This was an individual patient-level pooled reanalysis of patient-reported data from prospective, randomized, double-blind, parallel-group studies in adult patients with moderate-to-severe osteoarthritis of the knee treated for at least 3 weeks with OEC or DIC. Appropriate trials were identified with a systemic literature and database search. Data were extracted from the original case-report forms and reanalyzed by a blinded evaluation committee. The primary end point was the improvement of the Lequesne algofunctional index (LAFI) score at study end vs baseline. Secondary end points addressed LAFI response rates, treatment-related pain-intensity changes, adverse events, and laboratory parameters. Results Six trials were identified that enrolled in total 774 patients, of whom 759 had post-baseline data for safety analysis, 697 (n=348/349 with OEC/DIC) for intent to treat, 524 for per protocol efficacy analysis, and 500 for laboratory evaluation. LAFI scores – the primary efficacy end point – decreased comparably with both treatments and improved with both treatments significantly vs baseline (OEC 12.6±2.4 to 9.1±3.9, DIC 12.7±2.4 to 9.1±4.2, effect size 0.9/0.88; P<0.001 for each). In parallel, movement-related 11-point numeric rating-scale pain intensity improved significantly (P<0.001) and comparably with both treatments from baseline (6.4±1.9/6.6±1.8) to study end (3.8±2.7/3.9±2.5). Overall, 55/81 OEC/DIC patients of the safety-analysis population (14.7%/21.1%, P=0.022) reported 90/133 treatment-emergent adverse events, followed by premature treatment discontinuations in 22/39 patients (5.9%/10.2%, P=0.030). Changes in laboratory parameters were significantly less with OEC vs DIC: on average 18.8% vs 86.3% of patients presented a decrease with respect to hemoglobin, hematocrit, or erythrocyte count (P<0.001), and 28.2% vs 72.6% showed an increase in AST, ALT, or GGT (P<0.001). Conclusion When compared with DIC, OEC showed comparable efficacy and a superior tolerability/safety profile associated with a significantly lower risk of treatment-emergent adverse events, related study discontinuations, and changes in laboratory parameters.
... Serrapeptase has been analyzed to have a high degree of substrate specificity (Miyata et al., 1970b;Aiyappa and Harris, 1976). It is an immunologically active enzyme and it is anti-oedemic, analgesic, anti-inflammatory, solubilizes non-living tissues such as mucous, plaques and blood clots hence it is named as fibrinolytic/thrombolytic enzymes since it has the ability to degrade insoluble proteins like fibrin and other mediators of inflammation (Klein and Kullich, 2000). Serrapeptase is taken as a supplement that can boost the cardiovascular system and greatly augment overall health (Robert, 2009). ...
... Serrapeptase has a potential to cure and treat disorders like atherosclerosis, arthritis, bronchitis, carpal tunnel syndrome, fibrocystic breast disease, Crohn's disease, leg ulcers, traumatic swelling, fibromyalgia, breast engorgement, migraine, Alzheimer's disease, sinusitis, hepatitis, lung disorders, arthritis, diabetes, carotid artery blockage, thrombosis, uterine fibroids (Klein and Kullich, 2000). Serrapeptase may also be used as a remedy for women suffering from endometriosis. ...
... Serrapeptase reduces inflammation in 3 ways: 1. by breaking down insoluble protein by-products like fibrin, 2. By thinning the fluids formed during injury which in turn speeds up tissue repair process, 3. Reducing pain by inhibiting the release of paininducing substances like amines (Sellman, 2003). It can also modify the cell adhesion molecules that are involved in guiding inflammatory cells to the site of infection (Klein and Kullich, 2000). It is orally effective in treating inflammation caused by laryngitis, catarrhal rhino-pharyngitis, sinusitis, breast engorgement, carpal tunnel syndrome, inflammation in prostate gland, acute and chronic ear-nose-throat disease, and chronic emphysema (Tachibana et al., 1984;Vicari et al., 2005;UmaMaheswari et al., 2016). ...
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Background Serrapeptase is a proteolytic enzyme with many favorable biological properties like anti-inflammatory, analgesic, anti-bacterial, fibrinolytic properties and hence, is widely used in clinical practice for the treatment of many diseases. Although Serrapeptase is widely used, there are very few published papers and the information available about the enzyme is very meagre. Hence this review article compiles all the information about this important enzyme Serrapeptase. MethodsA literature search against various databases and search engines like PubMed, SpringerLink, Scopus etc. was performed. ResultsWe gathered and highlight all the published information regarding the molecular aspects, properties, sources, production, purification, detection, optimizing yield, immobilization, clinical studies, pharmacology, interaction studies, formulation, dosage and safety of the enzyme Serrapeptase. Conclusion Serrapeptase is used in many clinical studies against various diseases for its anti-inflammatory, fibrinolytic and analgesic effects. There is insufficient data regarding the safety of the enzyme as a health supplement. Data about the antiatherosclerotic activity, safety, tolerability, efficacy and mechanism of action of the Serrapeptase are still required.
... This is no surprise considering that fruits and vegetables contain high concentrations of dietary fiber, flavonoids, carotenoids, and vitamins, which have all been associated with reductions in markers of inflammation, as discussed above. Beyond these ingredients, certain fruits contain particular compounds such as anthocyanins and bromelain, which may also be anti-inflammatory [147][148][149][150][151]. Anthocyanins are the pigments found in fruits such as strawberries, cherries, blackberries, and black currants. ...
... These anti-inflammatory properties have been observed in vitro via its modulating effect on certain inflammatory cytokines [150]. The benefits are also apparent in clinical trials which report the effectiveness of bromelain for treating certain inflammation-derived diseases/conditions (e.g., osteoarthritis) [151]. ...
Article
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Research examining immune function during obesity suggests that excessive adiposity is linked to impaired immune responses leading to pathology. The deleterious effects of obesity on immunity have been associated with the systemic proinflammatory profile generated by the secretory molecules derived from adipose cells. These include inflammatory peptides, such as TNF- α , CRP, and IL-6. Consequently, obesity is now characterized as a state of chronic low-grade systemic inflammation, a condition considerably linked to the development of comorbidity. Given the critical role of adipose tissue in the inflammatory process, especially in obese individuals, it becomes an important clinical objective to identify lifestyle factors that may affect the obesity-immune system relationship. For instance, stress, physical activity, and nutrition have each shown to be a significant lifestyle factor influencing the inflammatory profile associated with the state of obesity. Therefore, the purpose of this review is to comprehensively evaluate the impact of lifestyle factors, in particular psychological stress, physical activity, and nutrition, on obesity-related immune function with specific focus on inflammation.
... Also chickens of group 3 showed highest body gain in all treated groups and had (103%) body gain relative to control. This may due to antiinflammatory 26 and to proteolytic ability characteristics of Serrapeptase induced by the experimental infection with E. coli and Mycoplasma gallisepticum. Serrapeptase supplementation has a positive effect on general health status of infected birds so it was improved bird performance through this experiment. ...
... Anti-inflammatory mechanism involve degradation of inflammatory mediators, suppression of edema, activation of fibrinolysis, reduction of immune complexes and proteolytic modification of cell-surface adhesion molecules which guide inflammatory cells to their targets. 26 Serratiopeptidase showed significant antiinflammatory effect in soft tissue injury to upper limb, lower limb or both reflected in decrease in swelling more as compared to results observed by Aceclofenac. 28 Lactic acid dehydrogenase (LDH) is an intra cellular enzyme that is widely distributed in the tissues of the body, particularly in the kidney, heart, skeletal muscle, brain, liver and lung. ...
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The aim of this study was to evaluate the effect of using graded levels of enzyme Serratiopeptidase, treatment on growth performance, immune response and some blood parameters of broiler chickens. One hundred twenty 1-day-old broiler chicks were randomly assigned to 4 treatment groups; each group included 3 replicates of 10 birds. Birds were treated as the following group (1) birds were non infected and non treated used as control group. Group (2) birds were only infected with E. coli and Mycoplasma gallisepticum (MG) at 14th day of age. While birds of group (3) were infected with E. coli and Mycoplasma gallisepticum (MG) at 14th day of age and treated with Serrapeptase in drinking water at a dose of 2 g/liter for the first 3 days of each week. Group (4) birds were infected with E. coli and Mycoplasma gallisepticum (MG) at 14th day of age and were treated with Serrapeptase in drinking water at a dose of 1 g / liter for the first 3 days of each week. The results showed significant improvement in final body weight, body gain and feed conversion of birds which was treated with Serrapeptase at 2g /liter drinking water. Similar trend was noted for the effect of Serratiopeptidase on total serum proteins of infected chickens, Serratiopeptidase significantly corrected the total protein from (6.86±0.11) in the infected non treated group to (7.88±0.17 and 7.81±0.15) in groups 3 and 4 respectively. Serratiopeptidase significantly decreased the total cholesterol, serum LDH and the inflammatory markers tested (CRP and ESR). Serratiopeptidase treatment improved the immunological response to NDV vaccination, and decreased the re-isolation and shedding of MG and E. coli
... In a multi-centre study conducted in Germany, it was reported that bromelain produced a positive outcome compared to placebo for patients with arthritis [21] . In a more recent study, a double blinded trial was conducted to compare the oral enzyme preparation of Phlogenzym (containing bromelain, with trypsin and rutin) with an NSAID (diclofenac) during a 3-week treatment among 73 patients suffering osteoarthritis of the knee [22] . There is also experimental evidence of its effects on blood coagulation where increases in the serum fibrinolytic activity and prostaglandin levels have been recorded due to a decrease in PGE2 and thromboxane A2. ...
... Essentially, this phenomenon is important for reducing inflammation [1] . The role of the analgesic is a secondary effect on factors of reducing pain-inducing, contains immune complexes, debris, and oedema [22] . Moreover, for cases like bradykinin it has found its direct influence effect on pain mediators. ...
Article
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Inflammation is a complicated problem for today’s human beings. Large numbers of people have been diagnosed with arthritis along with inflammation. This is beside the others that suffer inflammation caused by an injury. There are alternatives that can be considered as temporary or permanent treatments of chronic inflammatory diseases. Plants, as well as other biological resources, are most welcomed to the therapeutic area. Using the plants’ compounds with high potential as novel techniques are today’s bio-pharmacologist concern. Bromelain has been more attractive due to its characteristics. This review is an overview of anti-inflammatory and anti-cancer effect of bromelain as a confident treatment for all inflammatory disease.
... (13) Normally, the body produces approximately 15-30 mg of hydrocortisone per day. (14,15) Suppression of each stage of the inflammatory response appears to be the major action of the glucocorticoids. There is a decrease in capillary dilatation, leukocyte migration, and phagocytosis, a decrease in the total number of circulating lymphocytes, basophils, eosinophils, and monocytes, and an inhibition of the formation of granulation tissue by retarding fibroblast proliferation and collagen synthesis. ...
... Serratiopeptidase or serrapeptase is a protein (proteolytic) enzyme isolated from the non-pathogenic enterobacteria Serratia E15 found in silkworms. (15) Swelling involves a three-dimensional volumetric change at the tissue and cellular level. No technique has been proved to be superior or more accurate than any other in analyzing swelling. ...
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Health professionals still prefer to give various drug regimens for patients undergoing surgical removal of mandibular third molar to counteract swelling and pain. The study result help in deciding treatment regimen to be followed after third molar surgeries and suggests better patient comfort level is achieved with use of dexamethasone compared to serratiopeptidase for patients undergoing third molar surgeries. In this study serratiopeptidase and dexamethasone had equal and minimal effect on trismus. Serratiopeptidase can be used as an alternative drug to control inflammation in cases where corticosteroids are contraindicated.
... It exhibits properties like antioedemic, analgesic, anti-inflammatory, dissolution of mucous, plaques and blood clots. Serrapeptase is effective in treating various diseases like atherosclerosis, arthritis, bronchitis, fibrocystic breast disease, crohn's disease, breast engorgement, Alzheimer disease, hepatitis, lung disorders, diabetes, and uterine fibroids 8 . ...
... The optimum pH was determined by adjusting the pH of the production medium of wild and mutant strain to different pH of 4,5,6,7,8,9,10 and the maximum enzyme activity of 2171.0 EU/ mL and 2812.14EU/mL was observed at pH 7 in the wild and mutant Serrapeptase respectively (Fig. 4C) and hence it is considered as optimum pH for Serrapeptase production. ...
Article
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Serrapeptase is a proteolytic enzyme with many favourable biological properties like anti-inflammatory, analgesic, anti-bacterial, fibrinolytic properties and hence, is widely used in clinical practice for the treatment of many diseases. The activity of microbial enzymes is usually low and hence enhancing the enzyme activity is an integral and crucial area of research. In this study, a mutant with higher serrapeptase activity was developed by multiple exposures of Serratia marcescens to Ultra Violet radiation (UV) and Ethyl methyl sulfonate (EMS) individually and also a combination of both the methods was used. The mutant exposed only to UV radiation for 40 seconds indicated an increase in enzyme activity of 3234.9 EU/mL in comparison to wild-type strain (2770 EU/mL). The mutant exposed to only EMS indicated a very small increase in enzyme activity of 2797 EU/mL in comparison to wildtype strain (2770 EU/mL) but a lower enzyme activity than the UV mutant. Combinational exposure of wild-type to UV and EMS gave a better mutant with an enzyme activity of 3437.6 EU/mL which was higher than all the above methods. Optimization of temperature, incubation period and pH was studied in the wild type and mutant strains and found slight increase in activity in the mutant strain than the wild strain. The mutant serrapeptase has a molecular weight of approximately 50kDa and also exhibited fibrinolysis activity with a maximum blood clot lysis of 35% with 100 U/mL of Serrapeptase.
... Serratiopeptidase a proteolytic enzyme derived from non-pathogenic enterobacteria Serratia sp E-15 [12] has antiinflammatory and anti-edemic activity in a number of tissues [13]. Antiinflammatory mechanism involve degradation of inflammatory mediators, suppression of oedema, activation of fibrinolysis, reduction of immune complexes and proteolytic modification of cell-surface adhesion molecules which guide inflammatory cells to their targets [14]. Analgesic effect is believed to be due to cleavage of bradykinin, a messenger molecule involved in pain signalling [14]. ...
... Antiinflammatory mechanism involve degradation of inflammatory mediators, suppression of oedema, activation of fibrinolysis, reduction of immune complexes and proteolytic modification of cell-surface adhesion molecules which guide inflammatory cells to their targets [14]. Analgesic effect is believed to be due to cleavage of bradykinin, a messenger molecule involved in pain signalling [14]. This study evaluated and compared the efficacy and safety of serratiopeptidase and aceclofenac in reducing swelling and pain following soft tissue injury. ...
Article
The aim of this study was to evaluate and compare the efficacy and safety of serratiopeptidase and aceclofenac in reducing swelling and pain following soft tissue injury. This study included 100 patients with soft tissue injury to upper limb, lower limb or both. They were randomly divided into two groups of 50 each to receive serratiopeptidase and aceclofenac. Evaluation of efficacy was made using tape measurement (for swelling), and visual analogue scale (for pain) on day 0, week 1and week 2. Serratiopeptidase showed significant anti-inflammatory effect and mild analgesic effect. None of the patient was required to be put on another analgesic or any alteration in treatment. Aceclofenac showed superior analgesic effect as compared to serratiopeptidase. Mild to moderate adverse effects were reported. The most common adverse effect reported was dyspepsia. All were mild and did not require any alteration or discontinuation of treatment.
... A number of clinical trials [15][16][17][18][19] have assessed the use of bromelain in joint inflammation, and these have been reviewed. 20 They have been either open studies 15,19 or equivalence studies designed to assess the comparative effectiveness against standard NSAID treatment. ...
... 20 They have been either open studies 15,19 or equivalence studies designed to assess the comparative effectiveness against standard NSAID treatment. [16][17][18] Their findings suggest that bromelain may be beneficial in the treatment of OA, and as effective as standard NSAID treatment. In addition, safety reports reveal no serious adverse reactions, and tolerability appears good. ...
... This finding is in agreement with findings from previous studies, [15][16][17] although those studies had not reported any randomization and one of the studies was on upper third molar surgery. 17 Bromelain's mode of action as an analgesic agent is multifaceted and thought to be both as a secondary effect of reducing paininducing factors, such as edema, debris, and immune complexes, 18 and through a direct influence on pain mediators, such as bradykinin. 19 This justifies the use of bromelain as an effective alternative to NSAIDs to control patients' pain after third molar surgery. ...
Article
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The purpose of the present study was to compare the effect of oral bromelain (4 × 250 mg) versus oral diclofenac sodium (4 × 25 mg) on pain, swelling, trismus, and quality of life (QOL) after surgical removal of impacted lower third molars. A randomized, double-blind, placebo-controlled study was planned. The sample included patients requiring extraction under local anesthesia of a single partial bony impacted mandibular third molar. The patients were randomly distributed into 1 of 3 groups: bromelain, diclofenac, and placebo. Treatment started 1 day before surgery and continued for 4 days. The predictor variable was the type of the drug given to the patients. The outcome variables were pain, swelling, and trismus, which were measured at 1, 3, and 7 days postoperatively. The other study variables included QOL measures to assess the patients' perception regarding the effect of surgery on their well-being and daily activities. A validated questionnaire was used to measure QOL. The data were analyzed using analysis of variance, multiple measures analysis of variance, or Pearson's χ(2) test, as appropriate. P < .05 was considered significant. A total of 45 subjects requiring surgical removal of a single impacted mandibular third molar under local anesthesia were included in the present study. The bromelain and diclofenac groups both showed a significant reduction in pain compared with the placebo group at all intervals (P < .05). Diclofenac also resulted in a significant reduction of swelling at 3 and 7 days, and bromelain resulted in an insignificant reduction. A nonsignificant reduction in trismus occurred in both treatment groups compared with the placebo group. Both treatment groups also showed a significant difference in the effect on QOL in most subscales and total scores (P < .05). The effect was comparable between the 2 treatment groups for all parameters and at all intervals. The results of our study have shown that oral bromelain is an effective therapy to improve the QOL after surgical removal of impacted lower third molars, with an effect on the postoperative sequelae comparable to that of preemptive diclofenac sodium.
... Mechanisms of action include destruction or inactivation of bradykinin and cell surface enzymes involved in the formation of eicosanoids, molecular debridement, reduction in the viscosity of extracellular fluid, activation of endogenous proteases (plasmin) and substituting for endogenous proteases involved in limiting the inflammatory cascade. 35,36 ...
... This also enhances tissue repair and reduces pain. 152 In vivo activity. SP was suspected to be destroyed inside the alimentary tract, due to the drastic changes in pH and the large protein structure of this enzyme, and as such would require enteric encapsulation in order to retain its bioactivity. ...
Article
Formation of endogenous thrombi in blood vessels is one of the leading causes of death in our modern life. According to data provided by the World Health Organization (WHO) in 2000, heart diseases are responsible for 29% of the total mortality rate in the world. For this, a tremendous amount of research has been done in the area of prevention and treatment of these diseases. The classical therapy of these thrombi relies upon the use of antiplatelets, anticoagulants, or even surgeries. Relatively recently, the fibrinolytic enzymes produced by microorganisms, snakes, earthworms, insects, plants, and other organisms are being successfully used in the treatment of blood clots, especially with regard to the direct dissolving action on fibrin in tandem with less cost and side effects in comparison with the first-generation thrombolytic agents, streptokinase and urokinase. Furthermore, recombinant DNA technology has succeeded in improving and decreasing the undesirable effects of the first generation of enzymes. Recombinant PAs or rt-PAs like alteplase, retelase, saruplase, tenecteplase, lanoteplase, and desmoteplase became available in the drug markets with advantages of less binding loci with PAI-1 to avoid degradation while providing faster and more complete reperfusion in a greater number of patients with less risk of bleeding and intracranial hemorrhage. This review is the first to cover all the natural and recombinant thrombolytic agents used in enzyme therapy.
... The isolated protein belongs to alkaline metalloprotease and known to activate the Hageman factor-kallikrein-kinin systems of mammals and directly involve in degradation or inhibition of IgG and IgA immune factors as well as regulatory proteins such as 2-macroglobulin, 2-anplasmin and anti-thrombin III [1]. Because of these functionalities, it is administered in dietary supplements for the treatment of assorted inflammatory disorders in Asia and Europe, it gained wide clinical usage as cardiovascular, anti-inflammatory, respiratory, or immune support agent and as an adjunct to antibiotic therapy and to treat other chronic inflammatory diseases, like atherosclerosis, arthritis, bronchitis, carpel tunnel syndrome, fibrocystic breast disease, and sinusitis [2]. . Interestingly, this enzyme production is mostly reported from clinical isolates [3,4] however, reports from marine microbial strain, Pseudomonas sp., also noticed in the literature [5,6]. ...
Article
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A well characterized alkaline metalloprotease enzyme called serralysin with fibrinolytic activity has been reported in the newly isolated Serratia marcescens RSPB11. In view of its potential application in thrombolytic therapy this study has been made for understanding the nutritional parameters requirement needed for production. Therefore, medium components required for the production of serralysin were optimized using a two step statistical approach. Fermentation variables were selected in accordance with the Plackett-Burman design and were further optimized via response surface methodological approach. A total of seven parameters viz., casein, dextrose, KH2PO4, MgSO4, NaCl, CaCl2 and inoculum have been considered for the optimization studies. The statistical model was constructed via central composite design (CCD) using five screened variables (casein, dextrose, KH2PO4, CaCl2 and inoculum size). An overall 51.8% increase in protease production was achieved in the optimized medium as compared with the unoptimized casein medium. With the application of statistical design methodology serralysin production increased significantly with optimized casein medium (23910 U/ml) when compared to yeast extract-peptone medium (5363 U/ml).
... Serrapeptase is being used to treat chronic inflammatory disease such as atherosclerosis, arthritis, bronchitis, fibrocystic breast disease and sinusitis (Klein and Kullich, 2000). ...
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ABSTRACT Alzheimer’s disease (AD) is a challenging neurodegenerative disorder in the elderly that is characterized by impairment of memory and eventually by disturbances in reasoning, planning, language and perception. The current study was planned to elucidate the protective role of the proteolytic enzymes, serrapeptase and nattokinase, in ameliorating neuroinflammation and apoptosis associated with AD induced in rats. Sixty adult male albino rats were enrolled in the present study and randomly classified into six groups; Group ( 1) set as control group, Group (2) AD induced group in which rats were orally administered with AlCl 3 (17 mg/ kg b.wt. ) for 45 days and Groups from (3) to (6) were orally administered with AlCl 3 for 45 days and simultaneously supplemented with low and high doses of serrapeptase ( 10.800 U/ kg b.wt. and 21.600 U/ kg b.wt.) and nattokinase (360 FU/ kg b.wt. and 720 FU/ kg b.wt.) respectively. Brain cholinesterase activity, TGF-β , IL-6 , Bcl-2 and P53 levels were estimated as well as histological investigation of the brain tissue of the different studied groups was carried out. In comparison with the control group, AlCl 3, administration produced significant elevation in cholinesterase activity, TGF - β ,IL-6 and P 53 levels while it induced significant reduction in Bcl -2 level . Regarding the groups treated with either serrapeptase or nattokinase in different doses, our findings showed significant decrease in cholinesterase activity, TGF- β ,IL-6 and P53 levels accompanied with significant increase in Bcl-2 level as compared to untreated AD induced group. These results are greatly supported by the histological findings. Thus, it could be concluded that serrapeptase and nattokinase may be considered as newly neuroprotective agents against inflammation and apoptosis characterizing AD through their proteolytic, anti -inflammatory and anti -apoptotic effects. Key Words: Alzheimer’s disease, Proteolytic enzymes, Inflammation, , Apoptosis, Rats.
... The isolated protein belongs to alkaline metalloprotease and known to activate the Hageman factor-kallikrein-kinin systems of mammals and directly involve in degradation or inhibition of IgG and IgA immune factors as well as regulatory proteins such as 2-macroglobulin, 2-anplasmin and anti-thrombin III (10,11). Because of these functionalities, it is administered in dietary supplements for the treatment of assorted inflammatory disorders in Asia and Europe, it gained wide clinical usage as cardiovascular, anti-inflammatory, respiratory, or immune support agent and as an adjunct to antibiotic therapy (12) and to treat other chronic inflammatory diseases, like atherosclerosis, arthritis, bronchitis, carpel tunnel syndrome, fibrocystic breast disease, and sinusitis (13). Recent studies have even suggested the use of oral serratia peptidase, aid in the prevention of viral infections, such as AIDS and hepatitis B and C (14). ...
Article
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A high proteolytic enzyme producing marine isolate has been evaluated for its extracellular protease production with respect to different major nutritional sources. The phylogenetic analysis (16S rRNA ribotyping) of the isolated strain revealed that the strain belongs to Serratia marcescens and the sequence has been submitted to EMBL underthe accession No. HE613732. Carbon source utilization profile indicated that the isolate has potential to use wide range of carbohydrates ranging from monosaccharides to polysaccharides. This isolate produces cellulase, amylase and chitinase extracellularly. Among tested carbon sources, dextrose among monosacchardies, maltose among disaccharides and starch among polysaccharides supported the best growth as well as enzyme production. Maltose among all carbon sources revealed high ratio of biomass growth Vs enzyme yield. Type of complex nitrogen source influenced the enzyme and biomass production independently. Tryptone supported more than 95% improved enzyme yields compared to combination of yeast extract and peptone. Present study revealed that growth and enzyme production in this isolate is differently regulated by type of complex nitrogen source. Yeast extract supplementation supported for maximum biomass development while other complex nitrogen sources supported equally for biomass and enzyme production. To the best of our knowledge, this strain revealed higher enzyme yields compared to literature reports suggesting commercial potential of this isolate.
... Serratiopeptidase induces fibrinolytic, anti-inflammatory and anti-edemic (prevents swelling and fluid retention) activity to number of tissues, and its antiinflammatory effects are superior to other proteolytic enzymes [2]. It is used to treat chronic inflammatory diseases, such as atherosclerosis, arthritis, bronchitis, carpel tunnel syndrome, fibrocystic breast disease, and sinusitis [3]. Fujisaki et al. proposed that, the oral serratiopeptidase can be used as an aid in the treatment or prevention of viral diseases, such as AIDS and hepatitis B and C [4]. ...
Article
The ultrasound assisted three phase partitioning (UATPP) is a novel bioseparation method for separation and purification of biomolecules. In the present work, UATPP was investigated for the first time for purification of serratiopeptidase from Serratia marcescens NRRL B 23112. Effect of various process parameters such as ammonium sulphate saturation, t-butanol to crude extract ratio, pH, ultrasonic frequency, ultrasonic intensity, duty cycle and irradiation time were evaluated and optimized. The optimized conditions were found to be as follows: ammonium sulphate saturation 30% (w/v), pH 7.0, t-butanol to crude ratio 1:1 (v/v), ultrasound frequency 25 kHz, ultrasound intensity 0.05 W/cm2, duty cycle 20% and irradiation time 5 min. The maximum purity and recovery obtained from UATPP was 9.4 fold and 96% respectively as compared to the Three Phase Partitioning (TPP) (4.2 fold and 83%). Also the process time for UATPP was significantly reduced to 5 min from 1 h as compared to TPP. The results indicate that, UATPP is an efficient technique for the purification of serratiopeptidase with maximum purity, recovery and reduced processing time.
... This study demonstrated that bromelain was no more effective than placebo at lowering CRP which in combination with fibrinogen is a signature of inflammatory processes in the body. (27) The results in this RCT contrast with the claims that bromelain has its beneficial effects in its anti-inflammatory properties in a number of clinical trials, particularly in joint inflammation (17,28,29) as well as its importance in finding it effective as an adjunct in the treatment of acute thrombophlebitis due to inflammation of a vein. (30) Since elevated CRP alone has been indicated as a marker for early bacterial infection, active rheumatoid disease, Crohn's disease and acute myocardial infarction and following trauma. ...
Article
Objective To assess whether the dietary supplement (bromelain) has the potential to reduce plasma fibrinogen and other cardiovascular disease (CVD) risk factors in patients with diabetes. Methods This randomized placebo controlled, double blind, parallel design, efficacy study was carried out in China and investigated the effect of 12 weeks of bromelain (1,050 mg/day) on plasma fifibrinogen. This randomized controlled trial (RCT) recruited 68 Chinese diabetic patients [32 males and 36 females; Han origin, mean age of 61.26 years (standard deviation (SD), 12.62 years)] with at least one CVD risk factor. Patients were randomized into either bromelain or placebo group. While bromelain group received bromelain capsule, the placebo group received placebo capsule which consisted inert ingredient and has no treatment effect. Subjects were required to take 1,050 mg (3×350 mg) of either bromelain or starch-fifilled placebo capsules, two to be taken (2×350 mg) after breakfast and another (350 mg) after dinner, daily for 12 weeks. Plasma fibrinogen, CVD risk factors and anthropometric indicators were determined at baseline and at 12 weeks. Results The change in the fifibrinogen level in the bromelain group at the end of the study showed a mean reduction of 0.13 g/L (standard deviation (SD) 0.86g/L) compared with the mean reduction of 0.36 g/L (SD 0.96 g/L) for the placebo group. However, there was no signifificant difference in the mean change in fifibrinogen between the placebo and bromelain groups (mean difference=0.23g/L (SD 0.22 g/L), =0.291). Similarly, the difference in mean change in other CVD risk factors (blood lipids, blood pressure), blood glucose, C-reactive protein and anthropometric measures between the bromelain and placebo groups was also not statistically signifificant. Statistical differences in fifibrinogen between bromelain and placebo groups before the trial despite randomization may have inflfluenced the results of this study. Conclusion This RCT failed to show a benefificial effect in reducing fifibrinogen or inflfluencing other selected CVD risk factors but suggests other avenues for subsequent research on bromelain.
... Serratiopeptidase also works by modifying cell-surface adhesion molecules, which guide inflammatory cells to their targets. These adhesion molecules are known to play an important role in the development of arthritis and other autoimmune diseases (Klein and Kullich 2000). ...
Article
Conversion of fibrinogen to fibrin inside blood vessels results in thrombosis, leading to myocardial infarction and other cardiovascular diseases. In general, there are four therapy options: surgical operation, intake of antiplatelets, anticoagulants, or fibrinolytic enzymes. Microbial fibrinolytic enzymes have attracted much more attention than typical thrombolytic agents because of the expensive prices and the side effects of the latter. The fibrinolytic enzymes were successively discovered from different microorganisms, the most important among which is the genus Bacillus. Microbial fibrinolytic enzymes, especially those from food-grade microorganisms, have the potential to be developed as functional food additives and drugs to prevent or cure thrombosis and other related diseases. There are several assay methods for these enzymes; this may due to the insolubility of substrate, fibrin. Existing assay methods can be divided into three major groups. The first group consists of assay of fibrinolytic activity with natural proteins as substrates, e.g., fibrin plate methods. The second and third groups of assays are suitable for kinetic studies and are based on the determination of hydrolysis of synthetic peptide esters. This review will deal primarily with the microorganisms that have been reported in literature to produce fibrinolytic enzymes and the first review discussing the methods used to assay the fibrinolytic activity.
... It is usually prescribed for treating inflammatory, traumatic and post-operative swelling and pain. Serrapeptidase being a miracle enzyme, used to treat chronic inflammatory disease such as atherosclerosis, arthritis, bronchitis, fibrocystic breast disease and sinusitis [4] as well as Alzheimer's disease. Recent studies have even suggested the use of oral SPR to aid in the treatment or prevention of viral diseases, such as AIDS and hepatitis B and C [5]. ...
Article
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Objective: Serrapeptidase is a therapeutic enzyme broadly used as an anti-inflammatory drug to treat inflammatory diseases like arthritis, bronchitis, fibrocystic breast disease and sinusitis. The objective of present study is in silco analyzes of the substrate and inhibitor binding sites of serratiopeptidase, expressed from a cloned gene. Methods: The gene encoding Serrapeptidase was amplified from genomic DNA of Serratia marcescens MTCC 8707, an isolated from the flowers of summer squash plants. The gene was sequenced, the nucleotide sequence of 1464 nucleotides was submitted to Gen Bank nucleotide database and accession number GI: KP869847 obtained. The develop amino acid sequence was used to predict 3D structure using different bioinformatics tools and software’s Further, CABS-dock and Swiss Dock, the docking servers were used for enzyme-substrate/inhibitor binding site analysis. The inflammatory mediators, bradykinin, and substance-P were used as substrates, whereas, EDTA and Lisinopril were used as an inhibitor for serrapeptidase. UCSF Chimera program was used for interactive visualization and analysis of docked results. Results: The docking studies show substrates bradykinin and substance-P bind near zinc binding site with minimum RMSD value and the inhibitors EDTA and lisinopril showed favorable interaction at zinc binding site of serrapeptidase with minimum free energy. Conclusion: The result of docking studies confirm that the substrate or inhibitor binds near zinc binding domain (HEXXH.) and the peptide bond of the substrate can be effectively cleaved by serrapeptidase.
... Serratiopeptidase seems to act as analgesic, anti-inflammatory, and fibrinolytic/caseinolytic [59][60][61]. As for the antiinflammatory property, this enzyme reduces swelling by decreasing the amount of fluid in the tissues, thinning the fluid, and facilitating fluid drainage. ...
Article
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The nonhormonal medical treatment can be divided into empirical, when the cause has not been identified, and nonempirical, if the pathogenic mechanism causing male infertility can be solved or ameliorated. The empirical nonhormonal medical treatment has been proposed for patients with idiopathic or noncurable oligoasthenoteratozoospermia and for normozoospermic infertile patients. Anti-inflammatory, fibrinolytic, and antioxidant compounds, oligo elements, and vitamin supplementation may be prescribed. Infection, inflammation, and/or increased oxidative stress often require a specific treatment with antibiotics, anti-inflammatory drugs, and/or antioxidants. Combined therapies can contribute to improve sperm quality.
... Over the last decade, enzyme-based therapeutics attract huge attention in modern medicine due to their selectivity and efficiency (Majima et al. 1988;Klein and Kullich 2000). Interestingly, several enzymes such as tissue plasminogen activator (t-PA), staphylokinase and L-asparaginase have been approved for management of multiple life-threatening diseases or disorders, including acute myocardial infarction, pulmonary embolism, acute arterial occlusion, lymphoproliferative disorders and lymphomas (particularly acute lymphoblastic leukemia (ALL) and Hodgkin's lymphoma) (Khanna et al. 2013). ...
Article
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Serratiopeptidase is a bacterial protease that has been used medicinally in variety of applications. Though, some drawbacks like sensitivity to environmental conditions and low penetration into cells limited its usage as a potent pharmaceutical agent. This study aimed to produce four novel truncated serratiopeptidase analogs with different lengths and possessing one disulfide bridge, in order to enhance protease activity and thermal stability of this enzyme. Mutagenesis and truncation were performed using specific primers by conventional and overlap PCR. The recombinant proteins were expressed in E. coli cells then purified and their protease activity and stability were checked at different pH and temperatures in comparison to the native form of the enzyme, Serra473. Enzyme activity assay showed that T306 [12–302 ss] was not further active which could be due to the large truncation. However, T344 [8–339 ss], T380 [8–339 ss] and T380 [12–302 ss] proteins showed higher proteolytic activity comparing to Serra473. These analogs were active at temperatures of 25–90 °C and pH 6–9.5. Interestingly, remaining enzyme activity of T344 [8–339 ss], T380 [8–339 ss] and T380 [12–302 ss] forms at 90 °C calculated as 87, 83 and 86 percent, respectively, comparing to the activity at room temperature. However, residual activity at the same conditions was 50% for the full length enzyme. Formation of disulfide bond in engineered serratiopeptidases could be the main reason for higher thermal stability compared to Serra473. Thermostability of T344 [8–339 ss], as the most thermostable designed serratiopeptidase, was additionally confirmed using differential scanning calorimetry. Graphical abstract
... Every health system possesses both pro and anti-inflammatory molecules and balance between brings tissue homeostasis [45]. Lipid mediators primarily derived from polyunsaturated fatty acids (PUFAs) are a key player for resolution of inflammation ( Fig. 3) [46]. ...
Article
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Inflammation remains key event during most of the diseases and physiological imbalance. Acute inflammation defines protective measure by immune system to remove cause and failure of resolution lead to chronic inflammation. Over a period of time, numbers of drugs mostly chemical have been deployed to combat acute and chronic inflammation. In the recent time enzyme based anti-inflammatory, drugs became popular over conventional chemical based. Serratiopeptidase a proteolytic enzyme from trypsin family possess tremendous scope in combating inflammation. Serine protease possesses a higher affinity for cyclooxygenase (COX-I and COX-II) a key enzyme associated with production of different inflammatory mediators including interleukins (IL), prostaglandins (PGs) and thromboxane (TXs) etc. Currently, arthritis, sinusitis, bronchitis, fibrocystic breast disease, and carpal tunnel syndrome, etc. are the leading inflammatory disorders affected entire the globe. In order to conquer inflammation, both acute and chronic world, physician mostly relies on conventional drugs. The most common drugs to combat acute inflammation are Nonsteroidal anti-inflammatory drugs (NSAIDs) alone and or in combination. However, during chronic inflammation, NSAIDs are often used with steroidal drugs such as autoimmune disorders (RA. These drugs possess several limitations such as side effect and ADR etc. In order to overcome these limitations and complications enzyme based drugs (anti-inflammatory) emerged and aiming a new high since last one decade. Serine protease, the largest proteolytic family has been reported for several therapeutic applications, including anti-inflammatory. Serratiopeptidase is a leading enzyme has a very long history in medical as an effective anti-inflammatory drug. Current study emphasizes present scenario and future prospect of serratiopeptidase as an anti-inflammatory drug. The study also illustrates a comparative analysis of conventional drugs and enzyme based therapeutic to combat inflammation.
... Evidence shows that bromelain is more effective if administered orally [10]. Bromelain is well tolerated by the gastrointestinal (GI) system, and animal studies have shown that it has no toxic effect up to 10 g/kg body weight [11,12]. Considering the positive effects of bromelain mentioned earlier, this study aimed to assess the effect of bromelain intake on pain, bleeding, and wound healing at the donor site after FGG. ...
Article
Full-text available
efficacy of bromelain for pain relief and wound healing, this study aimed to assess the effect of bromelain on wound healing, pain, and bleeding at the donor site following free gingival grafting (FGG). Materials and Methods: This randomized, controlled double-blind clinical trial was performed on 26 patients with gingival recession. The patients were randomly divided into two groups of bromelain and placebo (n=13). Treatment was started on the day of surgery and was continued for 10 days. Pain, bleeding, and epithelialization at the donor site were the variables evaluated in this study using a questionnaire. The level of pain was determined using a visual analog scale (VAS) considering the number of analgesic tablets taken within 7 days postoperatively. Bleeding was determined according to the patient’s report, and epithelization was assessed by applying 3% hydrogen peroxide (H2O2) to the donor site. The donor site epithelialization was assessed at 7 and 10 days after surgery. Results: Bromelain caused a significant reduction in pain at the donor site (2.605±0.509) compared to the placebo (4.885±0.519; P<0.05). The number of donor sites with complete epithelialization was higher in the bromelain group compared to the placebo, but this difference was not statistically significant (P>0.05). The two groups were the same regarding postoperative bleeding (P>0.05). Conclusions: The results showed that oral bromelain (500 mg/day) can be effective in the reduction of pain at the donor site after FGG and may also enhance wound healing. Oral bromelain does not increase the risk of postoperative bleeding. Key words: Bromelain; Wound Healing; Transplant Donor Site; Operative Surgical Procedure
... This enzyme is also known by the name of Serralysin, Serratia-protease, or Serrapeptase [10], it has seven cofactors of calcium and, in its active form, one bivalent metal ion (Zn 2 ) [11]. Moreover, it has been used in different therapeutic applications for the treatment of arthritis, sinusitis, carpal tunnel syndrome, chronic bronchitis, atherosclerosis, fibrocystic breast disease, postoperative swelling, and pain due to its anti-inflammatory, analgesic, and anti-edematous effects [10,[12][13][14][15][16][17][18][19][20][21][22]. Several bacteria isolated from different organisms have been used for the production of serratiopeptidase [1,[7][8][9]. ...
Article
Serratiopeptidase, a metalloprotease produced by Serratia marcescens, is produced through a fermentation process using carbohydrates and proteins as carbon and nitrogen sources. However, some byproducts of the silk industry could be an alternative source for serratiopeptidase production. Therefore, the present work is focused on the purification and characterization of a serratiopeptidase produced from the C8 isolate of Serratia marcescens and obtained from a Colombian silkworm hybrid using casein or silkworm pupae. The protease was purified using ultrafiltration, anion-exchange, and size-exclusion chromatography. The purified enzyme showed a molecular weight of ~50 kDa with a purity above 96%, an isoelectric point of ~4.6, optimum pH and temperature of 6 and 50 °C, and stability at 4 °C for one month. The kinetic constants using azocasein as substrate were 0.63 mM (Km), 2,016 μM/min (Vmax), 41.41 s-1 (Kcat), and 6.56 × 107 M-1 s-1 (Kcat/Km). Inhibition by 5 mM EDTA or 1,10-phenanthroline was recovered by adding Zn2+ at the same concentration. Mass spectrometry analysis indicated 94% homology with the sequence of serratiopeptidase produced by the E-15 strain. We purified and characterized a serratiopeptidase produced by the C8 isolate of S. marcescens in a culture medium based on a renewable source from the silk industry.
... Serratiopeptidase has proved to be a superior alternative to traditional NSAIDS having pronounced side effects, which are prescribed to treat osteoarthritis, rheumatoid arthritis and other related disorders. Serratiopeptidase also referred as serrapeptase has been prescribed for treating chronic sinusitis, carpel tunnel syndrome, torn ligaments and post operative inflammation [3][4][5]. Due to its caseinolytic and fibrinolytic properties, it plays an important role in controlling atherosclerosis [6]. Serratiopeptidase is produced by enterobacterium Serratia marcescens which is isolated and purified from its fermentation broth. ...
Article
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Circular Dichroism is a sensitive yet simple analytical tool for analysis of protein conformation and structural changes which can occur due to untoward process changes and handling. Serratiopeptidase, produced by fermentation is a proteolytic enzyme which is used as an anti-inflammatory drug. The isolation of pure serratiopeptidase from fermentation broth involves a number of unit operations during its manufacturing. Taking into account a variety of processing and storage during its manufacture; the objective of this study was to determine whether these variations lead to changes in the secondary structure of serratiopeptidase and hence loss in its biological activity. The impact of manufacturing changes on structure and activity of serratiopeptidase during the development was assessed by carrying out three comparative studies. Structural variability was observed when there was drastic variation in the conditions of manufacturing. Thus the data presented here illustrates the use of circular dichroism as quick process analytical tool which can be used to monitor the manufacturing process qualitatively and assure the quality of the product. The comparative quantitative analysis of serratiopeptidase as against circular dichroism was carried out by well established techniques such as HPLC and caseinolytic assay.
... As a result even though its antigenicity is masked, the enzymatic activity is retained and slowly transferred to the site of inflammation (Mohankumar and Raj, 2011).  Serratiopeptidase reduces swelling, improves microcirculation and expectoration of sputum, etc. since it hydrolyses bradykinin, histamine and serotonin responsible for inflammation (Klein and Kullich, 2000).  Serratiopeptidase is gaining wide acceptance in Europe and Asia as a potent analgesic and antiinflammatory drug to treat chronic inflammatory disease (Ruchir and Singhal, 2010). ...
Poster
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Serratiopeptidase is a proteolytic enzyme (EC No MH366301) widely used to control various inflammatory disorders since it reduces capillary permeability induced by histamine, bradykinin and serotonin. It promotes healing and repair by breaking down abnormal exudates, proteins and improves absorption of decomposed products through lymphatics and blood. The present study deals with the isolation of a potent Serratia culture capable of synthesizing serratiopeptidase and determination of cultural parameters influencing the fermentation. Soil and compost samples were considered for the isolation procedure. The isolated bacteria were screened for their serratiopeptidase synthesizing ability in mineral salt medium supplemented with casein. Isolate demonstrating highest serratiopeptidase synthesis was identified using partial 16S rDNA sequencing. Submerged fermentation conditions considered for the overproduction of serratiopeptidase included concentration of casein, nature of carbon and nitrogen sources. A total of 5 Serratia cultures were isolated, among which isolate MU1 (showing maximum enzyme production) was selected for further studies. Based on molecular characterization it was identified as Serratia marcescens. Improvement in enzyme synthesis was observed when the fermentation broth was supplemented with casein (1% w/v) and glucose (0.8% w/v). Casein acted as a sole source of nitrogen and augmentation of the medium with inorganic nitrogen sources did not increase enzyme production. Therefore it can be concluded that Serratia marcescens MU1 is a potent producer of serratiopeptidase and supplementation of the fermentation broth with simple sugars and organic nitrogen sources improves the yield of the enzyme.
... Serratiopeptidase which is also known as serralysin/serratiaprotease/serrapeptase is a proteolytic enzyme has antiinflammatory benefits [21]. Drugs involved this enzyme are regarded as modern medicines due to their selectivity and efficiency [22]. ...
Article
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Objective: Knee osteoarthritis is a common disabling chronic disease globally. Many pharmacological agents have been used efficiently in treatment of knee osteoarthritis. This study aims to evaluate metformin and serratiopeptidase together in treatment and stop of osteoarthritis progression by different mechanisms. Methods: Present study was a randomized clinical trial study conducted in Al-Kindi teaching hospital through the period from 1st January to 30th of May, 2017 on two groups of 80 osteoarthritis patients (group I; treated with metformin 850 mg oral tablets) and (group II; treated with metformin 850 mg oral tablets and serratiopeptidase 20 mg oral tablets). Parameters of two groups were compared with those of 40 normal healthy controls. Results: Patients in group II showed a highly significant reduction in pain scores post-treatment (p<0.001). Tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß) and interleukin 8 (IL-8) levels were significantly lowered among patients in group II treatment (p<0.001). Lower inflammatory parameters levels were observed among healthy controls and the parameters levels of group II patients were lower than those of group I patients. Conclusion: Metformin and serratiopeptidase regimen was efficient and safe in the treatment of knee osteoarthritis.
... analgesic action of serratiopeptidase possibly functions through inhibiting the release of pain-inducing amines [26]. Serratiopeptidase is a potent anti-biofilm molecule and also disrupts amyloid fibrils in vitro as well as in vivo [27,28]. ...
Article
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Background: Serratia marcescens, a Gram-negative nosocomial pathogen secretes a 50 kDa multi-domain zinc metalloprotease called serratiopeptidase. Broad substrate specificity of serratiopeptidase makes it suitable for detergent and food processing industries The protein shows potent anti-inflammatory, anti-edemic, analgesic, antibiofilm activity and sold as an individual or fixed-dose enteric-coated tablets combined with other drugs. Although controversial, serratiopeptidase as drug is used in the treatment of chronic sinusitis, carpal tunnel syndrome, sprains, torn ligaments, and postoperative inflammation. Since the native producer of serratiopeptidase is a pathogenic microorganism, the current production methods need to be replaced by alternative approaches. Heterologous expression of serratiopeptidase in E. coli was tried before but not found suitable due to the limited yield, and other expression related issues due to its inherent proteolytic activity such as cytotoxicity, cell death, no expression, minimal expression, or inactive protein accumulation. Results: Recombinant expression of mature form serratiopeptidase in E. coli seems toxic and resulted in the failure of transformation and other expression related issues. Although E. coli C43(DE3) cells, express protein correctly, the yield was compromised severely. Optimization of protein expression process parameters such as nutrient composition, induction point, inducer concentration, post-induction duration, etc., caused significant enhancement in serratiopeptidase production (57.9 ± 0.73% of total cellular protein). Expressed protein formed insoluble, enzymatically inactive inclusion bodies, and gave 40-45 mg/l homogenous (> 98% purity) biologically active and conformationally similar serratiopeptidase to the commercial counterpart upon refolding and purification. Conclusion: Expression of mature serratiopeptidase in E. coli C43(DE3) cells eliminated the protein expression associated with toxicity issues. Further optimization of process parameters significantly enhanced the overexpression of protein resulting in the higher yield of pure and functionally active recombinant serratiopeptidase. The biological activity and conformational features of recombinant serratiopeptidase were very similar to the commercially available counterpart suggesting it-a potential biosimilar of therapeutic and industrial relevance.
... In fact, four proteases perform very well in some specific indications (Table 1): (1) Serratiopeptidase is widely applied in allergic skin reactions, muscle pains, joint aches and gastric disturbances (Bhagat et al., 2013), wound debridement, and arthritis (Shinde and Kanojiya, 2014), and it is also used in surgery (postoperative inflammation and traumatic), gynecology (engorgement of breasts), otolaryngology (bronchitis and laryngitis), dentistry (periodontitis and pericoronitis) (Nirale and Menon, 2010;Jadav et al., 2010;Rajaram et al., 2016) and orthopedics (osteoarticular infection and traumatic swelling) (Bhagat et al., 2013). Serratiopeptidase is a powerful anti-inflammatory (Klein and Kullich, 2000), analgesic, anti-edemic, anti-atherosclerotic and topical rapid-acting drug. Serratiopeptidase has been mainly used in Europe and Japan for many years. ...
Article
Anti-inflammatory enzymes promote the dissolution and excretion of sticky phlegm, clean the wound surface and accelerate drug diffusion to the lesion. They play important roles in treating different types of inflammation and pain. Currently, various formulations of anti-inflammatory enzymes are successfully prepared to improve the enzymatic characteristics, pharmacokinetic properties and anti-inflammatory efficacies. The work was performed by systematically searching all available literature. An overall summary of current research about various anti-inflammatory enzymes and their novel formulations is presented. The original and improved enzymatic characteristics, pharmacokinetic properties, action mechanisms, clinical information, storage and shelf life, treatment efficacies of anti-inflammatory enzymes and their different formulations are summarized. The influencing factors such as enzyme type, source, excipient, pharmaceutical technique, administration route and dosage are analyzed. The combined application of enzymes and other drugs are included in this paper. Anti-inflammatory enzymes were widely applied in treating different types of inflammation and diseases with accompanying edema. Their novel formulations increased enzymatic stabilities, improved pharmacokinetic properties, provided different administration routes, and enhanced anti-inflammatory efficacies of anti-inflammatory enzymes but decreased side effects and toxicity. Novel enzyme formulations improve and expand the usage of anti-inflammatory enzymes.
... Serratiopeptidase is a leading enzyme which has a very long history in medical use as an effective anti-inflammatory drug. Serratiopeptidase, which is an extracellular metalloprotease has an anti-inflammatory, antiedemic and fibrinolytic activity [11,12]. The observation of it's antiinflammatory effects has led to its use in Japan for the first time [13]. ...
Article
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Background Serratiopeptidase has been clinically used in controlling surgical and non-surgical inflammatory conditions. This study was conducted to assess the therapeutic effect of Serratiopeptidase in patients undergoing surgical removal of impacted mandibular third molar. Methods This randomized clinical trial investigated the efficacy of Serratiopeptidase and Paracetamol after surgical removal of impacted third molar for 5 days (n = 67) as compared with an equivalent dose of placebo and Paracetamol (n = 66). Outcome measures were reported pain, trismus and swelling using Laskin method. All outcome measures were recorded on days 0, 1, 2, 4, and 5 post-surgeries. Results In this clinical trail 133 patients (mean age 23 years, 54% female) completed the study. Baseline characteristics were comparable across treatment groups. Serratiopeptidase significantly improved trismus compared with control on the 4th day (27.30 ± 7.3 mm and 32.06 ± 7.7 mm, respectively (P < 0.001) Swelling markedly improved, The distance from the lower edge of the earlobe to the midpoint of the symphysis for cases vs control were 111.49 ± 8.1 mm and 115.39 ± 9.9 mm, respectively (P < 0.001). Reported pain, showed no statistical significance difference. Conclusion Serratiopeptidase resulted in better inflammation improvement than placebo over 5 days. Further studies are warranted to assess longer-term and clinical outcomes, as well as safety. Clinical relevance Serratiopeptidase administered postoperatively helps in improving trismus and swelling after removal of impacted lower third molars. Trial registration The study was registered in ClinicalTrial.gov under the number NCT02493179. Registered 1st of June 2015, https://clinicaltrials.gov/ct2/results?cond=serratiopeptidase.
... Bromelain influences inflammation by decreasing PGE2 and thromboxane A2 and modulation of immune cell surface adhesion molecules (156). Phlogenzyme (which contains 90 mg Bromelain, trypsin and rutin) compared favorably to diclofenac 100-150 mg by reducing pain 80% in patients with knee osteoarthritis during a 4 week trial (157). No serious adverse events were reported. ...
Chapter
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The doctor of the future will give no medicine, but will interest his patients in the care of the human frame, in a proper diet, and in the cause and prevention of disease. —Thomas Edison (1847–1931)
... Bromelain is also used in the treatment of osteoarthritis. It reduced soft tissue swelling by 72.4% [164] and pain [72,[165][166][167]. Postoperative pain, edema, and erythema were significantly lowered in another study group by using the prescribed amount of bromelain, which implies its significance in the treatment of chronic wounds [168]. ...
Article
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Bromelain is an effective chemoresponsive proteolytic enzyme derived from pineapple stems. It contains several thiol endopeptidases and is extracted and purified via several methods. It is most commonly used as an anti-inflammatory agent, though scientists have also discovered its potential as an anticancer and antimicrobial agent. It has been reported as having positive effects on the respiratory, digestive, and circulatory systems, and potentially on the immune system. It is a natural remedy for easing arthritis symptoms, including joint pain and stiffness. This review details bromelain’s varied uses in healthcare, its low toxicity, and its relationship to nanoparticles. The door of infinite possibilities will be opened up if further extensive research is carried out on this pineapple-derived enzyme.
... Serratiopeptidase also works by modifying cell-surface adhesion molecules, which guide inflammatory cells to their targets. These adhesion molecules are known to play an important role in the development of arthritis and other autoimmune diseases (Klein and Kullich 2000). ...
... It is proved to be a superior alternative to traditional NSAIDS like diclofenac sodium and ketoprofen which have pronounced side effects. Serratiopeptidase is also referred as serrapeptase which has been used to treat chronic sinusitis, carpal tunnel syndrome, sprains, torn ligaments, and postoperative inflammation [10][11][12]. Thus serratiopeptidase is proved to be a stronger caseinolytic agent than any other known alkaline or neutral proteases. ...
Article
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A review is presented on different analytical techniques used for qualitative and quantitative analysis of serratiopeptidase, a proteolytic enzyme, which has recently gained importance as an anti-inflammatory agent. Efforts have been made to collate all the relevant references to the extent possible. The review discusses the advantages and disadvantages of the cited analytical techniques which will help to give insight into the methods used for estimation of serratiopeptidase as such, from clinical isolates and from its dosage forms. The review highlights the basic as well as advanced techniques performed for estimating serratiopeptidase. The techniques illustrated here have been demonstrated to be useful for qualitative and quantitative determination of serratiopeptidase and may find application in analyzing other related proteases.
... Evidence shows that bromelain is more effective if administered orally [10]. Bromelain is well tolerated by the gastrointestinal (GI) system, and animal studies have shown that it has no toxic effect up to 10 g/kg body weight [11,12]. Considering the positive effects of bromelain mentioned earlier, this study aimed to assess the effect of bromelain intake on pain, bleeding, and wound healing at the donor site after FGG. ...
Article
Full-text available
Objectives: Considering the optimal efficacy of bromelain for pain relief and wound healing, this study aimed to assess the effect of bromelain on wound healing, pain, and bleeding at the donor site following free gingival grafting (FGG). Materials and methods: This randomized, controlled double-blind clinical trial was performed on 26 patients with gingival recession. The patients were randomly divided into two groups of bromelain and placebo (n=13). Treatment was started on the day of surgery and was continued for 10 days. Pain, bleeding, and epithelialization at the donor site were the variables evaluated in this study using a questionnaire. The level of pain was determined using a visual analog scale (VAS) considering the number of analgesic tablets taken within 7 days postoperatively. Bleeding was determined according to the patient's report, and epithelization was assessed by applying 3% hydrogen peroxide (H2O2) to the donor site. The donor site epithelialization was assessed at 7 and 10 days after surgery. Results: Bromelain caused a significant reduction in pain at the donor site (2.605±0.509) compared to the placebo (4.885±0.519; P<0.05). The number of donor sites with complete epithelialization was higher in the bromelain group compared to the placebo, but this difference was not statistically significant (P>0.05). The two groups were the same regarding postoperative bleeding (P>0.05). Conclusions: The results showed that oral bromelain (500 mg/day) can be effective in the reduction of pain at the donor site after FGG and may also enhance wound healing. Oral bromelain does not increase the risk of postoperative bleeding.
Article
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Serrapeptase (SP) and nattokinase (NK) are proteolytic enzymes belonging to serine proteases. In this study, we hypothesized that SP and NK could modulate certain factors that are associated with Alzheimer's disease (AD) pathophysiology in the experimental model. Oral administration of aluminium chloride (AlCl3) in a dose of 17 mg/kg body weight (bw) daily for 45 days induced AD-like pathology in male rats with a significant increase in brain acetylcholinesterase (AchE) activity, transforming growth factor β (TGF-β), Fas and interleukin-6 (IL-6) levels. Meanwhile, AlCl3 supplementation produced significant decrease in brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) when compared with control values. Also, AlCl3 administration caused significant decline in the expression levels of disintegrin and metalloproteinase domain 9 (ADAM9) and a disintegrin and metalloproteinase domain 10 (ADAM10) genes in the brain. Histological investigation of brain tissue of rat model of AD showed neuronal degeneration in the hippocampus and focal hyalinosis with cellular as well as a cellular amyloid plaques formation. Oral administration of SP or NK in a rat model of AD daily for 45 days resulted in a significant decrease in brain AchE activity, TGF-β, Fas and IL-6 levels. Also, the treatment with these enzymes produced significant increase in BDNF and IGF-1 levels when compared with the untreated AD-induced rats. Moreover, both SP and NK could markedly increase the expression levels of ADAM9 and ADAM10 genes in the brain tissue of the treated rats. These findings were well confirmed by the histological examination of the brain tissue of the treated rats. The present results support our hypothesis that the oral administration of proteolytitc enzymes, SP and/or NK, would have an effective role in modulating certain factors characterizing AD. Thus, these enzymes may have a therapeutic application in the treatment of AD.
Article
Background: Osteoarthritis (OA) is a joint disease involving articular cartilage degeneration causing patients pain, joint stiffness, physical disability, and significantly reducing their quality of life (QoL). Purpose: The aim of this study was to assess whether the daily consumption of a gastroresistant food supplement formulation containing a combination of Boswellia serrata and bromelain could improve the QoL of patients suffering from various forms of OA. Materials and Methods: Forty-nine patients were enrolled in this pilot study conducted from June 2015 to October 2016. Patients took a Boswellia- and bromelain-based supplement for a period between 1 and 6 months. At baseline and at the end of the study, patients completed a self-assessment QoL questionnaire regarding their independence in performing daily activities. QoL scores were compared between baseline and follow-up by means of the Wilcoxon signed-rank test in all patients and in the subgroups of patients with knee, hip, or generalized OA. Results: Forty-nine patients, 6 men and 43 women, aged between 23 and 92 years, (mean age 63.24) participated in the study. At follow-up (3.0 ± 0.7 months), a significant improvement was observed for 7 of 10 QoL questions and, overall, for the total QoL score. The most significant improvements were observed in the joints that were more strongly affected at baseline. A similar trend was observed when separately considering patients with knee, hip, or generalized OA. No patients experienced adverse events and no drug interactions were reported. Conclusions: From this pilot study, it emerges that the use of the gastroresistant formulation containing the combination of Boswellia and bromelain supplements can represent a valuable nonpharmacological tool for improving the QoL of patients suffering from different forms of OA. Further studies should be conducted to confirm this first evidence.
Chapter
Pineapple is native to the South American Tropics and was widely introduced elsewhere during the sixteenth and seventeenth centuries. The crop is now widely grown throughout the tropics and subtropics. The international pineapple canning industry is based on plantations in Thailand, the Philippines, Malaysia and north Sumatra as well as in Hawaii, Brazil, Taiwan, South Africa, Kenya, Ivory Coast, Mexico and Puerto Rico.
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This randomized, double-blind, placebo-controlled, and comparator-controlled trial evaluated the safety and efficacy of an enzyme combination, as Wobenzym, in adults with moderate-to-severe osteoarthritis (OA) of the knee. Adults (n = 150) received Wobenzym, diclofenac (a nonsteroidal anti-inflammatory drug, NSAID), or placebo for 12 weeks. Improvement in pain scores (Lequesne Functional Index) did not differ between subjects treated with Wobenzym or diclofenac, and both treatment groups improved compared to placebo (P < 0.05). Reduction in total WOMAC scores (secondary outcome measure) did not differ between Wobenzym and diclofenac, although only diclofenac emerged as different from placebo (P < 0.05). The median number of rescue medication (paracetamol) tablets consumed was less in the Wobenzym group compared to placebo (P < 0.05), while there was no difference between diclofenac and placebo. Adverse events were similar in frequency in Wobenzym and placebo groups (7.2% and 9.1% of subjects, resp.) and higher in diclofenac group (15.6%). Wobenzym is comparable to the NSAID diclofenac in relieving pain and increasing function in adults with moderate-to-severe painful knee OA and reduces reliance on analgesic medication. Wobenzym is associated with fewer adverse events and, therefore, may be appropriate for long-term use.
Article
Osteoarthritis and rheumatoid arthritis are the two most common types of arthritis. Cartilage breakdown is a key feature of both diseases which contributes to the pain and joint deformity experienced by patients. Therefore, anti-arthritis drugs are of great importance. The aim of this review is to present recent progress in studies of various agents against osteoarthritis and rheumatoid arthritis. The structures and activities of anti-arthritic agents, which used in medical practice or are in development, are presented and discussed. The effects and mechanisms of action of opioids, glucocorticoids, non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, natural products derived from plants, nutraceuticals, and a number of new and perspective agents are considered. Various perspective targets for the treatment of osteoarthritis and rheumatoid arthritis are also discussed. Trials of good quality are needed to draw solid conclusions regarding efficacy of many of the studied agents. Unfortunately, to date, there is no pharmacologic agent proven to prevent the progression of both diseases, and there is an urgent need for further development of better anti-arthritic agents. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
Background Serratiopeptidase for pain, facial swelling and trismus associated with surgical removal of impacted molar is under investigation. However conclusive evidence on the use of serratiopeptidase is lacking. Hence a systematic review and meta-analysis of randomized controlled studies was carried out. Methods Electronic databases were searched for eligible studies and necessary data extracted. The data were analysed using non-Cochrane mode in RevMan 5.0. 95% confidence interval (95% CI) was used to represent the deviation from the point estimate. The heterogeneity between the studies was assessed using Forest plot visually, I2 statistics and Chi square test with a statistical P value of <0.10 to indicate statistical significance. Random-effect models were used in case of moderate to severe heterogeneity. ResultsFive studies were included for final review. Serratiopeptidase improved trismus better than corticosteroids with the MD, 95% as 4.42 [3.84, 5]. As regards to swelling, no significant difference was observed for serratiopeptidase when compared to corticosteroids. Paucity of studies precludes any conclusion for other outcome measures as well as for other comparator drugs. Conclusion Serratiopeptidase could be used safely and effectively to improve trismus and facial swelling after surgical removal of impacted molar.
Article
The aim of this study was to compare the short-term efficacy and tolerability of an oral enzyme therapy (Phlogenzym®) with the nonsteroidal antiinflammatory drug, diclofenac, in patients with active osteoarthritis of the knee. Sixty-three patients with active osteoarthritis of the knee were treated in a randomized, double blind, parallel group trial for 21 days. Thirty-one patients were included in the Phlogenzym® group and 32 patients were included in the diclofenac group. Efficacy was primarily evaluated by the Lequesne index and by using the visual analog scale (VAS) for pain at rest and in motion. In addition, overall assessment of efficacy and tolerability (both by patients and the physician), various laboratory parameters, range of motion without pain (0°), circumference of the affected knee, self-judgment of impairment and therapy outcome were evaluated descriptively. Patients were evaluated at baseline, at weekly intervals throughout the study and at 4 weeks after discontinuing medication intake. All 63 patients were evaluated on an intent-to-treat data set. Statistical evaluation showed that in the main endpoints, the Lequesne index and VAS, the Phlogenzym® group was equivalent to the diclofenac group. The mean value of the Lequesne index decreased from 15.48 to 9.81 after 7 weeks in the Phlogenzym® group and from 15.81 to 10.83 after 7 weeks in the diclofenac group. In the statistical evaluation the lower band of the 95% confidence interval of the Mann-Whitney estimator was above 0.44, the limit for equivalence, at all times. The secondary criteria showed no significant differences. In the majority of patients, overall assessment of efficacy and tolerance were judged in both drug groups as very good or good. In conclusion, short-term evaluation indicates that Phlogenzym® as an oral enzyme formulation can be considered as an effective and safe alternative to nonsteroidal antiinflammatory drugs such as diclofenac in the treatment of active osteoarthritis of the knee.
Article
Renal cell hypertrophy, a major feature of diabetic nephropathy, is caused by an accumulation of extracellular matrix due to an increase of protein synthesis and inhibition of protein degradation based on reduced proteolytic activity. Substitution of proteases may increase reduced proteolytic activity in the kidney. Therefore, intraperitoneal or orally applied Phlogenzym®, a combination preparation consisting of the proteases trypsin, bromelain and the free radical scavenger rutoside, was examined in several models of rat renal fibrosis (streptozotocin-induced diabetes, subtotal nephrectomy and Goldblatt hypertension). Phlogenzym® attenuated the progression of kidney fibrosis in all models. This effect was accompanied by reduced synthesis and/or enhanced elimination of the profibrotic cytokine transforming growth factor-β1 (TGF-β1) mediated by the proteinase activated form of the antiproteinase α2-macroglobulin, which is a scavenger of this cytokine. In vitro, inhibition of both TGF-β1 expression and tubular cell hypertrophy induced by advanced glycation end-products was achieved by coadministration of either TGF-β antibodies or trypsin. Many investigators have shown that orally applied proteases are absorbed and systemically available and that they partially retain their enzymatic activity. A placebo-controlled feasibility study of 24 patients with diabetic nephropathy treated over a period of 16 weeks with oral Phlogenzym® was performed to test the clinical safety and efficacy of this drug. Patients tolerated Phlogenzym® very well and seemed to benefit from this treatment with regard to the development of proteinuria and serum creatinine. An end-point study (combined end-point: doubling of serum-creatinine, requirement for dialysis, or death) involving approximately 400 patients should confirm the benefits of Phlogenzym® treatment in combination with angiotensin-converting enzyme inhibition in patients with diabetic nephropathy.
Article
Treatment with bromelain-containing enzyme preparation for 3–4 weeks is effective for treatment of knee osteoarthritis (OA). Here, we aimed to assess 16-week treatment with bromelain in mild-to-moderate knee OA patients. We performed a randomized, single-blind, active-controlled pilot study. Forty knee OA patients were randomized to receive oral bromelain (500 mg/day) or diclofenac (100 mg/day). Primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) analyzed by Wilcoxon signed rank test. Secondary outcome was the short-form 36 (SF-36). Plasma malondialdehyde (MDA) and nitrite were measured as oxidative stress markers. There was no difference in WOMAC and SF-36 scores compared between bromelain and diclofenac groups after 4 weeks. At week 4, the improvement of total WOMAC and pain subscales from baseline was observed in both groups; however, two patients given diclofenac had adverse effects leading to discontinuation of diclofenac. However, observed treatment difference was inconclusive. At week 16 of bromelain treatment, the patients had improved total WOMAC scores (12.2 versus 25.5), pain subscales (2.4 versus 5.6), stiffness subscales (0.8 versus 2.0), and function subscales (9.1 versus 17.9), and physical component of SF-36 (73.3 versus 65.4) as compared with baseline values. OA patients had higher plasma MDA, nitrite, and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-stimulated whole blood but lower plasma α-tocopherol than control subjects. Plasma MDA and LPS-stimulated PGE2 production were decreased at week 16 of bromelain treatment. Bromelain has no difference in reducing symptoms of mild-to-moderate knee OA after 4 weeks when compared with diclofenac.
Article
Purpose Osteoarthritis (OA) is a chronic and degenerative disorder associated with joint pain and loss of joint function. It is reported that polyphenols could yield articular benefits in patients with OA through the inhabitation of key inflammatory pathways. This meta-analysis was conducted to assess the efficacy and safety of polyphenol products for OA treatment. Methods This study included searches of PubMed, EMBASE, and the Cochrane Library databases from inception to November 6, 2019. Randomized controlled trials (RCTs) comparing polyphenols versus NSAIDs or placebo for human OA were included. Standardized mean differences (SMD) or risk ratios (RRs) were calculated for all relevant outcomes. Meta-analyses were conducted by using random effect models, and heterogeneity was assessed by using the I² statistic. Findings A total of 18 RCTs (N = 1724) were eligible for analysis. Polyphenol products showed a significant advantage over placebo on pain relief (SMD, –1.11; 95% CI, –1.35 to –0.87) and functional improvement (SMD, –1.14; 95% CI, –1.38 to –0.90). No differences in safety outcomes were detected between polyphenols and placebo. There were no differences in efficacy outcomes between polyphenols and NSAIDs, although patients receiving polyphenols had a lower but nonsignificant risk of experiencing gastrointestinal dysfunction compared with those treated with NSAIDs. Polyphenols and NSAIDs in combination yielded more significant benefits in efficacy than NSAIDs alone. Implications The results of our study suggest that polyphenols may be a promising alternative for OA by relieving symptoms while reducing safety risks. However, the generalizability of our results may be limited by the quality and sample size of the available research, as well as the heterogeneity between RCTs. High-quality clinical trials are needed to make meaningful clinical practice recommendations.
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Summary In the course of a randomized, double-blind, cross-over study, 10 healthy volun- teers received a daily oral dosage of 30 coated Wobenzym® tablets (a mixture of proteolytic enzymes) or a placebo for two weeks. A quantification of the complete hemorheological profile served as the primary endpoint. No changes were observed in the placebo group for any of the measured variables. Under medication with the active preparation, however, a decrease in blood and plasma viscosity, erythrocyte rigidity and erythrocyte aggregation could be observed. The parameters of the blood count, serum electrophoresis and colloidosmotic pressures were unaltered under therapy with either the placebo or Wobenzym®. No adverse drug reactions were observed with either the placebo or the active medication. It is concluded that the oral application of Wobenzym® significantly changes the flow properties of blood in healthy volunteers. Further clinical trials must be performed in order to determine whether these effects can be employed for improving blood perfusion, for instance in the event of ischemic disease.
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Human peripheral blood mononuclear cells from healthy donors were treated ex vivo with the proteolytic enzyme bromelain and studied by flow cytometry. Bromelain-treated lymphocytes exhibited 60-90% reduced cell surface staining for CD44 and CD62-L molecules. While the staining for molecules CD16, CD56 and CD49d was unaffected, a moderate increase (10-40%) in expression of the beta(2)-integrins CD11a-c was seen. This selective modulation of cell adhesion molecules (CAM) was seen on T cells and NK cells, as well. The selective modulation of CAM may help explain some of the clinical effects observed after bromelain treatment in patients suffering from chronic inflammatory disease, HIV and cancer.
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One hundred and thirty-four patients with either osteoarthritis or rheumatoid arthritis, and with a history of current or past non-steroidal anti-inflammatory drug (NSAID) treatment, were interviewed regarding the benefits, expectations and side-effects of NSAID therapy. Their willingness to accept risks in medical treatment was also evaluated. Both groups experienced positive effects of the NSAID treatment corresponding to their expectations. However, rheumatoid arthritis patients were significantly more willing to accept gastrointestinal side-effects when given an effective NSAID than the osteoarthritis patients, and they were also more willing to take risks in trying a hypothetical new NSAID that had been shown to be effective in clinical trials.
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To assess the efficacy and safety of avocado/soybean unsaponifiables (ASU) in the treatment of patients with symptomatic osteoarthritis (OA) of the knee or hip, as well as the potential residual effects of ASU after stopping treatment, to determine whether ASU might be a symptomatic slow-acting drug for the treatment of OA. One hundred sixty-four patients with regular, painful, primary OA of the knee (n = 114) or hip (n = 50) entered a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial with a 6-month treatment period and a 2-month posttreatment followup. A 15-day washout period for nonsteroidal antiinflammatory drugs (NSAIDs) preceded the study. Efficacy was judged according to 1) Lequesne's functional index (LFI) and 2) pain on Huskisson's visual analog scale (VAS; 100-mm scale), intake of NSAIDs/analgesics, and overall disability score (by 100-mm VAS). Eighty-five patients received ASU; 79 received placebo. One hundred forty-four patients were evaluable at month 6 (75 taking ASU; 69 taking placebo). The mean +/- SEM LFI score decreased from 9.7 +/- 0.3 to 6.8 +/- 0.4 in the ASU group and from 9.4 +/- 0.3 to 8.9 +/- 0.4 in the placebo group (P < 0.001 for intergroup difference at month 6). Pain decreased from 56.1 +/- 1.6 mm to 35.3 +/- 2.3 in the ASU group and from 56.1 +/- 1.8 mm to 45.7 +/- 2.6 in the placebo group (P = 0.003 at month 6). NSAID consumption was slightly lower in the ASU group. Fewer patients in the ASU group required NSAIDs (48%, versus 63% in the placebo group; P = 0.054). The success rate was 39% in the ASU group and 18% in the placebo group. Overall functional disability was significantly reduced in the ASU group. Improvement appeared more marked in patients with hip OA. A residual effect was observed at month 8. Tolerance was good to excellent for most patients. ASU treatment showed significant symptomatic efficacy over placebo in the treatment of OA, acting from month 2 and showing a persistent effect after the end of treatment.
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Although widely used, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a high incidence of gastrointestinal (GI) side-effects. Inhibition of the cyclooxygenase (COX) enzyme is the basis for both the efficacy and toxicity of NSAIDs. The discovery of two COX isoforms, constitutive COX-1 and inducible COX-2, has led to the hypothesis that selective inhibition of COX-2 will minimize the potential for GI toxicity without compromising efficacy. The Meloxicam Large-scale International Study Safety Assessment (MELISSA) trial reported here was therefore set up to investigate the tolerability of meloxicam, a preferential inhibitor of COX-2, compared to diclofenac. MELISSA was a large-scale, double-blind, randomized, international, prospective trial, conducted over 28 days in patients with symptomatic osteoarthritis. Patients received either meloxicam 7.5 mg or diclofenac 100 mg slow release, the recommended doses for the treatment of osteoarthritis. Evaluation of the profile of adverse events was the main aim of the trial, together with assessment of efficacy. A total of 9323 patients received treatment (4635 and 4688 in the meloxicam and diclofenac groups, respectively). Significantly fewer adverse events were reported by patients receiving meloxicam. This was attributable to fewer GI adverse events (13%) compared to diclofenac (19%; P < 0.001). Of the most common GI adverse events, there was significantly less dyspepsia (P < 0.001), nausea and vomiting (P < 0.05), abdominal pain (P < 0.001) and diarrhoea (P < 0.001) with meloxicam compared to diclofenac. Five patients on meloxicam experienced a perforation, ulcer or bleed vs seven on diclofenac (not significant). No endoscopically verified ulcer complication was detected in the meloxicam group compared to four with diclofenac. There were five patient days of hospitalization in patients on meloxicam compared to 121 with diclofenac. Adverse events caused withdrawal from the study in 254 patients receiving meloxicam (5.48%) compared to 373 (7.96%) on diclofenac (P < 0.001). These differences were attributable to differences in reported GI adverse events (3.02% on meloxicam vs 6.14% on diclofenac; P < 0.001). Differences in efficacy, as assessed by visual analogue scales, consistently favoured diclofenac. In all instances, 95% confidence intervals did not cross zero, suggesting a statistically significant effect. However, differences were small (4.5-9.01% difference) and did not reach pre-determined levels of clinical significance. Nevertheless, significantly more patients discontinued meloxicam because of lack of efficacy (80 out of 4635 vs 49 out of 4688; P < 0.01). The MELISSA trial confirms earlier studies suggesting that meloxicam has a significantly improved GI tolerability profile in comparison with other NSAIDs, including diclofenac. These results may in part reflect the preferential COX-2 selectivity of meloxicam, although the dose and other aspects of tolerability may be important. These results may provide support for the hypothesis that selective inhibition of COX-2 relative to COX-1 might be an effective approach towards improved NSAID therapy.
Chapter
The discovery of enzymes, other than kallikreins, which release kinins from blood plasma was made by Rocha e Silva et al. (1949a) when they observed the formation of bradykinin by adding either trypsin or Bothrops jararaca venom to plasma globulins One year later Beraldo (1950a, b) reported the kininliberating activity of fibrinolysin (plasmin), when it was incubated with plasma globulins precipitated by half saturation with ammonium sulfate. A cysteineactivated protease secreted by Clostridium histolyticum was next shown to release from fraction IV-4 of bovine plasma a bradykinin-like polypeptide (J L Prado et al., 1956). This group of kinin-releasing enzymes, kininogenases, has been growing up to the present time and now includes several proteolytic enzymes.
Article
Three groups of randomly selected mice were immunized and boosted with Type II collagen; age-matched nonimmunized controls were maintained. Beginning on day 28, groups were given 120 mg/kg oral Phlogenzym® twice daily, 40 mg/kg oral ibuprofen twice daily, or no therapy. Swelling of the footpads, measured with a tensioning caliper generally appeared on day 21, and was identical in the three immunized groups until day 31; subsequently, mice given Phlogenzym® or ibuprofen had significantly less swelling than the untreated mice, with no difference between the two therapies. At sacrifice, there was severe joint degeneration in the untreated groups at 42 and 49 days, with ankylosis in 3 of 8 untreated mice examined at 49 days. Joint degeneration was moderate at day 42 and moderate to severe at day 49 in the ibuprofen-treated mice, but mild at day 42 and generally mild at day 49 in Phlogenzym®-treated mice (chi-squared = 5.8, p < 0.05). Computer morphometry revealed an average cartilage thickness of 720 μm in normals, 630 μm in Phlogenzym®-treated diseased mice, 380 μm in ibuprofen-treated diseased mice, and 290 μm in untreated diseased mice (F = 9.8, p < 0.01). Radiographic scores correlated with the pathologic scores. We conclude that Phlogenzym® protects articular cartilage significantly better than ibuprofen in this murine model of rheumatoid arthritis, despite equal antiinflammatory potency.
Article
Background: Gastrointestinal tract (GI) complications associated with nonsteroidal anti-inflammatory drug (NSAID) use are the most common serious adverse drug reactions in the United States. Nonsteroidal antiinflammatory drugs cause both minor GI side effects such as abdominal pain and vomiting and serious GI events such as ulcers and bleeding. This study evaluates the event rates for all NSAID-induced GI complications in patients with rheumatoid arthritis, describes the time course of these events, and evaluates the role of prophylactic therapy with antacids and H2 receptor antagonists.Methods: We studied 1921 patients with rheumatoid arthritis from 8 ARAMIS (Arthritis, Rheumatism, and Aging Medical Information System) centers. Patients were selected for the study if they were treated with NSAIDs and had at least 2.5 years of observation available. Information on GI complications attributed to NSAIDs was obtained from validated patient self-reports collected every 6 months and supplemented by review of hospital records for all hospitalizations.Results: Approximately 15% of the 1921 patients reported an NSAID-induced GI side effect during the 2.5-year observation period. Forty-two patients had a serious GI complication requiring hospitalization; 34 of these 42 patients did not have a preceding GI side effect. Patients who were taking antacids and H2 receptor antagonists did not have a significantly lower risk for serious GI complications than did those not taking such medications. Asymptomatic patients taking these medications had a significantly higher risk for GI complications compared with those who did not take these medications (standardized odds ratio, 2.14; 95% confidence interval, 1.06-4.32).Conclusions: A large majority of patients with serious GI complications do not have preceding mild side effects. Prophylactic treatment with antacids and H2 receptor antagonists is of questionable value and may increase the risk for subsequent serious GI complications.Arch Intern Med. 1996;156:1530-1536
Article
Guidelines for the medical management of patients with OA of the hip are reported in an accompanying article (5). Herein, we present guidelines for the medical management of patients with OA of the knee. Because many of the specific approaches are common between these two conditions, the reader is referred to the guidelines for OA of the hip for a detailed discussion (5). Differences in approach and treatment strategies which are unique to OA of the knee, including the role of intraarticular corticosteroid injections, will be discussed.
Article
Salicylates and nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of painful disorders. This article reviews the efficacy, side effects, and costs of these agents and proposes a practical approach to using them in a cost-effective manner. Although there may be some differences in efficacy among available drugs, these do not appear sufficient to justify using the more expensive agents in most cases. Adverse effects, especially gastrointestinal (GI), add to the cost of using these drugs. Aspirin and all nonsalicylate NSAIDs share a risk of causing gastric ulcer, upper GI bleeding, and GI perforation. Prostaglandin inhibition by these agents may lead to reduced glomerular filtration rate and renal failure. There may be modest differences in GI and renal risks with the different agents, but these are minimal. Prophylaxis against gastric ulceration with anti-ulcer drugs has been recommended, and one agent, misoprostol, is approved for use in the United States for this purpose. Whether use of prophylaxis will increase or decrease the costs associated with NSAID therapy remains to be determined. Nonacetylated salicylates may cause less GI adverse effects and may be somewhat "renal sparing." Strategies that would reduce the cost of care for painful musculoskeletal disorders without compromising quality of care include using acetaminophen instead of an NSAID for noninflammatory disorders, trying nonacetylated salicylates as less expensive and safer alternatives to NSAIDs, using one agent at a time, allowing sufficient time to evaluate the therapeutic effect before changing agents, returning to the least expensive and/or safest drug if a trial of several in succession fails to find one that is clearly better, and reserving prophylactic use of antiulcer agents for patients who are at especially high risk and for whom anti-inflammatory effects are clearly needed. (Arch Intern Med. 1992;152:1995-2002)
Article
Aspirin breaks the gastric mucosal barrier. We studied the effect of aspirin on this barrier, correlating changes in potential difference and ultrastructure. Mean control potential difference for seven subjects was -48 +/- 1.0 mV. Oral aspirin, 600 mg in 100 ml of saline, reduced potential difference to -39 +/- 1.4 mV (P less than 0.001) within 10 minutes. Gastric biopsies were taken during control, aspirin- instillation, and recovery periods. Damage was present in all biopsies after aspirin. Light microscopy showed focal cell disruption, loss of mucous granules, and apical membrane rupture. Transmission electron microscopy showed intact tight junctions. Scanning electron microscopy showed loss of normal cobblestone cell apices, giving a honeycombed surface. Ten minutes after aspirin, 25% of surface epithelial cells were damaged. Marked recovery was noted at 1 hr, with a normal potential difference and only 9% cell damage. We conclude that single "routine" doses of aspirin cause focal damage to normal human gastric mucosa.
Article
Of the different types of visual analogue and graphic rating scales tested in a series of experiments, only two were satisfactory: these were the visual analogue scale and the graphic rating scales used horizontally with the words spread out along the whole length of the line. Other types of scale used gave distributions of results which were not uniform. Unusual distribution of results occurred when patients selected a position adjacent either to descriptive terms or preferred numbers. In some experiments, the distribution of results was determined by the nature of the experiment. Alternation of the ends of a scale did not affect the results. The behaviour of the graphic rating scale was different in patients accustomed to completing it and in those not so accustomed.The results of pain severity measured by these methods showed a very good correlation with pain severity measured by the simple descriptive pain scale. Changes in visual analogue scores also correlated well with changes in simple descriptive pain scores. The visual analogue and graphic rating scales were more sensitive than the traditional simple descriptive pain scale. Most patients could readily use visual analogue and graphic rating scales despite having no previous experience. The failure rate was slightly lower with the graphic rating method. Use of these scales is the best available method for measuring pain or pain relief.
Article
Treatment of T cells with the cysteine protease bromelain has been widely used to enhance the binding of human T cells to human E (autologous E rosettes) and has been shown to remove surface T cell CD44 molecules. Ligand binding to CD44 has been shown to markedly augment T cell activation. To study the activation potential of bromelain-treated CD44 T cells, we have compared the proliferation of sham- and bromelain-treated normal human PBMC to mitogenic CD2 mAb. We found that bromelain not only removed T cell CD44, but also removed the CD45RA isoform of CD45 as well as E2/MIC2, CD6, CD7, CD8, and Leu 8/LAM1 molecules. T cell proliferation in response to CD2 mAb was increased 325% in bromelain-treated PBMC compared to sham-treated PBMC (p < 0.005). Reciprocal treatment experiments using purified T cells and monocytes demonstrated that the enhancement of T cell CD2 activation by bromelain occurred only when T cells were treated with bromelain and was accompanied by increased adhesion of T cells to monocytes. These data demonstrate that expression of portions of the extracellular domains of the CD44, CD45RA, E2/MIC2, CD6, CD7, CD8, and Leu 8/LAM1 surface molecules are not required for CD2 activation of human T cells. Rather, the removal of these surface molecules by bromelain is associated with enhanced T cell-monocyte aggregation and enhanced CD2-mediated T cell activation. Taken together with data that CD44, E2/MIC2, CD6, and CD7 mAb inhibit CD2/lymphocyte function-associated Ag-3-mediated cellular interactions and also augment CD2-mediated triggering of T cells, these data suggest that members of the bromelain-sensitive group of surface molecules may comprise a set of CD2-associated adhesion ligands that acts in concert to modulate human T cell activation.
Article
The etiology, natural history, epidemiology, prevention, and treatment of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) effects are reviewed. Current evidence suggests that NSAIDs cause acute cellular damage by a topical effect that is exacerbated by impaired healing. Although acute gastric injury from NSAIDs is rapid and almost uniform from patient to patient, not all patients develop serious chronic injury. Some adaptation to the effects of NSAIDs does occur. Endoscopic studies have found that 14-31% of long-term NSAID users have gastric or duodenal ulcers. Data on individual drugs are inconsistent, but they suggest that enteric-coated aspirin, salsalate, and ibuprofen cause the lowest incidence of GI hemorrhage. Preventive measures tested to date include reduction in gastric acid production (histamine H2-receptor antagonists) and attempts to increase mucosal defenses (sucralfate or misoprostol). Misoprostol is the only drug with FDA-approved labeling for prevention of NSAID-induced gastropathy. NSAID-related ulcers heal in most patients within two to three months when they are treated with H2-receptor antagonists with or without antacid, omeprazole, or misoprostol. In patients with multiple risk factors, prophylaxis with misoprostol would be appropriate unless the clinician is concerned solely about reactivation of a duodenal ulcer, in which case an H2-receptor antagonist would also be appropriate. Full-dose treatment with H2-receptor antagonists, omeprazole, or misoprostol will heal NSAID-induced ulcers, even when NSAID therapy is continued.
Article
Toxicity Index scores were computed from symptoms, laboratory abnormalities, and hospitalizations attributed to nonsteroidal antiinflammatory drug (NSAID) therapy in 2,747 patients with rheumatoid arthritis receiving 5,642 courses of 11 NSAIDs over 8,481 patient-years. Substantial differences in overall toxicity were found, the differences between drugs often being clinically significant (2-3 times as toxic) and highly statistically significant. The results strengthened after adjustment for differing patient characteristics, held generally across multiple ARAMIS (Arthritis, Rheumatism, and Aging Medical Information System) data bank centers, and persisted after use of different techniques for the weighting of side effects. The most toxic side effects were experienced by patients taking indomethacin (mean +/- SEM score 3.99 +/- 0.58), tolmetin sodium (3.96 +/- 0.74), and meclofenamate sodium (3.86 +/- 0.66). Least toxic were coated or buffered aspirin (1.19 +/- 0.10), salsalate (1.28 +/- 0.34), and ibuprofen (1.94 +/- 0.43). The most toxic drugs were generally taken in the lowest relative doses. There are statistical differences in overall toxicity between different NSAIDs as used in rheumatoid arthritis, and these differences are both clinically and statistically significant.
Article
Evidence has accumulated that nonsteroidal anti-inflammatory drugs (NSAIDs) cause clinically important gastroduodenal ulcers. The pathogenesis, which involves the impairment of mucosal resistance to injury in an acid-peptic environment, is multifactorial and controversial. Ulcers caused by NSAIDs can occur either in mucosa inflamed because of infection with Helicobacter pylori or in histologically normal mucosa. The use of these drugs has been linked to an unexpectedly high incidence of ulcer complications, and a history of peptic ulcer disease is common in such cases. Nonsteroidal anti-inflammatory drugs thus appear both to exacerbate an underlying peptic diathesis and to cause de novo ulcers. The association between the use of these drugs and ulcer complications is supported by ulcer prevalence data from cross-sectional studies, and by data from case-controlled and cohort studies, and from randomized, experimental trials. Drug-induced gastric ulcers have been prevented by misoprostol, but not by H2 blocker therapy. Several therapies have been reported to promote ulcer healing despite continued use of NSAIDs, but adequate controlled trials have not been done. Small gastric and duodenal ulcers readily heal, whereas larger gastric ulcers require vigorous and prolonged therapy. The relative efficacies of various therapies in preventing ulcers, healing ulcers, or preventing complications remain to be established.
Article
Gastroduodenal lesions of the mucosa are known to be the most frequent side effect during therapy with non-steroidal antiinflammatory drugs (NSAIDs). We investigated the radioimmunological determination of serum-pepsinogen I as an indicator for the quality of the gastroduodenal mucosa. A good correlation was found between the endoscopy findings of 78 patients and contemporary determinations of serum-pepsinogen. Further, a follow-up of pepsinogen I was made during the treatment of 107 patients with degenerative rheumatic diseases with eight different NSAIDs. The results recommend the determination of pepsinogen I as an indicator of gastroduodenal mucosal changes under therapy with NSAIDs; this determination gives a deciding factor for the gastrolesive potency of an NSAID.
Article
Several in vitro investigations and animal experiments are described which may be used as experimental basis for the enzymatic treatment of rheumatoid arthritis and, possibly, also other immune complex diseases. Demonstration of absorption of unaltered orally-administered radiolabelled enzymes is shown in guinea pigs and rabbits. In vitro experiments with 4 types of soluble immune complexes which were incubated with gradually increasing amounts of enzymes showed dose-dependent cleavage of complexes. Antigen-induced experimental arthritis of rabbits, fed different amounts of a therapeutically used mixture of enzymes at different times, could be inhibited by this treatment, in dependence of dosage and time of feeding. With respect to the therapeutic applications of this study, the results favour the use of a high dosage repeated daily administration, since duration of effect seems limited.
Article
We conducted a study to determine the costs of caring for patients with arthritis. Data were obtained from the Medicaid Management Information System (MMIS) of Washington, DC. A retrospective analysis was undertaken of all direct medical costs related to individual Medicaid recipients who obtained treatment for arthritis. First, all data were adjusted for patient compliance with nonsteroidal anti-inflammatory drugs (NSAIDs). Second, we determined the actual expenditure of treating arthritis. Last, the medical costs of treating adverse gastrointestinal side effects were examined. There was a linear relationship between compliance and pharmaceutical dose schedule per diem. Treatment costs per quarter were $145; 54 percent of the cost was for NSAIDs with the remainder equally divided between physician and hospital costs. Approximately 25 percent of the population experienced NSAID-related gastrointestinal side effects that required further medical care. The per-quarter mean cost of treating these adverse gastrointestinal drug reactions was $66 per person, which added nearly 46 percent to the per-quarter mean cost of treatment. The total cost of treating patients with arthritis therefore averaged $211 per quarter. Nearly one third of overall cost went to provide medical care to the 25 percent of the population who experienced adverse reactions, and slightly more than two thirds went towards treating the disease itself. Overall costs of treating adverse drug reactions were accounted for by pharmaceuticals (about 42 percent), usually the histamine (H2)-receptor antagonist cimetidine, rare but expensive inpatient hospital care (about 38 percent) and physician visits (about 20 percent).
The index for hip disease (ISH) was established, validated and appraised as a new assessment test for the trial of new drugs as well as for long-term follow-up of patients, and to help with future indications for surgery. The ISH deals with pain, maximum walking distance, and some activities of daily living. Inter-observer reproducibility is good (mean deviation 0.55 points; p less than 0.05). In a short-term, double-blind crossover trial, the ISH, judged according to its power to distinguish between the active drug period and the placebo period, appears as one of the best assessment tests. In the long term, total hip prosthesis is most often justified when the ISH score reaches 10-12 points. The index of severity for knee disease (ISK) was validated and appraised by the same statistical methods. Its value in non-steroidal anti-inflammatory drug (NSAID) or analgesic trials is lower than the value of the ISH. However, its use is still justified for that purpose, and for long-term follow-up of osteoarthritis of the knee.
Article
The medical records of 265 patients with peptic ulcer disease were reviewed for a history of nonsteroidal anti-inflammatory drug (NSAID) use preceding hospital admission. Ninety-five patients (36%) gave a history of regular use of such agents. The admission characteristics of the peptic ulcer patient group not using NSAIDs (age, sex, ulcer location, admission indication, method of diagnosis) were virtually identical to those of the group taking NSAIDs. Although 24.5 per cent of patients not taking NSAIDs were admitted because of hemorrhage from their ulcer compared with 28.4 per cent of NSAID users, only 7.5 per cent of nonusers required surgery for hemorrhage control compared to 29.6 per cent of users. Eighty per cent of patients regularly using more than one NSAID required surgery for an ulcer complication. Hemorrhage mortality was 5 per cent among nonusers compared with 14.8 per cent among users. It is concluded that NSAID use by patients with peptic ulcers adversely affects therapeutic response in general and significantly impairs normal hemostatic mechanisms in patients bleeding from an ulcer.
Article
4 types of immune complexes according to the Heidelberger curve were prepared as an in vitro model for immune complexes in rheumatoid arthritis and collagen diseases. Immune complexes of high and moderate antigen excess and immune complexes of high and moderate antibody excess were incubated with increasing concentrations of a mixture of enzymes or papain or pancreatin. The concentration of immune complexes was determined by a solid phase C1q radioimmunoassay before and after incubation. Up to 90% of the complexes of antigen excess were disintegrated even by low doses of enzymes (5-10 mg%); total cleavage appeared at 80 mg% enzyme concentration. Complexes of the antibody excess zone were gradually disintegrated by enzyme concentrations gradually increasing from 5 to 80 mg%, where total cleavage appeared. Single enzymes showed less cleavage activity than enzyme mixtures. Although enzymes were administered to supernatants of the Heidelberger precipitation containing soluble immune complexes as well as enzyme inhibitors, enzymatic activity was not impaired and immune complexes were disintegrated. The results of these investigations are discussed in regard to treatment with enzymes.
Article
The presentation of peptic ulcer in 132 elderly patients is compared with that in 67 younger patients. Abdominal pain was not present in one third of the elderly group. Absence of pain was associated with the older age group to a highly significant degree (P less than 0.001).
Article
Treatment of patients with OA of the knee should be individualized and tailored to the severity of the symptoms. In individuals with mild symptomatic OA, treatment may be limited to patient education, physical and occupational therapy and other nonpharmacologic modalities, and pharmacologic therapy including non-opioid oral and topical analgesics. In patients who are unresponsive to this treatment regimen, the use of NSAIDs in addition to nonpharmacologic therapy is appropriate unless medically contraindicated. Judicious use of intraarticular steroid injections has a role either as monotherapy or an adjunct to systemic therapy in patients with knee OA who have symptomatic effusions. The role of joint lavage and arthroscopic debridement in patients with OA of the knee who are unresponsive to conservative medical therapy needs further study, and these procedures cannot be routinely recommended for all patients at this time. Patients with severe symptomatic OA of the knee require an aggressive approach to decreasing pain, increasing mobility, and decreasing functional impairment; such patients may benefit from orthopedic consultation and evaluation for osteotomy or total joint arthroplasty.
Article
The thiol protease bromelain has been shown to remove T-cell CD44 molecules from lymphocytes and to affect T-cell activation. We investigated the effect of a highly purified bromelain protease F9 (F9) on the adhesion of peripheral blood lymphocytes (PBL) to human umbilical vein endothelial cells (HUVEC). Preincubation of the lymphocytes with F9 reduced the adherence to about 20% of unstimulated and to about 30% of phorbol-dibutyrate (P(Bu)2) stimulated lymphocytes. Using flow cytometry, both crude bromelain and protease F9 reduced the expression of CD44, but not of LFA-1, on PBL. F9 was about 10 times more active than crude bromelain; at 2.5 micrograms/ml of F9 about 97% inhibition of CD44 expression was found. A mAb against CD44 was tested and found to block the F9-induced decrease in PBL-binding to HUVEC. The results indicate that F9 selectively decreases the CD44 mediated binding of PBL to HUVEC.
Article
In vitro treatment of human peripheral blood mononuclear cells (PBMNC) with proteolytic enzymes (bromelain, papain) and amylase leads to the production of large amounts of tumor necrosis factor-alpha (TNF-alpha), interleukin-1-beta (IL-1 beta), and interleukin-6 (IL-6) in a time and dose dependent manner. Increased TNF-alpha and IL-6 production was already found after 4-6 hours of incubation, and plateau levels were reached after 12-16 hours. Plateau levels up to 1500 pg TNF-alpha/ml/10(6) PBMNC, 13000 pg IL-1 beta/ml/10(6) PBMNC, and 23000 pg IL-6/ml/10(6) PBMNC were observed. Control cultures contained below 35 pg/ml/10(6) PBMNC of TNF-alpha, IL-1 beta or IL-6. In contrast to TNF-alpha which was undetectable after more than 24 hours, peak levels of IL-1 beta and IL-6 were still present at 24 hours. After incubation of the enzyme solution for some hours at 56 degrees C the cytokine inducing capacity disappeared. Neutralization experiments with inactivating antibodies, radioimmunoassay, and western blotting after electrophoretic separation showed that the TNF-like activity found in the lytic assay was due to TNF-alpha. Interferon-alpha (IFN-alpha) and Interferon-gamma (IFN-gamma), which had no effect alone, synergistically increased TNF-alpha production when applied together with the enzymes. A commercial mixture of these enzymes (Wobenzym), which was also investigated, showed a similar concentration and time dependence, as well as synergism with the interferons. A synergistic effect on TNF-alpha production was also found with the enzymes and phorbol ester (PMA).
Article
In the course of time, general components of the hyaline cartilage, chondrocytes and cartilage matrix, can lose its quality due to nutritive, toxic and enzymatic influences but also due to excessive mechanical usage so that the hyaline articular cartilage fulfils no longer its function as a hydroelastic bumper. This results in progressive mechanical cartilage destruction and sklerosing reconstruction of the subchondral bone. The parts of the matrix that are freed by the mechanical abrasion can function as inflammatory mediators and set an accompanying synovitis going. It is this secondary synovitis that then leads to a painful manifestation of osteoarthrosis. In this case, an antiphlogistic therapy is necessary, because during a secondary synovitis cytokines are set free that endanger the yet intact articular cartilage.
Article
Symptoms and disability vary considerably over time and among individuals with similar degrees of radiographic osteoarthritis. The results of recent clinical studies have reaffirmed that many patients prefer nonsteroidal anti-inflammatory drugs (NSAIDs) to analgesics while also demonstrating that many individuals who have been receiving NSAIDs can manage without them. Certain but as yet poorly characterized patients appear to respond more favorably to treatment with NSAIDs. Thus, both chronic unquestioning use of NSAIDs and denial of NSAIDs to individuals with osteoarthritis are extreme and inappropriate approaches to treatment. Concerns about the gastrointestinal toxicity of NSAIDs remain, although strategies to prevent this toxicity provide some reassurance and should be considered for use in individuals who are at particular risk. These strategies include the use of NSAIDs that are selective inhibitors of the prostaglandin endoperoxide synthase II isoenzyme and are potentially less ulcerogenic or the coprescription of prostaglandin analogues or other ulcer-healing drugs. The costs and benefits of such approaches have yet to be established. Cartilage metabolism is adversely affected by certain NSAIDs in vitro, but the relevance of these observations remains unclear. In our view, the judicious use of NSAIDs in the treatment of osteoarthritis is acceptably safe and indicated in individuals in whom pain cannot be managed by simple analgesics and nonpharmacologic approaches.
Article
Therapy with non-steroidal anti-inflammatory drugs often causes gastroduodenal side effects. Changes in the gastric mucosa were studied by determination of serum pepsinogen I and pepsinogen II by the means of radioimmunoassay. 41 patients with degenerative rheumatic diseases were divided into two groups, 21 patients receiving 600 mg S(+) ibuprofen daily (3 x 200mg) and 20 patients receiving 900 mg S(+) ibuprofen daily (3 x 300 mg) over a 14-day period. No significant increase occurred in mean and median values of pepsinogen I and II. Indeed, no changes in serum pepsinogen I and II were noted in 80% of the patients in the higher dosage group and in more than 90% of the lower dosage group. None of the gastroduodenal side effects frequently reported during therapy with non-steroidal anti-rheumatic drugs occurred.
Article
Rheumatoid arthritis is a systemic inflammatory disease of the joints and major internal organs that has an unknown aetiology. Cell adhesion molecules (CAMs) are expressed on the surface of cells, enabling homotypic and heterotypic cell-cell interactions that are fundamental in the process of the inflammatory reaction. Three major families of CAMs are now recognised, with numerous subtypes. Many of these molecules play an important role in the mechanism of disease in rheumatoid arthritis. E-Selectin and intercellular adhesion molecule (ICAM)-l are upregulated on the synovial endothelium, while vascular cell adhesion molecule (VCAM)-l plays an important role in the synovial lining layer cells and within the synovial stroma. The expression of CAMs may be blocked by monoclonal antibodies and modified by nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs. This has very important implications in the therapy of rheumatoid arthritis.
Article
Because the gastrointestinal complications of nonsteroidal anti-inflammatory drug (NSAID) use may be responsible for over 10,000 deaths each year, clinicians should consider limiting use of these agents. Risk factors such as previous ulcer disease, high dosage, concomitant corticosteroid use, age greater than 60 years and use of more than one NSAID concomitantly should be reviewed. If a patient has two or more risk factors, prophylaxis with misoprostol is indicated. In low-risk patients, prophylaxis with misoprostol is not indicated because of the risk of gastrointestinal side effects and high cost. Although it is common clinical practice to treat NSAID-induced dyspepsia with prophylactic antiulcer therapy, clinical studies do not support this approach. If an ulcer develops during NSAID therapy, treatment with a histamine H2 antagonist should be started. Discontinuation of the NSAID is recommended but is not necessary for ulcer healing. It is recommended that, once the ulcer heals, the patient also take misoprostol if NSAID usage is continued.
Article
Use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for hospitalization and death from gastrointestinal bleeding and perforation. To 1) estimate the extent to which NSAIDs are prescribed unnecessarily and NSAID-related side effects are inaccurately diagnosed and inappropriately managed and 2) identify the physician and visit characteristics associated with suboptimal use of NSAIDs. Prospective cohort study. Montreal, Canada. 112 physicians representing academically affilliated general practitioners, community-based general practitioners, and residents in family medicine and internal medicine. Blinded, office-based assessment of the management of two clinical cases (chronic hip pain due to early osteoarthritis and NSAID-related gastropathy) using elderly standardized patients. Quality of drug management and potential predictors of suboptimal drug management. Unnecessary prescriptions for NSAIDs or other drugs were written during 41.7% of visits. Gastropathy related to NSAID use was correctly diagnosed in 93.4% of visits and was acceptably managed in 77.4% of visits. The risk for an unnecessary NSAID prescription was greater when the contraindications to NSAID therapy were incompletely assessed (odds ratio, 2.3 [95% CI, 1.0 to 5.2]) and when the case was managed by residents in internal medicine (odds ratio, 4.1 [CI, 1.2 to 14.7]). The risk for suboptimal management of NSAID-related side effects was increased by incorrect diagnosis (odds ratio, 16.6 [CI, 3.6 to 76.5]) and shorter visits. Unnecessary NSAID prescribing and suboptimal management of NSAID-related side effects were sufficiently common to raise questions about the appropriateness of NSAID use in the general population. If these results reflect current practice, prescribing patterns may contribute to avoidable gastrointestinal morbidity in elderly persons.
Article
According to Lewis(1), the nonapeptide bradykinin is an important mediator of the acute inflammatory reaction. It is, therefore, of interest that orally given proteases were recently shown to antagonize 3 pharmacologic actions of bradykinin: vasodilatation, vascular permeability and smooth muscle contraction(2). The objects of the present investigation were: first, to assess the action of orally given streptokinase against the fourth pharmacologic action of bradykinin, namely, pain production; and second, to appraise the anti-inflammatory action of orally given streptokinase in a controlled animal and clinical experiment.Methods. 1. Analgesia study. The cantharidin blister technic of Armstrong et al. (3) was slightly modified. This study comprised 30 apparently healthy students and technicians. A band-aid containing 2 drops of tincture cantharidin was applied to the skin of the flexor surface of the forearm the evening before the day of the experiment. When the band-aid was removed the next morning, the a...
Phlogenzym® protease therapy ameliorates injury in experimental autoimmune arthritis induced by collagen II. B Lymphocytes and Autoimmunity
  • Subba C Rao
  • Nagy
  • Nu
  • Emancipator
Enzympräparate für Therapie und Prophylaxe
  • S Wörschhauser
  • Konservative
Konservative Ther