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Volume 3-4.new

Monograph
Bromelain
Description and Constituents
Bromelain is a general name for a family of sulfhydryl-con- taining, proteolytic enzymes obtained from Ananas comosus,the pineapple plant. Bromelain’s primary component is a sulf-hydryl proteolytic fraction. Bromelain also contains a peroxi-dase, acid phosphatase, several protease inhibitors, and organi-cally-bound calcium. It appears a great deal of the physiologi- cal activity of bromelain cannot be accounted for by its pro-teolytic fraction and that the beneficial effects of bromelainare due to multiple factors, not to one single, isolated factor.
A variety of designations have been used to indicate the activ-ity of bromelain, with published research varying in the desig-nation utilized. Rorer units (r.u.), gelatin dissolving units(g.d.u.), and milk clotting units (m.c.u.) are the most commonlyused measures of activity. One gram of bromelain standard- ized to 2000 m.c.u would be approximately equal to 1 gram with 1200 g.d.u. of activity or 8 grams with100,000 r.u. of activity.
Pharmacokinetics
Bromelain is absorbed intact through the gastrointestinal tract of animals, with up to 40 percent of the high molecular weight substances detected in the blood after oral administration. The highest concentration ofbromelain is found in the blood one hour after administration; however, its proteolytic activity is rapidlydeactivated.1 Mechanisms of Action
Bromelain’s anti-inflammatory activity appears to be due to a variety of physiological actions. Evi- dence indicates that bromelain’s action is in part a result of inhibiting the generation of bradykinin at theinflammatory site via depletion of the plasma kallikrein system, as well as limiting the formation of fibrin byreduction of clotting cascade intermediates.2-4 Bromelain has also been shown to stimulate the conversion ofplasminogen to plasmin, resulting in increased fibrinolysis.4 Bromelain might be capable of selectively modulating the biosynthesis of thromboxanes and prostacyclins, two groups of prostaglandins with opposite actions which ultimately influence activation ofcyclic-3,5-adenosine, an important cell-growth modulating compound. It is hypothesized that bromelain therapyleads to a relative increase of the endogenous prostaglandins, PGI2 and PGE2 over thromboxane A2.5 Bromelain has been shown to decrease aggregation of blood platelets.6 It is an effective fibrinolytic agent in vitro and in vivo; however, its effect is more evident in purified fibrinogen solutions than in plasma.7 Clinical Indications
Antitumor: Several studies, both animal and human, indicate bromelain might have some antimetastatic Page 302 Alternative Medicine Review ◆ Volume 3, Number 4 ◆ 1998
Copyright1998 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission ability.8-10 In doses of over 1000 mg daily, bromelain has been combined with chemotherapeutic agents suchas 5-FU and vincristine, resulting in tumor regression.8, 11 Immune Modulation: Bromelain can induce cytokine production in human peripheral blood mononuclear cells. Treatment leads to the production of tumor necrosis factor-alpha, interleukin-1-beta, andinterleukin-6 in a time- and dose-dependent manner.12,13 Bromelain has also been shown to remove T-cellCD44 molecules from lymphocytes and to affect T-cell activation.14 Debridement of Wounds: Bromelain applied topically as a cream (35% bromelain in a lipid base) can be beneficial in the elimination of burn debris and in acceleration of healing.15 A non-proteolytic componentof bromelain is responsible for this effect. This component, referred to as escharase, has no hydrolytic enzymeactivity against normal protein substrates or various glycosaminoglycan substrates, and its activity variesgreatly from preparation to preparation.16 Potentiation of Antibiotics: Antibiotic potentiation is one of the primary uses of bromelain in several foreign countries. In humans, some undetermined activity of bromelain has been documented to increaseblood and urine levels of antibiotics.17-19 Combined bromelain and antibiotic therapy has been shown to be more effective than antibiotics alone in a variety of conditions including pneumonia, bronchitis, cutaneous staphylococcus infection, throm-bophlebitis, cellulitis, pyelonephritis, perirectal and rectal abscesses,20 and sinusitis.21 Mucolytic: In a clinical study of 124 patients hospitalized with chronic bronchitis, pneumonia, bron- chopneumonia, bronchiectasis, or pulmonary abscess, those receiving bromelain orally showed a decrease inthe volume and purulence of the sputum.22 Digestive Aid: Bromelain has been used successfully as a digestive enzyme following pancreatec- tomy, in cases of exocrine pancreas insufficiency, and in other intestinal disorders.23 The combination of oxbile, pancreatin, and bromelain is effective in lowering stool fat excretion in patients with pancreatic steator-rhoea and resulting in a symptomatic improvement in pain, flatulence and stool frequency.24 Bromelain has been reported to heal gastric ulcers in experimental animals.25 In an extensive study of the effect of bromelain on the gastric mucosa, it was found that bromelain increased the uptake of radioactivesulfur by 50 percent and glucosamine by 30-90 percent. Increased uptake of these substances may allow thegastric mucosa to heal more rapidly.26 Surgical Procedures and Musculoskeletal Injuries: Bromelain’s most common application is in the treatment of inflammation and soft tissue injuries. It has been shown to speed healing from bruises andhematomas.27 Treatment with bromelain following blunt injuries to the musculoskeletal system results in aclear reduction in swelling, pain at rest and during movement, and tenderness.28 Administration of bromelainpre-surgically can reduce the average number of days for complete disappearance of pain andinflammation.29, 30 Cardiovascular and Circulatory Applications: Research has indicated that bromelain prevents or minimizes the severity of angina pectoris.31, 32 A drastic reduction in the incidence of coronary infarct afteradministration of potassium and magnesium orotate along with 120-400 mg of bromelain per day has beenreported.33 In a study involving 73 patients with acute thrombophlebitis, bromelain, in addition to Alternative Medicine Review ◆ Volume 3, Number 4 ◆ 1998 Page 303
Copyright1998 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission analgesics, was shown to decrease all symptoms of inflammation; including, pain, edema, tenderness, skintemperature, and disability.34 Toxicity, Side Effects and Allergic Reactions
Bromelain is considered to have very low toxicity, with an LD50 greater than 10g/kg. Toxicity tests on dogs, with increasing levels of bromelain up to 750 mg/kg administered daily, showed no toxic effects after sixmonths. Dosages of 1.5 g/kg/day administered to rats showed no carcinogenic or teratogenic effects.35 In human clinical tests, side effects are generally not observed; however, caution is advised if admin- istering bromelain to individuals with hypertension, since one report indicated individuals with pre-existinghypertension might experience tachycardia following high doses of bromelain.36 The allergenic potential of proteolytic enzymes should not be underestimated. They can cause IgE- mediated respiratory allergies of both the immediate type and the late-phase of immediate type.37 Bromelain,due to its use as a meat tenderizer and to clarify beer, is considered a potential ingestive allergen.
Bromelain has shown therapeutic benefits in doses as small as 160 mg/day; however, it is thought that, for most conditions, best results occur at doses of 750-1000 mg/day. Most research on bromelain has beendone utilizing four divided daily doses. Findings indicate that results are dose-dependent.
References
1.
White RR, Crawley FE, Vellini M, et al. Bioavailability of 125I bromelain after oral administration to rats.
Biopharm Drug Dispos 1988;9:397-403.
Kumakura S, Yamashita M, Tsurufuji S. Effect of bromelain on kaolin-induced inflammation in rats. Eur JPharmacol 1988;150:295-301.
Uchida Y, Katori M. Independent consumption of high and low molecular weight kininogens in vivo. Adv ExpMed Biol 1986;198:113-118.
Taussig SJ, Batkin S. Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical applica-tion. An update. J Ethnopharmacol 1988;22:191-203.
Felton GE. Fibrinolytic and antithrombotic action of bromelain may eliminate thrombosis in heart patients. MedHypotheses 1980;6:1123-1133.
Heinicke RM, Van der Wal M, Yokoyama MM. Effect of bromelain (Ananase) on human platelet aggregation.
Experientia 1972;28:844-845.
De-Giuli M, Pirotta F. Bromelain: interaction with some protease inhibitors and rabbit specific antiserum. DrugsExpClin Res 1978;4:21-23.
Gerard G. Anti-cancer therapy with bromelain. Agressologie 1972;13:261-274.
Taussig SJ, Szekerczes J, Batkin S. Inhibition of tumor growth in vitro by bromelain, an extract of the pineappleplant (Ananas comosus). Planta Med 1985;6:538-539.
Batkin S, Taussig SJ, Szekerezes J. Antimetastatic effect of bromelain with or without its proteolytic andanticoagulant activity. J Cancer Res Clin Oncol 1988;114:507-508.
Nieper HA. A program for the treatment of cancer. Krebs 1974;6:124-127.
Desser L, Rehberger A, Paukovits W. Proteolytic enzymes and amylase induce cytokine production in humanperipheral blood mononuclear cells in vitro. Cancer Biother 1994;9:253-263.
Desser L, Rehberger A. Induction of tumor necrosis factor in human peripheral-blood mononuclear cells byproteolytic enzymes.Oncology 1990;47:475-477.
Page 304 Alternative Medicine Review ◆ Volume 3, Number 4 ◆ 1998
Copyright1998 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Munzig E, Eckert K, Harrach T, et al. Bromelain protease F9 reduces the CD44 mediated adhesion of humanperipheral blood lymphocytes to human umbilical vein endothelial cells. FEBS Lett 1995;351:215-218.
Klaue P, Dilbert G, Hinke G, et al. Tier-experimentelle untersuchungen zur enzymatischen lokalbehandlungsubdermaler verbrennungen mit bromelain. Therapiewoche 1979;29:796-799.
Houck JC, Chang CM, Klein G. Isolation of an effective debriding agent from the stems of pineapple plants. IntJ Tissue React 1983;5:125-134.
Tinozzi S, Venegoni A. Effect of bromelain on serum and tissue levels of Amoxycillin. Drugs Exptl Clin Res1978;4:39-44.
Luerti M, Vignali ML. Influence of bromelain on penetration of antibiotics in uterus, salpinx and ovary. DrugsExp Clin Res 1978;4:45-48.
Renzinni G, Varengo M. The absorption of tetracycline in combination with bromelain by oral application.
Arzneim-Forsch 1972;22:410-412.
Neubauer RA. A plant protease for potentiation of and possible replacement of antibiotics. Exp Med Surg1961;19:143-160.
Hunter RG, Henry GW, Heinicke RM. The action of papain and bromelain on the uterus. Am J Ob Gyn1957;73:867-873.
Schafer A, Adelman B. Plasmin inhibition of platelet function and of arachidonic acid metabolism. J Clin Invest1985;75:456-461.
Knill-Jones RP, Pearce H, Batten J, et al. Comparative trial of Nutrizym in chronic pancreatic insufficiency. BritMed J 1970;4:21-24.
Balakrishnan V, Hareendran A, Sukumaran Nair C. Double-blind cross-over trial of an enzyme preparation inpancreatic steatorrhea. J Asso Phys Ind 1981;29:207-209.
Seligman B. Bromelain–an anti-inflammatory agent–thrombophlebitis. No toxicity. Angiology 1962;13:508-510.
Felton G. Does kinin released by pineapple stem bromelain stimulate production of prostaglandin E1-likecompounds? Hawaii Med J 1976;2:39-47.
Blonstein JL. Control of swelling in boxing injuries. Practitioner 1960;185:78.
Masson M. Bromelain in blunt injuries of the locomotor system. A study of observed applications in generalpractice. Fortschr Med 1995;113:303-306.
Tassman GC, Zafran JN, Zayon GM. Evaluation of a plant proteolytic enzyme for the control of inflammationand pain. J Dent Med 1964;19:73-77.
Tassman GC, Zafran JN, Zayon GM. A double-blind crossover study of a plant proteolytic enzyme in oralsurgery. J Dent Med 1965;20:51-54.
Nieper HA. Effect of bromelain on coronary heart disease and angina pectoris. Acta Med Empirica 1978;5:274-278.
Taussig SJ, Nieper HA. Bromelain: its use in prevention and treatment of cardiovascular disease, present status.
J IAPM 1979;6:139-151.
Nieper HA. Decrease of the incidence of coronary heart infarct by Mg- and K-orotate and bromelain. Acta MedEmpirica 1977;12:614-618.
Seligman B. Oral bromelains as adjuncts in the treatment of acute thrombophlebitis. Angiology 1969;20:22-26.
Taussig SJ, Yokoyama MM, Chinen N, et al. Bromelain: A proteolytic enzyme and its clinical application.
Hiroshima J Med Sci 1975;24:185-193.
Gutfreund A, Taussig S, Morris A. Effect of oral bromelain on blood pressure and heart rate of hypertensivepatients. Hawaii Med J 1978;37:143-146.
Gailhofer G, Wilders-Truschnig M, Smolle J, Ludvan M. Asthma caused by bromelain: an occupational allergy.
Clin Allergy 1988;18:445-450.
Alternative Medicine Review ◆ Volume 3, Number 4 ◆ 1998 Page 305
Copyright1998 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

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