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The using of sodium salicylate for stress prevention, reducing morbidity and mortality of the piglets and complement treatment of infectious pig diseases. [email protected] History In the 1st century AD Dioscorides, in the first known pharmacopoeia, referred to the medicinal properties of the willow tree The first veterinary use of a synthetic drug, the sodium salt of salicylic acid, was reported in 1875. P.Lees, J. vet. Pharmacol. Therap. 27, 479–490, 2004. Registration First choice oral NSAID with anti inflammatory, anti pyretic and analgesic properties, for early treatment of infections in swine and calves, alone or concurrent with antibiotic therapy. NSAID’s mode of action Cell damage Corticosteroids Phospholipids Phospholipase NSAIDs Arachidonic acid Cyclooxygenase Prostaglandins Lipoxygenase Leucotriens NSAID = Non Steroidal Anti-Inflammatory Drug = without the immune-suppressive effect of corticosteroids But NSAIDs do more Tegeder et al. Federation of American Societies for Experimental Biology Journal Vol 15 October 2001 , p 2060 ( 99 references on sodium salicylate in this article) E.coli does increase cAMP in the intestines. Sodium salicylate does reduce the amount of fluid. Therefore less loss of fluid in case of diarrhoea. Josef Szancer Dansk VetTidsskr., 1980,63,3, 1/2 Salicylates Sodium salicylate (Solacyl) belongs to the group of salicylates. Salicylates act through the active salicylic acid, which binds COX (Higgs, Proc. Acad. Sci. USA 1987) Salicylates have several effects: – Antipyretic fight fever – Anti-inflammatory fight inflammation – Analgesic fight pain T.D. WARNER and co-workers Proc. Natl. Acad. Sci. USA Vol. 96, pp. 7563–7568, June 1999 Pharmacology Chemistry SS. By acidification of the sodium salt we get salicylic acid. This is an acid-base reaction. Sodium salicylate Salicylic acid ASA. Before we get salicylic acid from acetyl salicylic acid, it has to be deacetylated. Hydrolysis of aspirin to salicylic acid by nonspecific esterases occurs in the liver and, to a lesser extent in the stomach (Clin Pharmacokinet. 1985 Mar-Apr;10(2):164-77.) Aspirin hydrolysis Salicylic acid To: Vet. applied pharmacology and therapeutics, Brander et al, 5th ed 1991 Differences ASA-SS Aspirine has effect on trombocyte aggregation due to de-acetylating effect (hydrolysation) needed to produce salicylate (Oberdisse, 2002), Sodium salicylate not. Acetyl group binds with thromboxane enzyme High bioavailability DOSAGE IV calf ss 35-40 SS mg/kg Oral calf SS IV pig SS Oral pig SS Cmax (mg/L) 53,98 92,10 Tmax (h) 1,97 1,07 IV poultry SS <10 T1/2 (h) 1,23 1,17 1,15 1,23 4,04 Vd (l/kg) 0,24 0,30 0,19 - 0,39 BA (%) 77,8 103 Swine and calve: Summary report: Sodium salicylate (extension to oral use in bovine and porcine) EMEA/MRL/897/04-FINAL Cattle: Coetzee et al, 2007, JVPT. Poultry: Baert et al, JVPT 25; 449-453 Oral cattle ASA Coetzee 50mg/kg LOW Plasma levels correspond to in water dosage When a dosage of 12mg/kg BW is targeted, which is reached by 118mg/L therapeutic solution, a plasma level of 7,2 mg/L will be reached as shown in table Patterson et al, Journal of Swine Health and Production — Volume 15, Number 3 T4 = 118,5mg/L SS in water corresponds with a targeted dose of 11.85mg/kg BW targeted dose Calculations based on full dissolution and a stable solution for 24 hrs. Pulse dosing plasma levels high Mg/L 120 100 80 12 mg/kg cont 60 35 mg/kg cont 35 mg/kg 1dd pulse 40 17,5 mg/kg 2dd pulse 20 0 t = 0 t=1 Efficacy treshold to affect cortisol levels acc Coetzee t=2 t=4 t=6 . t=8 t=10 t=12 t=14 t=18 t=19 t=20 t=21 t=22 t=23 t=24 -20 1. Cmax 92,10mg/L at dose of 35mg/kg (EMEA summary report) 2. The post NSAID effect will linger on until 5 µg/L Coetzee et al, 2007, JVPT. 3. If necessary, antibiotic treatment can be given between the Solacyl pulses Result for the pigs Continue to eat and drink Less disturbed by pen mates More mobile Tolerance Pigs tolerate dosages up to 175 mg/kg for up to 10 days without any significant adverse effects. Sodium salicylate has been reported to inhibit the formation of gastric ulcerations induced by aspirin, indomethacin, and absolute ethanol. (Adcock JE, Life Sci. 1983 Jun 20;32(25):2905-10 ) Solacyl Solacyl – indications Calves: Supportive treatment for reduction of pyrexia in acute respiratory disease, in combination with appropriate (e.g. antiinfective) therapy if necessary. Pigs: For the treatment of inflammation, in combination with a simultaneous antibiotic therapy. Solacyl 100 % - dosing Calves: 40 mg sodium salicylate per kg body weight, once daily during 1 to 3 days. Application: orally via drinking water or milk (substitute). Swine: 35 mg sodium salicylate per kg body weight per day, during 3 to 5 days. Application: orally via drinking water Solacyl – major practical use according swine veterinarians In order of importance: Respiratory infections ( sometimes alone preventively, sometimes curatively with an antibiotic) Vaccination reactions ( prevention and curatively); most of the time it is known which vaccines give problems on which farms; mostly with Bordetella vaccines. Solacyl – minor practical use according swine veterinarians Oedema disease ( therapeutically with antibiotics) Streptococcus suis (therapeutically with antibiotics) In the prevention of PSE meat or heart failure in heterozygote positive stress swine (Solacyl alone) Treatment of sick animals immediately before slaughter to prevent mortality and cannibalism. With Solacyl the animals continue to eat and are able to defend themselves. Solacyl – pulse medication Alternatively Solacyl can also be administered with the drinking water as pulse medication. Half of the calculated total daily amount of powder is mixed with 5-10 litres of clean water and stirred until evenly dispersed. This solution is then added, whilst stirring, into an amount of drinking water that will be consumed within approximately 3-4 hours and administered twice daily. Solacyl - dosage Rinse pipes during 1 to 2 hours between Solacyl and other medication through the water Solacyl - withdrawal Pigs: meat and offal: zero days Calves: meat and offal: zero days Do not use in cows producing milk for human consumption. Product Active Characteristics Activities Acetylsalicylic acid salicylate Insoluble More Cox 1 Antiinflammatory Antipyretic Analgesic Sodium salicylate salicylate Soluble More Cox 2 Antiinflammatory Antipyretic Analgesic Paracetamol paracetamol Insoluble Antipyretic Solacyl - aspirine Excellent solubility High bio-availability Low dosing for cattle Less stomach ulcers, stomach bleedings Fast action More Cox 2 Little influence on coagulation 0 days withdrawal Little soluble Low bio-availability High dosing in cattle Slow action More COX 1 Influence on coagulation No withdrawal …. Product characteristics 1 kg 100% powder in alu-foil bags Carton secondary packing to hold 6 bags Excellent water solubility Stability in hard water Stability in acidified water Stability in wet feed Stability in milk Stability in the unopened bag Stability in the opened bag Water solubility ASA 3,33 g per L the highest achievable dose of ASA in swine would be 3,1 mg per kg per day = not efficacious SS 1111,1 g per L efficacious doses can be reached in plasma. Budavari S, O’Neil MJ, Smith A, Heckelman PE, eds. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. 11th ed. Rahway, New Jersey: Merck and Company Inc; 1989:1367–1368. Stability in water a therapeutic solution of 350 mg per I water (therapeutic) a concentrated solution of 35 g per I water (stock) a concentrated solution of 105 g per I water (pulse stock) Stability in water Conclusions of these studies are that solubility and stability in both hard and soft water is very good. Solubility is no problem: in this study it was shown that up to 100g/L is dissolved in a few seconds. 24 hours after dissolution we still find 100% of the compound back when analysed. Stability in water - pH When dissolved in hard water that has a pH of about 8,5 pH will drop a little to around 8. In soft water of pH 6 it also remains clear and stable in solution. Stability in wet feed It has been demonstrated that sodium salicylate is stable for 24 hours in wet feed (30ºC, low pH) obtained from a commercial farm SOLACYL technical training Solacyl 100 % 100% Sodium salicylate Thanks for your attention