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VETERINARY MEDICAL SERVICES E X P L O R A T I O N S in Veterinary Medicine The Effect of ANTIROBE Capsules (clindamycin hydrochloride) on Gingival Crevicular Fluid and Immune Mediators in Dogs ® results THE BIG PICTURE. • Dental plaque and gingival indices were significantly lower in dogs treated with ANTIROBE (P ≤ 0.0001). • The volume of gingival crevicular fluid (GCF), a reliable indicator for the degree of inflammation, declined significantly following treatment with ANTIROBE Source Material: Zetner K, Pum G, Rausch W-D, Rausch-Fan X-H, Hung ST. Effect of clindamycin hydrochloride on gingival crevicular fluid and immune mediators in beagles. Praktische Tierarzt. 2001;82(1):22-32; Vet Therap. 2002;3(2):177-188. THE PROCESS OF DISCOVERY. Periodontitis is a common infection in veterinary practice and the leading cause of tooth loss in dogs. The condition begins with gingivitis, an inflammation of the gingiva and gums caused by accumulating bacteria. Left unchecked, the multiplying bacteria form plaque, which subsequently mineralizes into tartar. Bacteria eventually invade the sulcus, the crevice between the gingiva and the root. (See Figure 1 on page 3.) As the gingiva regress, underlying periodontal structures detach from the root, and pockets develop.Advancing periodontitis affects all of the periodontal structures, including cementum, periodontal ligaments, and alveolar bone. (P ≤ 0.0001). • Levels of immune mediators decreased significantly after treatment with ANTIROBE (P ≤ 0.05). The presence of immune mediators provides early evidence of the inflammatory and degenerative processes of periodontal disease. The junctional epithelium and underlying gingival plexus play a vital role in local defense mechanisms, inflammatory reactions, and gingival crevicular fluid (GCF) production. As soon as toxins cross the epithelial junction, they activate the immune system. This provocation increases the volume of GCF and releases numerous immune mediators, including leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and polymorphonuclear (PMN) elastase. Leukotriene B4 is a powerful proinflammatory agent, especially in the early stage of gingivitis. Prostaglandin E2 increases 2-fold to 3-fold in the GCF of dogs with gingivitis and 5-fold to 6-fold during active stages of periodontitis. Along with other immune mediators, PGE2 increases bone destruction. Levels of PMN elastase increase in the GCF of dogs with gingivitis and, in humans, correlate with probe depth and loss of attachment. In this study, Zetner and colleagues evaluated the effect of ANTIROBE Capsules on immune mediators. HOW THE STUDY WAS CONDUCTED. WHAT WAS LEARNED. ® In a double-blind, crossover study, 10 dogs received ANTIROBE Capsules (clindamycin hydrochloride) 11 mg/kg per day orally for 14 days, and 10 dogs served as untreated controls. Five months later, the treatments were reversed. Plaque and gingival indices were assessed on 6 reference teeth of each patient, and the volume of GCF was measured before and after the 2 study periods.The plaque index was scored from 0 to 4,1 as was the gingivitis index.2 Concentrations of PGE2 , PMN elastase, and LTB 4 were determined by ELISA. Calculus was removed ultrasonically and the teeth were polished at the end of each study period. Compared with untreated controls, 2 weeks of treatment with ANTIROBE Capsules decreased the amount of GCF by 65% in the first series and 73% in the second series.The plaque index fell 94% in the first series and 85% in the second series, and the gingivitis index decreased by 88% in the first series and 87% in the second.These positive changes accompanied similar reductions in immune mediators.The mean reduction in PGE2 was 33% in the first series and 40% in the second. Levels of LTB4 declined by 18% in the first series and 24% in the second series. Mean PMN elastase values were 45% higher before treatment with ANTIROBE than after. See Table 1. Table 1. Effects of oral treatment with clindamycin (11 mg/kg) on periodontal variables and immune mediators in beagles with periodontal disease. Series 1 Control (n = 10) Variable ANTIROBE (n = 10) Before Treatment After Treatment Before Treatment After Treatment 82.63 ± 32.87 83.90 ± 33.03 92.55 ± 32.66 32.55 ± 16.5*† Plaque index 2.63 ± 0.69 2.38 ± 0.61 2.83 ± 0.72 0.17 ± 0.38*† Gingivitis index 2.08 ± 0.67 2.12 ± 0.69 2.30 ± 0.65 0.27 ± 0.45*† Prostaglandin E2 (ng/mL) 44.21 ± 15.68 42.21 ± 12.82 44.66 ± 10.53 29.97 ± 5.38‡ Leukotriene B4 (ng/mL) 55.29 ± 6.21 50.55 ± 4.84 67.33 ± 7.51* 55.20 ± 8.85‡ Not done Not done Not done Not done Gingival crevicular fluid (units) PMN elastase Series 2 Control (n = 10) Variable ANTIROBE (n = 10) Before Treatment After Treatment Before Treatment After Treatment 68.02 ± 22.41 61.42 ± 19.23 75.65 ± 24.71 20.30 ± 9.45*† Plaque index 2.55 ± 0.65 2.40 ± 0.59 2.40 ± 0.59 0.37 ± 0.55*† Gingivitis index 2.22 ± 0.72 2.13 ± 0.77 2.35 ± 0.55 0.30 ± 0.46*† Prostaglandin E2 (ng/mL) 22.69 ± 4.24 24.97 ± 4.04 68.62 ± 31.84* 41.21 ± 16.39‡ Leukotriene B4 (ng/mL) 51.31 ± 9.76 53.41 ± 7.10 65.82 ± 10.29* 50.12 ± 8.03‡ PMN elastase (µg/L 42.21 ± 15.58 41.52 ± 16.49 74.76± 32.92* 41.38 ± 12.42‡ Gingival crevicular fluid (units) *Significantly different than control group value (P ≤ 0.05). † Significantly different than pretreatment value (P ≤ 0.0001). ‡ Significantly different than pretreatment value (P ≤ 0.05). PMN = polymorphonuclear. Data are shown as mean ± standard deviation. references Sulcus REFERENCES. Figure 1. Illustration of tooth and surrounding structures. 1. Logan EI, Boyce EN. Oral health assessment in dogs: parameters and methods. J Vet Dent. 1994;11:58-63. TALK IT OUT. Numerous researchers have documented the antimicrobial activity of ANTIROBE in the mouth.3-5 One group also noted that ANTIROBE reduces bacteria in the surrounding air during ultrasonic removal of calculus.6 This excellent antimicrobial activity likely results from clindamycin’s superior penetration of oral tissues, including saliva, the gingival crevice, and bone.Tissue concentrations of ANTIROBE have been shown to be higher than plasma concentrations.7,8 Professor Zetner postulates that the PGE2 activity may be a reflection of high concentrations of clindamycin in bone, which may help reduce decalcification and subsequent inflammation better than mechanical cleaning alone.ANTIROBE Capsules are contraindicated in animals with a history of hypersensitivity to clindamycin or lincomycin. ® THE FINAL WORD. 2. Silness J, Loe H. Periodontal disease in pregnancy. II. Correlation between oral hygiene and periodontal condition. Acta Odontol Scand. 1964;22:121-135. 3. Henke CL, Colmery BH. Treating canine dental infections with oral clindamycin hydrochloride. Vet Med. 1987;82:197-199. 4. Johnson DM, Erwin ME, Barrett MS, Gooding BB, Jones RN. Antimicrobial activity of ten macrolide, lincosamine and streptogramin drugs tested against Legionella species. Eur J Clin Microbiol Infect Dis. 1992;11(8):751-755. 5. Mischke R, Amtsberg G, Beckmann G, Schmidt H, Nolte I. Wirksamkeit und Verträglichkeit von Clindamycin als Begleitende Therapie von Gingivitis und Periodontitis nach Zahnsteinenfernung beim Hund. Kleintierpraxis. 1992;37:423-492. 6. Zetner K, Thiemann G. Die Bedeutung von Clindamycin und Pilzen bie Oralen Infektionen. Kleintierpraxis. 1993;38:689-760. 7. Burrows GE. Pharmacotherapeutics of macrolides, lincomycins, and spectinomycin. JAVMA. 1980;176:1072-1077. 8. ANTIROBE Capsules package insert. This study showed that treatment with ANTIROBE significantly reduced the indices of plaque and gingivitis while also significantly decreasing levels of destructive immune mediators.ANTIROBE is beneficial as an adjunct to cleaning teeth and treating periodontal disease, because of its direct antimicrobial effect and its ability to potentiate opsonization and phagocytosis.9 9. Gemmell CG, Peterson PK, Schmeling D, Mathews J, Quie PG. Antibiotic-induced modification of Bacteroides fragilis and its susceptibility to phagocytosis by human polymorphonuclear leukocytes. Eur J Clin Microbiol. 1983;2(4):327-334. ANTIROBE® NDC 0009-3043-01, NDC 0009-3044-01, NDC 0009-3045-01, NDC 0009-3045-08, NDC 0009-5015-01 brand of clindamycin hydrochloride capsules, USP ANTIROBE AQUADROPS® NDC 0009-3179-01 brand of clindamycin hydrochloride liquid Caution: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. DESCRIPTION ANTIROBE Capsules and ANTIROBE AQUADROPS Liquid contain clindamycin hydrochloride which is the hydrated salt of clindamycin. Clindamycin is a semisynthetic antibiotic produced by a 7(S)-chlorosubstitution of the 7(R)-hydroxyl group of a naturally produced antibiotic produced by Streptomyces lincolnensis var. lincolnensis. ANTIROBE Capsules (For Use in Dogs Only): 25 mg Capsule, each yellow and white capsule contains clindamycin hydrochloride equivalent to 25 mg of clindamycin. 75 mg Capsule, each green capsule contains clindamycin hydrochloride equivalent to 75 mg of clindamycin. 150 mg Capsule, each light blue and green capsule contains clindamycin hydrochloride equivalent to 150 mg of clindamycin. 300 mg Capsule, each light blue capsule contains clindamycin hydrochloride equivalent to 300 mg of clindamycin. ANTIROBE AQUADROPS Liquid (For Use in Dogs and Cats) is a palatable formulation intended for oral administration. Each mL of ANTIROBE AQUADROPS contains clindamycin hydrochloride equivalent to 25 mg clindamycin; and ethyl alcohol, 8.64%. ACTIONS Site and Mode of Action: Clindamycin is an inhibitor of protein synthesis in the bacterial cell. The site of binding appears to be in the 5OS sub-unit of the ribosome. Binding occurs to the soluble RNA fraction of certain ribosomes, thereby inhibiting the binding of amino acids to those ribosomes. Clindamycin differs from cell wall inhibitors in that it causes irreversible modification of the protein-synthesizing subcellular elements at the ribosomal level. MICROBIOLOGY: Clindamycin is a lincosaminide antimicrobial agent with activity against a wide variety of aerobic and anaerobic bacterial pathogens. Clindamycin is a bacteriostatic compound that inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. The minimum inhibitory concentrations (MICs) of Gram-positive and obligate anaerobic pathogens isolated from dogs and cats in the United States are presented in Table 1 and Table 2. Bacteria were isolated in 1998-1999. All MICs were performed in accordance with the National Committee for Clinical Laboratory Standards (NCCLS). Table 1. Clindamycin MIC Values (µg/mL) from Diagnostic Laboratory Survey Data Evaluating Canine Pathogens in the U.S. During 1998-991 Number of Isolates MIC50 MIC85 MIC90 Range Staphylococcus aureus Staphylococcus intermedius Staphylococcus spp. Beta-hemolytic streptococci Streptococcus spp. 17 28 18 46 11 0.5 0.25 0.5 0.5 0.5 0.5 0.5 0.5 0.5 ≥4.0 ≥4.0 ≥4.0 ≥4.0 ≥4.0 ≥4.0 0.25-≥4.0 0.125-≥4.0 0.25-≥4.0 0.25-≥4.0 0.25-≥4.0 Osteomyelitis/Bone3 Staphylococcus aureus Staphylococcus intermedius Staphylococcus spp. Beta-hemolytic streptococci Streptococcus spp. 20 15 18 21 21 0.5 0.5 0.5 0.5 ≥4.0 0.5 ≥4.0 ≥4.0 2.0 ≥4.0 0.5 ≥4.0 ≥4.0 2.0 ≥4.0 0.54 0.25-≥4.0 0.25-≥4.0 0.25-≥4.0 0.25-≥4.0 Dermal/Skin5 Staphylococcus aureus Staphylococcus intermedius Staphylococcus spp. Beta-hemolytic streptococci 25 48 32 17 0.5 0.5 0.5 0.5 ≥4.0 ≥4.0 ≥4.0 0.5 ≥4.0 ≥4.0 ≥4.0 0.5 0.25-≥4.0 0.125-≥4.0 0.25-≥4.0 0.25-0.5 Organism Soft Tissue/Wound2 1 The correlation between the in vitro susceptibility data and clinical response has not been determined. 2 Soft Tissue/Wound: includes samples labeled wound, abscess, aspirate, exudates, draining tract, lesion, and mass 3 Osteomyelitis/Bone: includes samples labeled bone, fracture, joint, tendon 4 No range, all isolates yielded the same value 5 Dermal/Skin: includes samples labeled skin, skin swab, biopsy, incision, lip Table 2. Clindamycin MIC Values (µg/mL) from Diagnostic Laboratory Survey Data Evaluating Feline Pathogens from Wound and Abscess Samples in the U.S. During 19981 Organism Bacteroides/Prevotella Fusobacterium spp. Peptostreptococcus spp. Porphyromonas spp. Number of Isolates MIC50 MIC90 Range 30 17 18 13 0.06 0.25 0.13 0.06 4.0 0.25 0.5 0.25 ≤0.015-4.0 ≤0.015-0.5 ≤0.015-8.0 ≤0.015-8.0 1 The correlation between the in vitro susceptibility data and clinical response has not been determined. PHARMACOLOGY Absorption: Clindamycin hydrochloride is rapidly absorbed from the canine and feline gastrointestinal tract. Dog Serum Levels: Serum levels at or above 0.5 µg/mL can be maintained by oral dosing at a rate of 2.5 mg/lb of clindamycin hydrochloride every 12 hours. This same study revealed that average peak serum concentrations of clindamycin occur 1 hour and 15 minutes after oral dosing. The elimination half-life for clindamycin in dog serum was approximately 5 hours.There was no bioactivity accumulation after a regimen of multiple oral doses in healthy dogs. Cat Serum Levels: Serum levels at or above 0.5 µg/mL can be maintained by oral dosing at a rate of 2.5 mg/lb of clindamycin hydrochloride every 24 hours. The average peak serum concentration of clindamycin occurs approximately 1 hour after oral dosing. The elimination half-life of clindamycin in feline serum is approximately 7.5 hours. In healthy cats, minimal accumulation occurs after multiple oral doses of clindamycin hydrochloride, and steadystate should be achieved by the third dose. METABOLISM AND EXCRETION Extensive studies of the metabolism and excretion of clindamycin hydrochloride administered orally in animals and humans have shown that unchanged drug and bioactive and bioinactive metabolites are excreted in urine and feces. Almost all of the bioactivity detected in serum after ANTIROBE product administration is due to the parent molecule (clindamycin). Urine bioactivity, however, reflects a mixture of clindamycin and active metabolites, especially N-dimethyl clindamycin and clindamycin sulfoxide. TOXICOLOGY AND SAFETY Rat and Dog Data: One year oral toxicity studies in rats and dogs at doses of 30, 100 and 300 mg/kg/day (13.6, 45.5 and 136.4 mg/lb/day) have shown clindamycin hydrochloride to be well tolerated. Differences did not occur in the parameters evaluated to assess toxicity when comparing groups of treated animals with contemporary controls. Rats administered clindamycin hydrochloride at 600 mg/kg/day (272.7 mg/lb/day) for six months tolerated the drug well; however, dogs orally dosed at 600 mg/kg/day (272.7 mg/lb/day) vomited, had anorexia, and subsequently lost weight. At necropsy these dogs had erosive gastritis and focal areas of necrosis of the mucosa of the gall bladder. Safety in gestating bitches or breeding males has not been established. Cat Data: The recommended daily therapeutic dose range for clindamycin hydrochloride (ANTIROBE AQUADROPS Liquid) is 11 to 33 mg/kg/day (5 to 15 mg/lb/day) depending on the severity of the condition. Clindamycin hydrochloride (ANTIROBE AQUADROPS Liquid) was tolerated with little evidence of toxicity in domestic shorthair cats when administered orally at 10x the minimum recommended therapeutic daily dose (11 mg/kg; 5 mg/lb) for 15 days, and at doses up to 5x the minimum recommended therapeutic dose for 42 days. Gastrointestinal tract upset (soft feces to diarrhea) occurred in control and treated cats with emesis occurring at doses 3x or greater than the minimum recommended therapeutic dose (11 mg/kg/day; 5 mg/lb/day). Lymphocytic inflammation of the gallbladder was noted in a greater number of treated cats at the 110 mg/kg/day (50 mg/lb/day) dose level than for control cats. No other effects were noted. Safety in gestating queens or breeding male cats has not been established. INDICATIONS ANTIROBE (brand of clindamycin hydrochloride) Capsules (for use in dogs only) and AQUADROPS Liquid (for use in dogs and cats) are indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below: Dogs: Skin infections (wounds and abscesses) due to coagulase positive staphylococci (Staphylococcus aureus or Staphylococcus intermedius). Deep wounds and abscesses due to Bacteroides fragilis, Prevotella melaninogenicus, Fusobacterium necrophorum and Clostridium perfringens. Dental infections due to Staphylococcus aureus, Bacteroides fragilis, Prevotella melaninogenicus, Fusobacterium necrophorum and Clostridium perfringens. Osteomyelitis due to Staphylococcus aureus, Bacteroides fragilis, Prevotella melaninogenicus, Fusobacterium necrophorum and Clostridium perfringens. Cats: Skin infections (wounds and abscesses) due to Staphylococcus aureus, Staphylococcus intermedius and Streptococcus spp. Deep wounds and infections due to Clostridium perfringens and Bacteroides fragilis. Dental infections due to Staphylococcus aureus, Staphylococcus intermedius, Streptococcus spp., Clostridium perfringens and Bacteroides fragilis. CONTRAINDICATIONS ANTIROBE Capsules and ANTIROBE AQUADROPS Liquid are contraindicated in animals with a history of hypersensitivity to preparations containing clindamycin or lincomycin. Because of potential adverse gastrointestinal effects, do not administer to rabbits, hamsters, guinea pigs, horses, chinchillas or ruminating animals. WARNINGS Keep out of reach of children. Not for human use. PRECAUTIONS During prolonged therapy of one month or greater, periodic liver and kidney function tests and blood counts should be performed. The use of ANTIROBE occasionally results in overgrowth of non-susceptible organisms such as clostridia and yeasts.Therefore, the administration of ANTIROBE should be avoided in those species sensitive to the gastrointestinal effects of clindamycin (see CONTRAINDICATIONS). Should superinfections occur, appropriate measures should be taken as indicated by the clinical situation. Patients with very severe renal disease and/or very severe hepatic disease accompanied by severe metabolic aberrations should be dosed with caution, and serum clindamycin levels monitored during high-dose therapy. Clindamycin hydrochloride has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, ANTIROBE should be used with caution in animals receiving such agents. Safety in gestating bitches and queens or breeding male dogs and cats has not been established. ADVERSE REACTIONS Side effects occasionally observed in either clinical trials or during clinical use were vomiting and diarrhea. To report adverse reactions or a suspected adverse reaction call 1-800-793-0596. DOSAGE AND ADMINISTRATION Dogs: Infected Wounds, Abscesses and Dental Infections Oral: 2.5-15.0 mg/lb body weight every 12 hours. Duration: Treatment with ANTIROBE products may be continued up to a maximum of 28 days if clinical judgment indicates. Treatment of acute infections should not be continued for more than three or four days if no response to therapy is seen. Dosage Schedule: Capsules ANTIROBE 25 mg, administer 1-6 capsules every 12 hours for each 10 pounds of body weight. ANTIROBE 75 mg, administer 1-6 capsules every 12 hours for each 30 pounds of body weight. ANTIROBE 150 mg, administer 1-6 capsules every 12 hours for each 60 pounds of body weight. ANTIROBE 300 mg, administer 1-6 capsules every 12 hours for each 120 pounds of body weight. Liquid ANTIROBE AQUADROPS, administer 1-6 mL/10 lbs body weight every 12 hours. Dogs: Osteomyelitis Oral: 5.0-15.0 mg/lb body weight every 12 hours. Duration: Treatment with ANTIROBE is recommended for a minimum of 28 days. Treatment should not be continued for longer than 28 days if no response to therapy is seen. Dosage Schedule: Capsules ANTIROBE 25 mg, administer 2-6 capsules every 12 hours for each 10 pounds of body weight. ANTIROBE 75 mg, administer 2-6 capsules every 12 hours for each 30 pounds of body weight. ANTIROBE 150 mg, administer 2-6 capsules every 12 hours for each 60 pounds of body weight. ANTIROBE 300 mg, administer 2-6 capsules every 12 hours for each 120 pounds of body weight. Liquid ANTIROBE AQUADROPS, administer 2-6 mL/10 lbs body weight every 12 hours. Cats: Infected Wounds, Abscesses, and Dental Infections 5.0 - 15.0 mg/lb body weight once every 24 hours depending on the severity of the condition. Duration: Treatment with ANTIROBE AQUADROPS Liquid may be continued up to a maximum of 14 days if clinical judgment indicates. Treatment of acute infections should not be continued for more than three to four days if no clinical response to therapy is seen. Dosage Schedule: ANTIROBE AQUADROPS, to provide 5.0 mg/lb, administer 1 mL/5 lbs body weight once every 24 hours; to provide 15.0 mg/lb, administer 3 mL/5 lbs body weight once every 24 hours. HOW SUPPLIED ANTIROBE Capsules are available as: 25 mg - bottles of 600 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .NDC 0009-3043-01 75 mg - bottles of 200 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .NDC 0009-3044-01 150 mg - bottles of 100 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .NDC 0009-3045-01 150 mg - blister packages of 100 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .NDC 0009-3045-08 300 mg - blister packages of 100 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .NDC 0009-5015-01 NADA #120–161, Approved by FDA ANTIROBE AQUADROPS Liquid is available as 20 mL filled in 30 mL bottles (25 mg/mL) supplied in packers containing 12 cartoned bottles with direction labels and calibrated dosing droppers. NDC 0009-3179-01. NADA #135–940, Approved by FDA To report a suspected adverse reaction or to request a material safety data sheet (MSDS), call 1-800-793-0596. Store at controlled room temperature 20° to 25° C (68° to 77° F) [see USP]. ANTIROBE Capsules Made in Canada for Pharmacia & Upjohn Company Kalamazoo, MI 49001, USA By Patheon YM Inc. Toronto, Ontario, M3B 1Y5, CANADA Revised October 2002 ANTIROBE is a registered trademark of Pharmacia & Upjohn Company. © 2002 Pharmacia Corporation. All rights reserved. ANTIROBE AQUADROPS Made by Pharmacia & Upjohn Company Kalamazoo, MI 49001, USA 813 805 712 692074 3179-01-000 www.pharmaciaAH.com 11.02.canine.Antirobe V01116