Tilmicosin

86913

869.13

XL4103X2E3

DTXSID5046011

29419090

186.15000

3.27930

1.18±0.1 g/cm3(Predicted)

926.6±65.0 °C(Predicted)

514.2ºC

1.545

In water, 1.5X10-2 mg/L at 25 °C (est)

0-6°C

0mmHg at 25°C

Henry's Law constant = 8.2X10-33 atm-cu m/mol at 25 °C (est)

pKa = 8.18 (tertiary amine)

310.2 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Hydroxyl radical reaction rate constant = 5.5X10-10 cu cm/molecule-sec at 25 °C (est)

3

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Implantation or injectable dosage form new animal drugs. Tilmicosin. Indications for use: For the treatment of bovine respiratory disease (BRD) associated with Mannheimia (Pasteurella) haemolytica. For the control of respiratory disease in cattle at high risk of developing BRD associated with Mannheimia (P.) haemolytica. ... For the treatment of ovine respiratory disease (ORD) associated with Mannheimia (P.) haemolytica.|The ADI for total residues of tilmicosin is 25 micrograms per kilogram of body weight per day.|Tolerances for residues of new animal drugs in food. Tolerances-(1) Cattle-(i) Liver (the target tissue). The tolerance for parent tilmicosin (the marker residue) is 1.2 parts per million (ppm). (ii) Muscle. The tolerance for parent tilmicosin (the marker residue) is 0.1 ppm. (2) Swine-(i) Liver (the target tissue). The tolerance for parent tilmicosin (the marker residue) is 7.5 ppm. (ii) Muscle. The tolerance for parent tilmicosin (the marker residue) is 0.1 ppm. (3) Sheep-(i) Liver (the target tissue). The tolerance for parent tilmicosin (the marker residue) is 1.2 ppm. (ii) Muscle. The tolerance for parent tilmicosin (the marker residue) is 0.1 ppm.|New animal drugs for use in animal feeds. Requirement of a medicated feed mill license. Tilmicosin is included on this list.|For more FDA Requirements (Complete) data for TILMICOSIN (6 total), please visit the HSDB record page.

|Danger|H302 (75%): Harmful if swallowed [Warning Acute toxicity, oral]|P260, P261, P264, P270, P271, P272, P273, P280, P285, P301+P312, P302+P352, P304+P312, P304+P340, P304+P341, P305+P351+P338, P312, P314, P321, P330, P333+P313, P337+P313, P342+P311, P363, P391, and P501|Aggregated GHS information provided by 6 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Inhalation, oral exposure, and direct contact with eyes should be avoided. /Tilmicosin phosphate/|Injection of tilmicosin in humans may be fatal. Caution should be exercised to avoid self-injection. An automatically powered syringe should not be used for administration. /Tilmicosin injection USP/

Concurrent use /of carbamazepine, cyclosporine, digoxin, hexobarbital, phenytoin or valproic acid/ with macrolide antibiotics has been associated with increased serum concentration of these medications; monitoring of serum concentrations of medications administered concurrently is recommended to avoid toxicity. /Macrolide antibiotics/|Concurrent use of the xanthines (except dyphylline) with macrolides may decrease hepatic clearance of xanthines, resulting in increased serum concentrations and/or toxicity; dosage adjustment of the xanthines may be necessary during and after therapy with macrolides. /Macrolide antibiotics/|Concurrent use /of midazolam or triazolam/ with macrolide antibiotics may decrease the clearance of these medications, increasing the pharmacologic effect of midazolam or triazolam. /Macrolide antibiotics/|Concurrent administration with macrolide antibiotics has been associated with increased anticoagulant effects; prothrombin time should be monitored carefully in patients receiving anticoagulants and macrolides concurrently. /Macrolide antibiotics/|For more Interactions (Complete) data for TILMICOSIN (8 total), please visit the HSDB record page.

LD50 Rat (non-fasted-male & female) oral > 2000 mg/kg/bw|LD50 Rat (fasted-female) oral 800 mg/kg/bw|LD50 Rat (fasted-male) oral 850 mg/kg/bw|LD50 Mouse (female) sc 109 mg/kg/bw|For more Non-Human Toxicity Values (Complete) data for TILMICOSIN (8 total), please visit the HSDB record page.

Tilmicosin's production and use as a veterinary antibacterial for the treatment of bovine respiratory disease(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2,800(SRC), determined from a log Kow of 3.80(2) and a regression-derived equation(3), indicates that tilmicosin is expected to have slight mobility in soil(SRC). The measured pKa of tilmicosin is 8.18 (tertiary amine)(2), indicating that this compound will exist primarily in the cation form in the environment and cations generally have lower mobility in soils than their neutral counterparts(4). Volatilization of tilmicosin from moist soil surfaces is not expected to be an important fate process(SRC) because cations do not volatilize. Tilmicosin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.6X10-32 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data were not available(SRC, 2006).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2800(SRC), determined from a log Kow of 3.80(2) and a regression-derived equation(3), indicates that tilmicosin is expected to adsorb to suspended solids and sediment(SRC). A pKa of 8.18(2) indicates that this compound will exist primarily as a cation in the environment and cations generally adsorb more strongly to sediments than their neutral counterparts(4). Volatilization from water surfaces is not expected because cations do not volatilize. According to a classification scheme(5), an estimated BCF of 450(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Biodegradation data were not available(SRC, 2006).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), tilmicosin, which has an estimated vapor pressure of 4.6X10-32 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase tilmicosin may be removed from the air by wet or dry deposition(SRC). Tilmicosin absorbs light at wavelengths >290 nm (UV max = 283 nm(3)) and therefore may be susceptible to direct photolysis by sunlight(4).

Tilmicosin contains hydrolyzable functional groups and therefore may undergo hydrolysis in the environment(1); however, a rate constant could not be estimated for this structure. Tilmicosin absorbs light at wavelengths >290 nm (UV max = 283 nm(2)) and therefore may be susceptible to direct photolysis by sunlight(1).

An estimated BCF of 450 was calculated for tilmicosin(SRC), using a log Kow of 3.80(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC), provided the compound is not metabolized by the organism(SRC).

The Koc of tilmicosin is estimated as 2,800(SRC), using a log Kow of 3.80(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that tilmicosin is expected to have slight mobility in soil. The measured pKa of tilmicosin is 8.18 (tertiary amine)(1), indicating that this compound will exist primarily as a cation in the environment and cations generally have lower mobility in soils than their neutral counterparts(4).

A pKa of 8.18(1) (tertiary amine) indicates that tilmicosin will exist primarily as a cation in the environment. Volatilization of tilmicosin from moist soil or water surfaces is not expected because cations do not volatilize. Tilmicosin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.6X10-32 mm Hg(SRC), determined from a fragment constant method(2).

While data specific to tilmicosin were not located(SRC, 2006), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Occupational exposure to tilmicosin may occur through dermal contact with this compound at workplaces where tilmicosin is produced or used(SRC). Exposure to tilmicosin among the general population may be limited to those who administer this substance to animals and those who eat foods made from animals containing residues of this substance(SRC).

MEDICATION (VET): Tilmicosin is available as an injectable formulation for the treatment of respiratory diseases in cattle and sheep and as a feed premix for the treatment and control of respiratory diseases in pigs.|THERAP CAT (VET): Antibacterial|MEDICATION (VET):The macrolides are used to treat both systemic and local infections. They are often regarded as alternatives to penicillins for the treatment of streptococcal and staphylococcal infections. General indications include upper respiratory tract infections, bronchopneumonia, bacterial enteritis, metritis, pyodermatitis, urinary tract infections, arthritis, and others. Formulations for treating mastitis are also available and often have the advantage of a short withholding time for milk. /Macrolides/|MEDICATION (VET): Tilmicosin is a macrolide antibiotic synthesized from tylosin. It has an antibacterial spectrum similar to tylosin with enhanced activity against Pasteurella multocida and Pasteurella hemolitica. Tilmicosin is recommended for the treatment of bacterial pneumonia in young cattle ... .|For more Therapeutic Uses (Complete) data for TILMICOSIN (8 total), please visit the HSDB record page.

/VET/: Tilmicosin is not labeled for use in female dairy cattle 20 months of age or older, veal calves, calves less than 1 month of age, or calves fed an all-milk diet.|Toxicity and side effects are uncommon for most macrolides (except tilmicosin), although pain and swelling may develop at injection sites. Hypersensitivity reactions have occasionally been seen. ... Horses are sensitive to macrolide-induced GI disturbances that can be serious and even fatal. ... Tilmicosin is characterized by cardiac toxicity (tachycardia and decreased contractility). It is contraindicated in swine and should not be used in an extra-label manner. cattle hae died after IV injection of tilmicosin.|Tilmicosin: All species: To avoid cardiotoxicity, tilmicosin should not be administered intravenously. Human: Injection of tilmicosin may be lethal. Although there is little information on the effects of tilmicosin in people, a variable susceptibility to cardiotoxic reactions in other species warrants caution with human exposure and close monitoring of the cardiovascular system, particularly after accidental injection. A physician should be consulted immediately in cases of accidental injection. Dogs: In laboratory dogs, tachycardia and decreased cardiac contractility have been noted in response to tilmicosin injection. Goats: Administration of tilmicosin to goats at intramuscular or subcutaneous doses >10 mg per kg of body weight (mg/kg) is likely to lead to toxicity. Horses: Administration of tilmicosin to horses at intramuscular or subcutaneous doses >10 mg/kg is likely to lead to toxicity. Pigs: Injection of tilmicosin into swine can be fatal as a result of cardiovascular toxicity. Administration of epinephrine to treat cardiovascular toxicity due to intravenous tilmicosin administration has been associated with an increased risk of death.|/VET:/ In cattle, tilmicosin is distributed into milk at effective antibacterial concentrations for susceptible pathogens, but detectable concentrations in milk are maintained for many weeks (up to 42 days). Tilmicosin should not be administered to lactating dairy cattle because of impractical withdrawal times.

Substances that inhibit the growth or reproduction of BACTERIA. (See all compounds classified as Anti-Bacterial Agents.)

Pigs were given a dose of 154 or 400 mg (14)C-tilmicosin in the diet following a similar dose given for 5 days. The recovery of radioactivity was 4 to 6% in urine and 62 to 75% in feces. Radioactivity was detected in the bile but was not quantified.|Pigs were administered a dose of 110 mg (14)C-tilmicosin in the diet over the course of one day. The recovery of radioactivity was 15% in the urine and 80% in the feces.|Tilmicosin is administered SC. Absorption after injection is rapid ... .|Beulah cross lambs were administered a single subcutaneous dose of 20 mg/kg bw per day (14)C-tilmicosin. The major radioactive component in the liver, kidneys and urine was the parent drug, together with lesser amounts of T1 and T2, and minor amounts of other unidentified substances.|For more Absorption, Distribution and Excretion (Complete) data for TILMICOSIN (13 total), please visit the HSDB record page.

Beulah cross lambs were administered a single subcutaneous dose of 20 mg/kg bw per day (14)C-tilmicosin. The major radioactive component in the liver, kidneys and urine was the parent drug, together with lesser amounts of T1 and T2, and minor amounts of other unidentified substances.|Fischer-344 rats (10 males and 10 females) were given gavage doses of 50 mg/kg bw per day (14)C-tilmicosin for 5 days. An analysis of fecal radioactivity for the presence of the sulfate metabolite that was found in the feces of pigs revealed the presence of a similar compound, but quantification was not undertaken.|Tilmicosin, labelled with (14)C in both the desmycosin macrolide ring and the piperidine ring, was given orally to 15 male and 15 female Fischer-344 rats. The dosage was 20 mg/kg bw per day for 3 days. In the liver, radiolabel corresponded to tilmicosin and a desmethyl derivative, T1 (demethylated in the mycaminose ring). The single radioactive substance identified in urine was unchanged tilmicosin, while in feces the major peak was parent compound with lesser amounts of desmethyl tilmicosin and a high molecular weight compound known to be present as an impurity in the administered substance, T2 (consisting of two macrolide rings and one piperidine ring).|In a summary of results obtained in cattle injected with (14)C-tilmicosin, it was reported that the radioactivity profile in the liver of treated rats was similar to that in the feces. In animals treated with a highly purified sample of tilmicosin, metabolite T2 was not detected in the liver, suggesting that its presence was a result of direct administration as a component of the drug substance. Radioactivity in the kidneys was essentially in the form of unchanged tilmicosin.|For more Metabolism/Metabolites (Complete) data for TILMICOSIN (6 total), please visit the HSDB record page.

The plasma half-lives of macrolides usually are 1-3 hr, ... /Macrolides/

Tilmicosin has in vitro activity against gram-positive organisms and mycoplasma and is active against certain gram-negative organisms, such as Hemophilus somnus, Mannheimia (Pasteurella) hemolytica, and Pasteurella multocida. However, M. hemolytica is more sensitive than P. multocida to tilmicosin. Other gram-negative organisms tested, including Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella, and Serratia species, are very resistant to tilmicosin. Some strains of Actinomyces also are extremely resistant to tilmicosin.|The antimicrobial mechanism seems to be the same for all of the macrolides. They interfere with protein synthesis by reversibly binding to the 50 S subunit of the ribosome. They appear to bind at the donor site, thus preventing the translocation necessary to keep the peptide chain growing. The effect is essentially confined to rapidly dividing bacteria and mycoplasmas. Macrolides are regarded as being bacteriostatic, ... . Macrolides are significantly more active at higher pH ranges (7.8-8). /Macrolides/|Macrolides have been reported to modify the host immune and inflammatory responses both in vivo and in vitro. /The authors/ examined the in vitro effect of the macrolides tilmicosin and tylosin, which are only used in the veterinary clinic, on the production of nitric oxide (NO), prostaglandin E2 (PGE2) and cytokines by lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and mouse peripheral blood mononuclear cells (PBMCs). Compared with 5 ug/mL, tilmicosin and tylosin concentrations of 10 ug/mL and 20 ug/mL significantly decreased the production of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), PGE2, NO, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6, and increased IL-10 production. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) gene expression were also significantly reduced. These results support the opinion that macrolides may exert an anti-inflammatory effect through modulating the synthesis of several mediators and cytokines involved in the inflammatory process.

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ Injection of tilmicosin may be lethal. Although there is little information on the effects of tilmicosin in people, a variable susceptibility to cardiotoxic reactions in other species warrants caution with human exposure and close monitoring of the cardiovascular system, particularly after accidental injection. A physician should be consulted immediately in cases of accidental injection. ... Administration of epinephrine to treat cardiovascular toxicity due to intravenous tilmicosin administration has been associated with an increased risk of death.|/SIGNS AND SYMPTOMS/ A total of 241 human exposures to tilmicosin (Micotil) were reported to the Rocky Mountain Poison Center from May 1992 to May 1993. Needlesticks and scrapes (n=112) and accidental injection (n=43) caused either no effect or local reactions including soreness, numbness, stinging, swelling, redness, burning and stiffness. Some injected subjects experienced anxiety, sweating, headache and lightheadedness. Skin exposures (n=50) resulted in redness and tingling of the skin, and eye exposures (n=11) resulted in stinging and swelling. Persons accidentally ingesting the drug (n=39) reported either no symptoms or bitter taste, nausea, numbness of lips and tongue, vomiting, thirst and headache.|/CASE REPORTS/ Over a 30-month period, 36 cases of accidental exposure to tilmicosin (Micotil) were reported to the Ontario Regional Poison Information Centre. Percutaneous injection (n=26) always resulted in pain at the site and seven subjects mentioned a variety of local reactions consistent with an irritant action. One person showed "peaked T waves" 30 minutes following the injection of 1 ml into his arm, but ECG changes were not noted in other subjects. The remaining subjects received splashes into the mouth or eyes or onto the skin. Unpleasant taste, a burning sensation on the hard palate and ocular irritation were each recorded in one person.

20-deoxo-20-(3,5-dimethylpiperidin-1-yl)desmycosin

Veterinary-labeled product(s): 300 mg (base) per mL (Rx) (Micotil). /Tilmicosin injection USP/|Veterinary-labeled product(s): 200 grams (base) per kg (90.7 grams (base) per pound) of premix (Rx) (Pulmotil 90). /Tilmicosin phospahte/

Macrolide antibiotic; structurally related to tylosin, ... prepared as 85:15 mixture of cis/trans isomers: European patent 103,465, ... US patent 4,820,695 (1984, 1989 both to Lilly).

Analyte: tilmicosin; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: tilmicosin; matrix: chemical identification; procedure: retention time of liquid chromatogram with comparison to standards|Analyte: tilmicosin; matrix: chemical purity; procedure: liquid chromatography with detection at 280 nm and comparison to standards|Analyte: tilmicosin; matrix: pharmaceutical preparation (injection solution); procedure: retention time of liquid chromatogram with comparison to standards (chemical identification)|Analyte: tilmicosin; matrix: pharmaceutical preparation (injection solution); procedure: liquid chromatography with detection at 280 nm and comparison to standards (chemical purity)

Analyte: tilmicosin; matrix: tissue (muscle); procedure: high-performance liquid chromatography with mass spectrometry detection; limit of detection: 50 ug/kg

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