Lingual and pharyngeal paralysis due to acute doxycycline intoxication in veal calves

Chiers, Koen; Weyens, P; Deprez, Piet; Heerden, Marjolein van; Meulemans, G; Baert, Kris; Croubels, Siska; Backer, Patrick De; Ducatelle, Richard

doi:10.1136/vr.155.1.25

Cited by 11 publications

(16 citation statements)

References 5 publications

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“…Although it has been stated that high concentrations of Dox in vitro , equivalent to 8 to 16 times the value of an average MIC could turn this time-dependent antibacterial drug into a concentration-dependent antibacterial drug [39], its cardiac toxicity refrains its use at higher doses. Hence, seeking large Cmax values is an unsafe approach [40,41]. Dox should be considered a time-dependent antibacterial drug in horses.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of a peroral single dose of two long-acting formulations and an aqueous formulation of doxycycline hyclate in horses

et al. 2013

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BackgroundDoxycyline (Dox) is a semisynthetic antibacterial drug with pharmacological advantages over its parent drug (tetracycline) in the treatment of various bacterial diseases in horses. Yet, at present a horse-customized pharmaceutical formulation is not available. Based on its pharmacokinetic/pharmacodynamic (PK/PD) ratio, Dox is considered a time-dependent antibacterial drug and ideally expected to achieve sustained plasma drug concentrations both at or slightly above the minimal inhibitory concentration (MIC) level for as long as possible between dosing intervals. Hence, the objective of this study was to formulate two long-acting (LA) doxycyline hyclate (Dox-h) formulations for oral administration and define their pharmacokinetics in non-fasted adult horses to obtain better bioavailability and longer mean residence time, features needed to comply better with its pharmacokinetic/pharmacodynamic (PK/PD) ratios.ResultsPharmacokinetic parameters were determined after the oral administration of a single 10 mg/kg bolus dose of two 20% Dox-h formulations: one based on a β cyclodextrin (Dox-β) matrix and a second one on a poloxamer (Dox-pol) matrix. The results were compared with the pharmacokinetics of a single 10 mg/kg bolus oral dose of a freshly made aqueous Dox-h solution (Dox-a). Dox-pol showed the greatest values for relative bioavailability (548%); maximum serum concentration (Cmax) value was 1.3 ± 0.7 μg/mL with time to reach the Cmax (Tmax) of 5.9 ± 1.7 h, area under the curve (AUC) of 17.0 ± 2.2 μg h/ml and elimination half-life (T½ β) of 4.9 ± 1.0 h.ConclusionsConsidering a minimal inhibitory concentration MIC of 0.25 μg/mL, clinically effective plasma concentrations might be obtained for up to 24 h administering Dox-pol. This is an oral paste formulation that might optimize the use of Dox-h in horses in terms of PK/PD ratio congruency, and it is likely that it may also improve prescription compliance due to its ease of administration.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of a peroral single dose of two long-acting formulations and an aqueous formulation of doxycycline hyclate in horses

et al. 2013

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“…Hence, seeking large Cmax values appears to be an unsafe approach [34,35] and DOX should be considered a time-dependant antibacterial drug [33]. In that context PK/PD compliance can be achieved when serum concentrations of the drug are barely above or at the minimal inhibitory concentration (MIC) level of the involved pathogen, but for as long as possible within the dosing interval [36].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of an injectable long-acting formulation of doxycycline hyclate in dogs

et al. 2012

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Based on its PK/PD ratios, doxycycline hyclate (DOX-h), a time-dependant antibacterial, is ideally expected to achieve both sustained plasma drug concentrations at or slightly above the MIC level for as long as possible between dosing intervals. Pursuing this end, a poloxamer-based matrix was used to produce a long-acting injectable preparation (DOX-h-LA) and its serum concentrations vs. time profile investigated after its SC injection to dogs (≤ 0.3 mL per injection site), and results compared with the oral (PO) and IV pharmacokinetics of DOX-h, prepared as tablet or as freshly made solution. A crossover (4 x 4 x 4) study design was employed with 12 Mongrel dogs, with washout periods of 21 days, and at dose of 10 mg/kg in all cases. DOX-h-LA showed the greatest values for bioavailability (199.48%); maximum serum concentration (Cmax) value was 2.8 ± 0.3 with a time to reach Cmax (Tmax) of 2.11 ± 0.12 h and an elimination half-life of 133.61 ± 6.32 h. Considering minimum effective serum concentration of 0.5 μg/mL, a dose-interval of at least 1 week h can be achieved for DOX-h-LA, and only 48 h and 24 h after the IV or PO administration of DOX-h as a solution or as tablets, respectively. A non-painful small bulge, apparently non-inflammatory could be distinguished at injection sites. These lumps dissipated completely in 30 days in all cases.

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“…Cardiac toxicity of this drug has been reported in calves with a single overdose 5-10 times larger with plasma concentrations ranging from 50 to 100 lg/mL. Hence, seeking large C max values appears to be an unsafe approach (Yeruham et al, 2002;Chiers et al, 2004). Thus, DOX should be considered a time-dependant antibacterial drug (Cunha et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of an injectable long‐acting parenteral formulation of doxycycline hyclate in pigs

Gutiérrez

Ocampo

Espinosa

et al. 2013

Vet Pharm & Therapeutics

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Based on its ideal PK/PD ratios, doxycycline hyclate (DOX-h), a time-dependant antibacterial, is ideally expected to achieve sustained plasma drug concentrations at or slightly above the MIC level for as long as possible between dosing intervals. Pursuing this end, a poloxamer-based matrix was used to produce a 10% long-acting injectable preparation (DOX-h-LA) and its serum concentrations vs. time profile investigated after its injection to pigs in the pericaudal s.c. by parallel design. Results were compared with the forced oral bolus dose and i.v. pharmacokinetics of DOX-h. For this study, 12 recently weaned pigs per group were included in this trial, and a dose of 20 mg/kg was injected in all cases. DOX-h-LA showed the greatest values for bioavailability (115.38%); maximum serum concentration (Cmax) value was 1.5 ± 0.2 with a time to reach Cmax of 3.41 ± 0.04 h and an elimination rate constant of 70.93 ± 0.87( ) h. Considering minimum effective serum concentration of 0.5 μg/mL, a dose interval of at least 5 days can be achieved for DOX-h-LA, whereas p.o. and i.v. dosing of DOX-h may only last 11 and 15 h, respectively. Pigs were slaughtered on day 30 after this trial, and no visible remnants of the preparation were detected neither fibrosis was observed after a thorough macroscopic and histopathological analysis.

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Lingual and pharyngeal paralysis due to acute doxycycline intoxication in veal calves

Cited by 11 publications

References 5 publications

Pharmacokinetics of a peroral single dose of two long-acting formulations and an aqueous formulation of doxycycline hyclate in horses

Pharmacokinetics of a peroral single dose of two long-acting formulations and an aqueous formulation of doxycycline hyclate in horses

Pharmacokinetics of an injectable long-acting formulation of doxycycline hyclate in dogs

Pharmacokinetics of an injectable long‐acting parenteral formulation of doxycycline hyclate in pigs

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