RESUMEN
This study aimed to evaluate the administration of doxycycline hyclate in a long-acting pharmaceutical preparation in pigs when administered either ad libitum as a feed medication or an oral bolus dose. In all instances, the studied dose was 20 mg/kg b.w. A total of 48 healthy crossbred, castrated male pigs (Landrace-Yorkshire) weighing 23 ± 4.3 kg were included in this trial. They were randomly assigned to six groups as follows: two groups for the experimental prototype 1 of doxycycline hyclate administering it ad libitum (Fad-lib) or as forced bolus (Fbolus); two groups for the experimental prototype 2 of doxycycline hyclate as for the former groups (FCad-lib and FCbolus), and two control groups receiving the same dose of doxycycline hyclate, but of a commercial premix, also as previously explained (Cbolus and Cad-lib). Statistical analysis of the mean pharmacokinetic values was carried out with Kruskal-Wallis and Dunn's tests. The relative bioavailability (Fr) of the best prototype, when administered ad libitum (FCad-lib), was five times larger than the reference group (Cadlib). These results allow the proposal that the referred differences achieved in the presented prototypes can mark a notable clinical difference, particularly in pathogens with some resistance.
Asunto(s)
Antibacterianos , Doxiciclina , Masculino , Animales , Porcinos , Doxiciclina/farmacocinética , Antibacterianos/farmacocinética , Disponibilidad Biológica , Área Bajo la Curva , SemividaRESUMEN
Drug delivery technology is a promising way to enhance the therapeutic efficacy of drugs. The purpose of this study is to evaluate the physical and chemical properties of hydroxyapatite ceramic microspheres loaded with doxycycline (HADOX), their effects on in vitro osteoblast viability, and their antimicrobial activity, and to determine the effects of DOX on the healing of rat sockets after tooth extraction. The internal microsphere porosity was sensitive to the treatment used to adsorb DOX onto microsphere surface; HA microspheres without DOX presented 26% of pores, whereas HADOX0.15 microspheres presented 52.0%. An initial drug release of 49.15 µg/ml was observed in the first 24 hr. The minimal inhibitory concentration (MIC) tested against Enterococcus faecalis demonstrated that bacterial growth was inhibited for up to 7 days. Results of cell viability and cell proliferation did not indicate statistical differences in the metabolic activity of HADOX samples relative to HA without DOX microspheres (p > .05). After 1 week, a discreet inflammation reaction was observed in the control group, and after 6 weeks, newly-formed bone was observed in the HADOX0.15 (p < .05). The HADOX did not interfere in the bone repair and controlled the early inflammatory response. HADOX could be a promising biomaterial to promote bone repair in infected sites.
Asunto(s)
Cerámica , Doxiciclina , Sistemas de Liberación de Medicamentos , Durapatita , Microesferas , Osteoblastos/metabolismo , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Cerámica/química , Cerámica/farmacocinética , Cerámica/farmacología , Doxiciclina/química , Doxiciclina/farmacocinética , Doxiciclina/farmacología , Durapatita/química , Durapatita/farmacocinética , Durapatita/farmacología , Enterococcus faecalis/crecimiento & desarrollo , Femenino , Masculino , Ratones , Ratas , Ratas WistarRESUMEN
Doxycycline hiclate is a broad spectrum antibiotic widely used in human and veterinary medicine. The inability to perform the parenteral administration of drugs and the lack of oral preparations can be mentioned as difficulties in the treatment of animals in the domestic environment. In this scenario, the aim of this study was to investigate the bioavailability of the drug by rectal route, to propose a potential suppository formulation containing 25â¯mg of doxycycline as an alternative to the available injectable formulations. Hydrophilic and lipophilic suppositories were prepared, in polyethylene glycol (S-PEG) or cocoa butter (S-CBT), respectively. The suppositories were prepared and evaluated concerning visual characteristics, content, average weight, melting range, content uniformity and in vitro release. A stability study was performed and the two most stable formulations were submitted to a pharmacokinetic study in rabbits. The bioavailability of the suppositories was compared to the data of the intravenous (i.v.) formulation. PEG suppository showed 49.13% bioavailability and CBT 51.43% with Cmax equal to 2.06⯱â¯2.96⯵g.mL-1 and 1.54⯱â¯0.28⯵g.mL-1, respectively. The data obtained suggest that rectal administration may become another method of administration of doxycycline in the treatment of bacterial infections.
Asunto(s)
Doxiciclina/farmacocinética , Administración Rectal , Animales , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Infecciones Bacterianas/tratamiento farmacológico , Disponibilidad Biológica , Química Farmacéutica/métodos , Doxiciclina/administración & dosificación , Masculino , Polietilenglicoles/química , ConejosRESUMEN
OBJECTIVE: To investigate the use of polymethyl methacrylate (PMMA) electrospun fiber mats containing different amounts of polyethylene oxide (PEO) as a doxycycline delivery system and to test antibacterial activity against an oral pathogen. METHODOLOGY: PMMA powders or PEO (mol wt 200 Kd) (10,20,30% w/w/) were dissolved in N, N-dimethylformamide (DMF) to obtain a final polymer concentration of 15% in DMF (w/v). 2% Doxycycline monohydrate was added to the solutions and submitted to vortex mixing. The solution was transferred to a plastic syringe and fit into a nanofiber electrospinning unit. The parameters applied were: voltage at 17.2 kV; distance of 20 cm between the needle tip and the collector plate; target speed at 2 m/min; and transverse speed at 1cm/min. Syringe pump speed was 0.15 mm/min. The drug release analysis was performed by removing aliquots of the drug-containing solution (in PBS) at specific periods. Doxycycline release was quantified using RP-HPLC. Fiber mats from all groups had their antibacterial action tested against S. mutans based on inhibition halos formed around the specimens. The experiments were performed in triplicate. Gravimetric analysis at specific periods was performed to determine any polymer loss. Morphological characterization of the electrospun fibers was completed under an optical microscope followed by SEM analysis. RESULTS: The addition of PEO to the PMMA fibers did not affect the appearance and diameter of fibers. However, increasing the %PEO caused higher doxycycline release in the first 24 h. Fibers containing 30% PEO showed statistically significant higher release when compared with the other groups. Doxycycline released from the fibers containing 20% or 30% of PEO showed effective against S. mutans. CONCLUSION: The incorporation of PEO at 20% and 30% into PMMA fiber mat resulted in effective drug release systems, with detected antibacterial activity against S. mutans.
Asunto(s)
Antibacterianos/farmacocinética , Doxiciclina/farmacocinética , Nanofibras/química , Polietilenglicoles/farmacocinética , Polimetil Metacrilato/farmacocinética , Análisis de Varianza , Antibacterianos/química , Cromatografía Líquida de Alta Presión/métodos , Doxiciclina/química , Inmersión , Microscopía Electrónica de Rastreo , Peso Molecular , Polietilenglicoles/química , Polimetil Metacrilato/química , Reproducibilidad de los Resultados , Streptococcus mutans/efectos de los fármacos , Factores de Tiempo , Agua/químicaRESUMEN
The objective of the study was to determine the therapeutic equivalence evaluated through in vitro studies of four brands of drugs containing amoxicillin, doxycycline, and fluconazole purchased at pharmaceutical facilities in Metropolitan Lima, and to establish their interchangeability with a reference product (RP). A validated method of visible ultraviolet spectrophotometry was used to determine the dissolution profile. The similarity factor (f2) was used to establish the therapeutic equivalence, being considered equivalent if the values of f2 were between 50 and 100. For doxycycline, the four drugs were equivalent in vitro to the RP; for amoxicillin, only two drugs were equivalent in vitro to the RP; and for fluconazole, none was equivalent in vitro to the RP. It is concluded that some amoxicillin and fluconazole drugs circulating in the national market do not meet the therapeutic equivalence assessed by in vitro studies; in other words, they are not interchangeable.
El objetivo del estudio fue determinar la equivalencia terapéutica evaluada mediante estudios in vitro de cuatro marcas de medicamentos conteniendo amoxicilina, doxiciclina y fluconazol adquiridos en establecimientos farmacéuticos de Lima Metropolitana y establecer su intercambiabilidad con un producto de referencia (PR). Se empleó un método validado de espectrofotometría ultravioleta visible para determinar el perfil de disolución. El factor de similitud (f2) se utilizó para establecer la equivalencia terapéutica, considerándose equivalentes si los valores de f2 se encontraban entre 50 y 100. Para doxiciclina los cuatro medicamentos fueron equivalentes in vitro al PR, para amoxicilina sólo dos medicamentos fueron equivalentes in vitro al PR y para fluconazol ninguno fue equivalente in vitro al PR. Se concluye que algunos medicamentos de amoxicilina y fluconazol que circulan en el mercado nacional no cumplen con la equivalencia terapéutica evaluada mediante estudios in vitro; es decir, no son intercambiables.
Asunto(s)
Amoxicilina/farmacocinética , Antibacterianos/farmacocinética , Antifúngicos/farmacocinética , Doxiciclina/farmacocinética , Fluconazol/farmacocinética , Estudios Transversales , Perú , Equivalencia TerapéuticaRESUMEN
When dental implants become infected, the progression of the disease is rapid. Commercially available dental implant surfaces can be easily contaminated, resulting in rapid progression of peri-mucositis and peri-implantitis. The aim of this study was to evaluate, in vitro, the pattern of doxycycline release from by dental implants with titanium nanotube surface (DINS) at different pHs to examine novel drug loading and chemical coating techniques. Nine DINS were loaded with doxycycline and subsequently coated with polylactic-co-glycolic acid (PLGA). High-performance liquid chromatography (HPLC) was used to measure the amounts of released doxycycline in a 30-day period. Cytotoxicity of the DINS was evaluated by an assay using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT). The results showed that the experimental DINS coated with doxycycline and PLGA showed a mean drug release during the experimental period for the groups: pH 7.4 (8.39 µg/mL), pH 6.4 (8.63 µg/mL). The pH 5.4 (15.18 µl/mL) doxycycline release from DINS was faster at pH 5.4 than those at pHs 6.4 and 7.4 (P = .0031 and .0034, respectively). This new surface treatment of dental implants with titanium nanotubes and subsequent drug loading demonstrated biocompatibility and sustained doxycycline release over a 30-day period. Additional studies are needed in order to adopt a stable drug release at neutral pH environment while warranting a constant drug release in an acidic pH environment.
Asunto(s)
Antibacterianos , Implantes Dentales , Doxiciclina , Nanotubos , Antibacterianos/farmacocinética , Doxiciclina/farmacocinética , Glicolatos , Glicoles , Copolímero de Ácido Poliláctico-Ácido PoliglicólicoRESUMEN
RESUMEN El objetivo del estudio fue determinar la equivalencia terapéutica evaluada mediante estudios in vitro de cuatro marcas de medicamentos conteniendo amoxicilina, doxiciclina y fluconazol adquiridos en establecimientos farmacéuticos de Lima Metropolitana y establecer su intercambiabilidad con un producto de referencia (PR). Se empleó un método validado de espectrofotometría ultravioleta visible para determinar el perfil de disolución. El factor de similitud (f2) se utilizó para establecer la equivalencia terapéutica, considerándose equivalentes si los valores de f2 se encontraban entre 50 y 100. Para doxiciclina los cuatro medicamentos fueron equivalentes in vitro al PR, para amoxicilina sólo dos medicamentos fueron equivalentes in vitro al PR y para fluconazol ninguno fue equivalente in vitro al PR. Se concluye que algunos medicamentos de amoxicilina y fluconazol que circulan en el mercado nacional no cumplen con la equivalencia terapéutica evaluada mediante estudios in vitro; es decir, no son intercambiables.
ABSTRACT The objective of the study was to determine the therapeutic equivalence evaluated through in vitro studies of four brands of drugs containing amoxicillin, doxycycline, and fluconazole purchased at pharmaceutical facilities in Metropolitan Lima, and to establish their interchangeability with a reference product (RP). A validated method of visible ultraviolet spectrophotometry was used to determine the dissolution profile. The similarity factor (f2) was used to establish the therapeutic equivalence, being considered equivalent if the values of f2 were between 50 and 100. For doxycycline, the four drugs were equivalent in vitro to the RP; for amoxicillin, only two drugs were equivalent in vitro to the RP; and for fluconazole, none was equivalent in vitro to the RP. It is concluded that some amoxicillin and fluconazole drugs circulating in the national market do not meet the therapeutic equivalence assessed by in vitro studies; in other words, they are not interchangeable.
Asunto(s)
Fluconazol/farmacocinética , Doxiciclina/farmacocinética , Amoxicilina/farmacocinética , Antibacterianos/farmacocinética , Antifúngicos/farmacocinética , Perú , Equivalencia Terapéutica , Estudios TransversalesRESUMEN
Abstract Objective: To investigate the use of polymethyl methacrylate (PMMA) electrospun fiber mats containing different amounts of polyethylene oxide (PEO) as a doxycycline delivery system and to test antibacterial activity against an oral pathogen. Methodology: PMMA powders or PEO (mol wt 200 Kd) (10,20,30% w/w/) were dissolved in N, N-dimethylformamide (DMF) to obtain a final polymer concentration of 15% in DMF (w/v). 2% Doxycycline monohydrate was added to the solutions and submitted to vortex mixing. The solution was transferred to a plastic syringe and fit into a nanofiber electrospinning unit. The parameters applied were: voltage at 17.2 kV; distance of 20 cm between the needle tip and the collector plate; target speed at 2 m/min; and transverse speed at 1cm/min. Syringe pump speed was 0.15 mm/min. The drug release analysis was performed by removing aliquots of the drug-containing solution (in PBS) at specific periods. Doxycycline release was quantified using RP-HPLC. Fiber mats from all groups had their antibacterial action tested against S. mutans based on inhibition halos formed around the specimens. The experiments were performed in triplicate. Gravimetric analysis at specific periods was performed to determine any polymer loss. Morphological characterization of the electrospun fibers was completed under an optical microscope followed by SEM analysis. Results: The addition of PEO to the PMMA fibers did not affect the appearance and diameter of fibers. However, increasing the %PEO caused higher doxycycline release in the first 24 h. Fibers containing 30% PEO showed statistically significant higher release when compared with the other groups. Doxycycline released from the fibers containing 20% or 30% of PEO showed effective against S. mutans. Conclusion: The incorporation of PEO at 20% and 30% into PMMA fiber mat resulted in effective drug release systems, with detected antibacterial activity against S. mutans.
Asunto(s)
Polietilenglicoles/farmacocinética , Doxiciclina/farmacocinética , Polimetil Metacrilato/farmacocinética , Nanofibras/química , Antibacterianos/farmacocinética , Polietilenglicoles/química , Streptococcus mutans/efectos de los fármacos , Factores de Tiempo , Agua/química , Microscopía Electrónica de Rastreo , Reproducibilidad de los Resultados , Análisis de Varianza , Cromatografía Líquida de Alta Presión/métodos , Doxiciclina/química , Polimetil Metacrilato/química , Inmersión , Antibacterianos/química , Peso MolecularRESUMEN
Composites of biodegradable polymers and calcium phosphate are bioactive and flexible, and have been proposed for use in tissue engineering and bone regeneration. When associated with the broad-spectrum antibiotic doxycycline (DOX), they could favor antimicrobial action and enhance the action of osteogenic composites. Composites of polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), and a bioceramic of biphasic calcium phosphate Osteosynt® (BCP) were loaded with DOX encapsulated in ß-cyclodextrin (ßCD) and were evaluated for effects on osteoblastic cell cultures. The DOX/ßCD composite was prepared with a double mixing method. Osteoblast viability was assessed with methyl tetrazolium (MTT) assays after 1day, 7day, and 14days of composite exposure; alkaline phosphatase (AP) activity and collagen production were evaluated after 7days and 14days, and mineral nodule formation after 14days. Composite structures were evaluated by scanning electron microscopy (SEM). Osteoblasts exposed to the composite containing 25µg/mL DOX/ßCD had increased cell proliferation (p<0.05) compared to control osteoblast cultures at all experimental time points, reaching a maximum in the second week. AP activity and collagen secretion levels were also elevated in osteoblasts exposed to the DOX/ßCD composite (p<0.05 vs. controls) and reached a maximum after 14days. These results were corroborated by Von Kossa test results, which showed strong formation of mineralization nodules during the same time period. SEM of the composite material revealed a surface topography with pore sizes suitable for growing osteoblasts. Together, these results suggest that osteoblasts are viable, proliferative, and osteogenic in the presence of a DOX/ßCD-containing BCP ceramic composite.
Asunto(s)
Fosfatos de Calcio , Ciclodextrinas , Doxiciclina , Portadores de Fármacos , Ácido Láctico , Osteoblastos/metabolismo , Osteogénesis/efectos de los fármacos , Poliésteres , Ácido Poliglicólico , Animales , Fosfatos de Calcio/química , Fosfatos de Calcio/farmacocinética , Fosfatos de Calcio/farmacología , Células Cultivadas , Ciclodextrinas/química , Ciclodextrinas/farmacocinética , Ciclodextrinas/farmacología , Doxiciclina/química , Doxiciclina/farmacocinética , Doxiciclina/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Ácido Láctico/química , Ácido Láctico/farmacocinética , Ácido Láctico/farmacología , Masculino , Osteoblastos/citología , Poliésteres/química , Poliésteres/farmacocinética , Poliésteres/farmacología , Ácido Poliglicólico/química , Ácido Poliglicólico/farmacocinética , Ácido Poliglicólico/farmacología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ratas , Ratas WistarRESUMEN
The aim of this study was to investigate in vitro the antimicrobial effect and diffusion against E. faecalis of new intracanal medications on the external root surface. The medications tested were a placebo gel (PC); the new formulations with either 3% nitrofurantoin (NIT) or 3% doxycycline hydrochloride (DX) and 2% chlorhexidine (CHX) gel as positive control. The new formulations were tested using the traditional agar diffusion test (ADT) and an adapted agar diffusion method (AADM), where the teeth were filled with the medications and left to diffuse on agar surface seeded with E. faecalis. In the ADT, the larger zones of microbial growth inhibition were seen in DX, followed by CHX and NIT. In the AADM test only DX and CHX showed antimicrobial effect. Statistically significant differences between groups were observed by the Kruskal-Wallis test (ï£2=47.126; p<0.001). The new intracanal formulations with DX and NIT have demonstrated antimicrobial effect against E. faecalis, but only DX was able to diffuse through the dentinal tubules and exert antimicrobial effect outside the roots.
Asunto(s)
Antibacterianos/farmacología , Cavidad Pulpar/efectos de los fármacos , Dentina/efectos de los fármacos , Doxiciclina/farmacología , Nitrofurantoína/farmacología , Irrigantes del Conducto Radicular/farmacología , Agar , Antibacterianos/farmacocinética , Carga Bacteriana/efectos de los fármacos , Clorhexidina/farmacocinética , Clorhexidina/farmacología , Medios de Cultivo , Cavidad Pulpar/metabolismo , Cavidad Pulpar/microbiología , Dentina/metabolismo , Dentina/microbiología , Difusión , Doxiciclina/farmacocinética , Enterococcus faecalis/efectos de los fármacos , Humanos , Ensayo de Materiales , Nitrofurantoína/farmacocinética , Placebos , Irrigantes del Conducto Radicular/farmacocinética , Preparación del Conducto Radicular/instrumentación , Preparación del Conducto Radicular/métodos , Raíz del Diente/efectos de los fármacos , Raíz del Diente/metabolismo , Raíz del Diente/microbiologíaRESUMEN
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.
Asunto(s)
Antibacterianos/farmacocinética , Doxiciclina/farmacocinética , Porcinos/metabolismo , Animales , Antibacterianos/administración & dosificación , Área Bajo la Curva , Disponibilidad Biológica , Preparaciones de Acción Retardada , Doxiciclina/administración & dosificación , Semivida , Inyecciones Subcutáneas , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Doxycyline (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. RESULTS: Pharmacokinetic 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 ß cyclodextrin (Dox-ß) 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 ß) of 4.9 ± 1.0 h. CONCLUSIONS: Considering 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.
Asunto(s)
Antibacterianos/farmacocinética , Doxiciclina/farmacocinética , Caballos/sangre , Absorción , Administración Oral , Animales , Antibacterianos/administración & dosificación , Área Bajo la Curva , Doxiciclina/administración & dosificación , Femenino , Semivida , Caballos/metabolismo , MasculinoRESUMEN
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.
Asunto(s)
Antibacterianos/farmacocinética , Perros/metabolismo , Doxiciclina/farmacocinética , Administración Oral , Animales , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Doxiciclina/administración & dosificación , Doxiciclina/sangre , Femenino , Semivida , Inyecciones Intravenosas/veterinaria , Inyecciones Subcutáneas/veterinaria , Masculino , Poloxámero/administración & dosificación , Poloxámero/farmacocinética , Comprimidos/farmacocinéticaRESUMEN
Doxycycline hyclate (CAS 24390-14-5, doxycycline-h), an antibacterial with time-dependent action, was formulated as a non-irritating long-acting parenteral formulation based on a beta-cyclodextrin: poloxamer-based matrix (doxycycline-h-LA). Tissue and serum concentrations vs time profile were investigated after its subcutaneous injection to Wistar rats. Serum concentration profiles and key pharmacokinetic (PK) variables of doxycycline-h-LA were compared to the corresponding profiles and PK values obtained with an aqueous formulation of doxycycline-h administered either intramuscularly, orally or intravenously to Wistar rats. In all groups, the dose was 10 mg/kg. Doxycycline-h-LA showed outstanding bioavailability (951% or 477% if a correction formula is considered), as compared to the one obtained with an aqueous formulation (106-82%, respectively). Corresponding values for maximum serum concentration were 3.19 microg/ml and 3.00 microg/ml, respectively, and elimination half-lives were completely different: 42.49 h and 2.77 h for doxycycline-h-LA and the aqueous formulation, respectively. Considering minimal inhibitory concentrations of doxycycline for sensitive and resistant bacteria (from < or = 0.5 to > or =1.5 microg/ml), doxycycline-h-LA could be injected every 2 or 3 days, while aqueous doxycycline-h would require a dosing interval from 7.5 to 11 h. But if tissue concentrations are taken as braking points, the dosing interval will vary from 48 to 94 h. For doxycycline-h-LA, mean tissue:serum ratios were 2:1 for lungs, 9.8:1 for kidneys and 2.2:1 for intestine homogenates. These values are in close agreement with those found for the distribution of doxycycline in other species.
Asunto(s)
Antibacterianos/farmacocinética , Doxiciclina/farmacocinética , Administración Oral , Algoritmos , Animales , Antibacterianos/administración & dosificación , Área Bajo la Curva , Química Farmacéutica , Doxiciclina/administración & dosificación , Excipientes , Inyecciones Intravenosas , Inyecciones Subcutáneas , Masculino , Soluciones Farmacéuticas , Poloxámero , Ratas , Ratas Wistar , Distribución Tisular , beta-CiclodextrinasRESUMEN
OBJECTIVE: To determine the pharmacokinetics after SC administration of an experimental, long-acting parenteral formulation of doxycycline hyclate in a poloxamer-based matrix and after IV and IM administration of an aqueous formulation of doxycycline hyclate in goats. ANIMALS: 30 clinically normal adult goats. PROCEDURES: Goats were allocated to 3 groups (10 goats/group). One group of goats received doxycycline hyclate (10 mg/kg) IM, a second group received the same dosage of doxycycline hyclate IV, and the third group received the long-acting parenteral formulation of doxycycline hyclate SC. Serum concentrations of doxycycline were determined before and at various intervals after administration. RESULTS: The long-acting parenteral formulation of doxycycline hyclate had the greatest bioavailability (545%); mean +/- SD maximum serum concentration was 2.4 +/- 0.95 microg/mL, peak time to maximum concentration was 19.23 +/- 2.03 hours, and elimination half-life was 40.92 +/- 4.25 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the long-acting parenteral formulation of doxycycline hyclate distributed quickly and widely throughout the body after a single dose administered SC, and there was a prolonged half-life. Bioavailability of the longacting parenteral formulation of doxycycline hyclate after SC administration was excellent, compared with bioavailability after IV and IM administration of an aqueous formulation of doxycycline hyclate. Although no local tissue irritation and adverse effects were detected, clinical assessment of drug-residues and toxicologic evaluations are warranted before this long-acting parenteral formulation of doxycycline hyclate can be considered for use in goats with bacterial infections.
Asunto(s)
Antibacterianos/farmacocinética , Doxiciclina/análogos & derivados , Animales , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/veterinaria , Disponibilidad Biológica , Doxiciclina/administración & dosificación , Doxiciclina/farmacocinética , Doxiciclina/uso terapéutico , Enfermedades de las Cabras/tratamiento farmacológico , Cabras , Semivida , Infusiones Parenterales/métodos , InyeccionesRESUMEN
Doxycycline hyclate (DOX-h) can be regarded as a time-dependant antibacterial. Hence, a parenteral long-acting formulation may be regarded as more pharmacologically sound. 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 s.c. injection to calves. Serum concentrations profiles for such a prepartion were compared to the corresponding profiles obtained with an aqueous formulation of DOX-h injected either i.m. or i.v. in 10 calves in a crossover study at dose of 10mg/kg, with washout periods. DOX-h-LA showed the greatest values for bioavailability (602%); maximum serum concentration (C(max)) value was 1.99microg/mL with a time to reach C(max) (T(max)) of 25h and an elimination half-life of 40.81h. Considering minimum effective serum concentration of 0.5microg/mL a dose-interval of 80h can be achieved for DOX-h-LA, and only 9.7h and 17h after the i.v. or i.m. administration of DOX-h, respectively.
Asunto(s)
Doxiciclina/análogos & derivados , Animales , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Bovinos , Preparaciones de Acción Retardada , Doxiciclina/administración & dosificación , Doxiciclina/farmacocinética , Inyecciones Intramusculares , Inyecciones Intravenosas , Inyecciones Subcutáneas , CinéticaRESUMEN
Segments of internal mammary arteries and saphenous veins and cultured smooth muscle cells were incubated with and without doxycicline. Metalloproteinases activity was assessed by zymography and Western Blot. Activity of Metalloproteinase-9 in saphenous veins was 217 percent less than in internal mammary arteries. In these vessels doxycicline decreased metalloproteinase-9 activity by 207 percent and metalloproteinase-1 expression. In cultured smooth muscle cells, the median inhibitory concentration of doxycicline for metalloproteinase-2 was 138 uM (r2=0.82). Internal mammary arteries and saphenous veins have different metalloproteinase activities, that are inhibited by doxycicline