Randomized, placebo-controlled, 28-day safety and pharmacokinetics evaluation of repeated oral cannabidiol administration in healthy dogs.

OBJECTIVE: To determine the safety and pharmacokinetics of various doses of plant-derived cannabidiol (CBD) versus placebo following repeated oral administration. ANIMALS: 20 healthy adult Beagles. PROCEDURES: In a randomized, blinded, placebo-controlled trial, dogs were randomized to 5 groups balanced in body weight and sex (n = 4 dogs/group) and received a CBD (1, 2, 4, or 12 mg/kg; from cannabis extract) or placebo oil formulation PO once daily for 28 days. Outcome variables were assessed through daily health observations, veterinary examinations, CBC, and serum biochemical analysis. Blood samples were collected at various time points to estimate 24-hour pharmacokinetic profiles of CBD and selected metabolites (7-carboxy-CBD and 7-hydroxy-CBD). RESULTS: Repeated CBD administration was well tolerated by dogs, with no clinically important changes in measured safety outcomes. Veterinary examinations revealed no clinically important abnormal findings. Adverse events were mild in severity. Relative to placebo administration, CBD administration at 12 mg/kg/d resulted in more gastrointestinal adverse events (mainly hypersalivation) and significantly higher serum alkaline phosphatase activity. Total systemic exposure to CBD increased on a dose-dependent basis following both acute (first dose) and chronic (28 days) administration. Within each CBD dose group, repeated administration increased total systemic exposure to CBD 1.6- to 3.3-fold. The 24-hour trough plasma CBD concentrations were also dose dependent, with a steady state reached following 2 weeks of administration. CONCLUSIONS AND CLINICAL RELEVANCE: Repeated, daily oral administration of the CBD formulation led to dose-dependent increases in total systemic exposure to CBD and 24-hour trough plasma concentrations in healthy dogs. These findings could help guide dose selection.

Safety and tolerability of escalating cannabinoid doses in healthy cats.

OBJECTIVES: The aim of this study was to determine the safety and tolerability of escalating doses of orally delivered cannabis oils predominant in cannabidiol (CBD), tetrahydrocannabinol (THC), or both CBD and THC in healthy cats. METHODS: In this placebo-controlled, blinded study, 20 healthy adult cats were randomized to one of five treatment groups (n = 4 per group): two placebo groups (sunflower oil [SF] or medium-chain triglyceride oil [MCT]), or three plant-derived cannabinoid oil groups (CBD in MCT, THC in MCT or CBD/THC [1.5:1] in SF). Up to 11 escalating doses of each formulation were delivered orally via syringe to fasted subjects, with at least 3 days separating doses. Safety and tolerability were determined from clinical observations, complete blood counts (CBCs) and clinical chemistry. Plasma cannabinoids (CBD, THC) and metabolites (7-COOH-CBD, 11-OH-THC) were assessed. RESULTS: Titration to maximum doses of 30.5 mg/kg CBD (CBD oil), 41.5 mg/kg THC (THC oil) or 13.0:8.4 mg/kg CBD:THC (CBD/THC oil) was safely achieved in all subjects. All observed adverse events (AEs) were mild, transient and resolved without medical intervention. Gastrointestinal AEs were more common with formulations containing MCT. Constitutional (lethargy, hypothermia), neurologic (ataxia) and ocular (protrusion membrana nictitans) AEs were more common with oils containing THC (CBD/THC and THC oils). There were no clinically significant changes in CBC or clinical chemistry across treatment groups. Higher plasma levels of the cannabinoids and their metabolites following administration of the CBD/THC combination product are suggestive of a pharmacokinetic interaction. CONCLUSIONS AND RELEVANCE: This is the first feline study to explore the safety and tolerability of CBD and THC, alone and in combination, in a controlled research setting. These findings will inform veterinarians of the safety profile of cannabinoids, particularly when considering the potential therapeutic use of CBD in cats or recognizing clinical signs associated with accidental exposure to THC-containing products.

Preliminary Investigation of the Safety of Escalating Cannabinoid Doses in Healthy Dogs.

Objective: To determine the safety and tolerability of escalating doses of three cannabis oil formulations, containing predominantly CBD, THC, or CBD and THC (1.5:1) vs. placebo in dogs. Design: Randomized, placebo-controlled, blinded, parallel study. Animals: Twenty healthy Beagle dogs (10 males, 10 females). Methods: Dogs were randomly assigned to one of five treatment groups (n = 4 dogs per group balanced by sex): CBD-predominant oil, THC-predominant oil, CBD/THC-predominant oil (1.5:1), sunflower oil placebo, medium-chain triglyceride oil placebo. Up to 10 escalating doses of the oils were planned for administration via oral gavage, with at least 3 days separating doses. Clinical observations, physical examinations, complete blood counts, clinical chemistry, and plasma cannabinoids were used to assess safety, tolerability, and the occurrence of adverse events (AEs). AEs were rated as mild, moderate, or severe/medically significant. Results: Dose escalation of the CBD-predominant oil formulation was shown to be as safe as placebo and safer than dose escalation of oils containing THC (CBD/THC oil or THC oil). The placebo oils were delivered up to 10 escalating volumes, the CBD oil up to the tenth dose (640.5 mg; ~62 mg/kg), the THC oil up to the tenth dose (597.6 mg; ~49 mg/kg), and the CBD/THC oil up to the fifth dose (140.8/96.6 mg CBD/THC; ~12 mg/kg CBD + 8 mg/kg THC). AEs were reported in all dogs across the five groups and the majority (94.9%) were mild. Moderate AEs (4.4% of all AEs) and severe/medically significant AEs (0.8% of all AEs) manifested as constitutional (lethargy, hypothermia) or neurological (ataxia) symptoms and mainly occurred across the two groups receiving oils containing THC (CBD/THC oil or THC oil). Conclusions and clinical significance: Overall, dogs tolerated dose escalation of the CBD oil well, experiencing only mild AEs. The favorable safety profile of 10 escalating doses of a CBD oil containing 18.3-640.5 mg CBD per dose (~2-62 mg/kg) provides comparative evidence that, at our investigated doses, a CBD-predominant oil formulation was safer and more tolerated in dogs than oil formulations containing higher concentrations of THC.

Dehydration of risedronate hemi-pentahydrate: analytical and physical characterization.

Dehydration of hydrates of pharmaceutical active ingredients (pharmaceutical hydrates) may easily occur during storage or manufacturing. Loss of water may have little effect on the crystal lattice, produce less hydrated forms or possibly amorphous forms. Characterizing the effects of water loss on crystal hydrate forms is important for understanding the behavior of pharmaceutical hydrates throughout the manufacturing and storage processes. This study shows that exposure of the hemi-pentahydrate form of risedronate monosodium to gentle heating (60 degrees C) or conditions of low relative humidity (<10% RH) results in the loss of 1 mole of channel-type water. Upon removal of the channel-type water, the crystal lattice adjusts producing a distinct phase characterized by X-ray, thermal, IR, Raman, and NMR data. Adjustment of the crystal lattice appears to compromise crystal integrity and can result in reduced crystallite and particle sizes.

Structural and analytical characterization of three hydrates and an anhydrate form of risedronate.

Four hydration states are reported for Risedronate monosodium. A single-crystal X-ray structure determination is provided as proof of assignment for the monohydrate, hemi-pentahydrate, and variable hydrate forms. The structure provided for the anhydrate form was determined through simulating annealing calculations and subsequent Reitveld refinement of a high-quality X-ray powder diffraction patterns Favorable comparisons of experimentally obtained X-ray powder patterns are made to those generated from the single crystal data. Characteristic infrared, Raman, and NMR spectra are provided and discussed for each form as are thermal analysis profiles. In addition, photomicrographs are provided for each of the forms isolated for this study. The hemi-pentahydrate is demonstrated to be the equilibrium form at room temperature and 37 degrees C, in the presence of water.

Double-blind pilot study on the effects of ketoconazole on intradermal skin test and leukotriene C4 concentration in the skin of atopic dogs.

Abstract The effects of ketoconazole on intradermal skin test results and on leukotriene C4 (LTC4 ) concentration in the skin of atopic dogs were evaluated in a pilot study. Twelve atopic dogs without a detectable Malassezia dermatitis were selected. All dogs had positive immedíate reaction to intradermal injection of house dust mite (HDM) at 25 PNU mL-1 . Six dogs received a control sugar tablet and six dogs received ketoconazole at 5 mg kg-1 PO b.i.d. for 3 weeks. On days 0 and 21, intradermal injections of saline, lipopolysaccharide (LPS) and house dust mite (HDM) were performed and biopsies of the injection sites were taken at 90 min postinjection to measure the concentration of LTC4 in the skin. Intradermal skin test results were not affected by ketoconazole therapy. Ketoconazole significantly decreased the concentration of LTC4 that could be elicited by the intradermal injection of saline and LPS. Ketoconazole also decreased the HDM-induced LTC4 but differences between the prevalues and postvalues were not statistically significant. The mean decrease of LTC4 concentration in the ketoconazole group was 37% for the saline injection, 42% for the LPS injection and 26% for HDM injection. In the control group no significant changes in the LTC4 concentrations were found over the 3-week time of the study. This pilot study showed that ketoconazole has anti-inflammatory properties and suggests that this drug may be effective in decreasing the skin concentrations of LTC4 in atopic dogs. Résumé- Les effets de kétoconazole sur les résultats des tests intradermiques et la concentration en leucotriène C4 (LTC4 ) dans la peau de chiens atopiques ont étéévalués dans une étude en double aveugle. Douze chiens atopiques sans dermite à Malassezia ont été selectionnés. Tous les chiens ont des tests intradermiques positifs aux acariens de la poussière de maison à 25 PNU mL-1 à 20 minutes. Six chiens ont reçu des comprimés de sucre, six autres ont reçu du kétoconazole à 5 mg kg-1 , 2 fois par jour par voie orale pendant 3 semaines. Aux jours 0 et 21, des injections intradermiques de liposaccharides (LPS), d'eau salée et d'aeariens de la poussière de maison sont réalisées et des biopsies des points d'injections sont effectuées 90 minutes après l'injection afin de mesurer la concentration en LTC4 dans la peau. Les résultats des tests intradermiques ne sont pas modifies par la thérapeutique au kétoconazole. Par contre, le kétoconazole diminue significativement la concentration en LTC4 induit par les injections intradermiques de LPS et d'eau salee. Le kétoconazole diminue également le LTC4 induit par les acariens de la poussière de maison, mais il n'existe pas de différence significative entre les valeurs avant et après. La diminution moyenne de LTC4 dans le groupe traité au kétoconazole est de 37% pour l'injection intradermique d'eau salée, de 42% pour l'injection intradermique de LPS et de 26% pour l'injection intradermique d'acariens de la poussière de maison. Dans le groupe de contrôle, aucune différence significative dans les concentrations en LTC4 n'est observée durant les 3 semaines de l'étude. Cette étude démontre que le kétoconazole a des propriétés antiinflammatoires et suggèrent qu'il peut être efficace dans la diminution des concentrations en LTC4 chez les chiens atopiques. [Marsella R, Kunkle, GA, Vaughn, DM, Macdonald, J. Double-blind pilot study in the effects of kétoconazole on intradermal skin test and leukotriene C4 concentration in the skin of atopic dogs. (Etude en double aveugle sur les effets du kétoconazole sur les tests intradermiques et la concentration en leucotriène C4 dans la peau de chiens atopiques.) Veterinary Dermatology 1997; 8: 3-10.] Resumen Se evaluaron en un estudio piloto los efectos del ketoconazol sobre los resultados del test intradérmico cutáneo y sobre las concentraciones de leucotrieno C4 (LTC4 ) en la piel de perros atópicos. Se seleccionaron doce perros atópicos sin Dermatitis por Malassezia detectable. Todos los perros mostraban respuesta positiva inmedíata a la inyección del ácaro del polvo doméstico (HDM) a 25 PNU mL-1 . Seis perros recibieron una tableta control de azúcar y seis recibieron ketoconazol a dosis de 5 mg kg-1 PO BID durante 3 semanas. En los días 0 y 21 se realizaron inyecciones intradérmicas de suero salino, lipopolisacárido (LPS) y ácaro del polvo doméstico, y se tomaron biopsias de las zonas inyectadas a los 90 minutos postinyección para cuantificar la concentración de LTC4 en la piel. Los resultados de los tests intradérmicos no se afectaron por la terapia con ketoconazol. El ketoconazol disminuyó significativamente la concentración de LTC4 que pudo haber provocado la inyección intradérmica de suero salino y LPS. El ketoconazol también disminuyó el LTC4 inducido por el HDM pero las diferencias entre los valores previos y posteriores no fueron estadisticamente significativos. La disminución en la concentración medía de LTC4 en el grupo de ketoconazol fue del 37% para la inyección de suero salino, 42% para la de LPS y 26% para la de HDM. En el grupo control no se encontraron alteraciones significativas en las concentraciones de LTC4 durante las 3 semanas que duró el estudio. Este estudio piloto mostró que el ketoconazol posee propiedades antiinflamatorias y sugiere que este fármaco puede ser efectivo en disminuir las concentraciones cutáneas de LTC4 en perros atópicos. [Marsella R, Kunkle, GA, Vaughn, DM, Macdonald, J. Double-blind pilot study in the effects of ketoconazole on intradermal skin test and leukotriene C4 concentration in the skin of atopic dogs. (Estudio doble ciego sobre los efectos del ketoconazol en los tests intradérmicos cutaneos y en la concentración de leucotrieno C4 en la piel de perros atópicos.) Veterinary Dermatology 1997; 8: 3-10.] Zusammenfasung In einer Pilotstudie wurden die Wirkung von Ketoconazol auf Ergebnisse des intrakutanen Hauttests und der Leukotrien C4 (LTC4 )-Konzentration in der Haut atopischer Hunde bewertet. Zwölf atopische Hunde ohne feststellbare Malassezia Dermatitis wurden ausgewählt. Alle Hunde hatten eine positive Sofortreaktion zu Hausstaubmilbenextrakt von 25 PNU mL-1 . Sechs Hunde erhielten eine Zuckertablette als Kontrolle und sechs Hunde erhielten Ketoconazol in einer Dosis von 5 mg kg-1 oral zweimal täglich für drei Wochen. An den Tagen 0 und 21 wurden intrakutane Injektionen von physiologischer Kochsalzlösung, Lipopolysaccharid (LPS) und Hausstaubmilbenextrakt durchgeführt und 90 Minuten danach Biopsien an den Injektionsstellen entnommen, um die Konzentration von LTC4 in der Haut zu messen. Ketoconazoltherapie hatte keinen Einfluss auf die Ergebnisse des Intrakutantests. Ketoconazol verminderte die LTC4 Konzentration in den intrakutanen Injektionsstellen von physiologischer Kochsalzlösung und LPS. Die Konzentrationen des von Hausstaubmilbenextrakt-induzierten LTC4 waren ebenfalls vermindert, die Unterschiede zwischen den Werten vor und nach der Injektion waren jedoch nicht statistisch significan. Die durchschnittliche Verminderung der LTC4 Konzentration in der Ketoconazol-Gruppe betrug 37% für die Injektion mit Kochsalzlösung, 42% für die Injektion mit LPS und 26% für die Injektion mit Hausstaubmilbenextrakt. In der Kontrollgrupe wurden während der dreiwöchigen Studie keine signifikanten Veränderungen in der LTC4 Konzentration festgestellt. Diese Pilotstudie zeigt die entzündungshemmende Wirkung von Ketoconazol und deutet darauf hin, daß dieses Medikament geeignet sein könnte, die Hautkonzentration von LTC4 in atopischen Hunden zu verringern. [Marsella R, Kunkle, GA, Vaughn, DM, Macdonald, J. Double-blind pilot study in the effects of ketoconazole on intradermal skin test and leukotriene C4 concentration in the skin of atopic dogs. (Doppelblind-Pilotstudie über die Wirkung von Ketoconazol auf den intrakutanen Hauttest und die Konzentration von Leukotrien C4 in der Haut atopischer Hunde.) Veterinary Dermatology 1997; 8: 3-10.].

Biochemical and histopathological evaluation of changes in sled dog paw skin associated with physical stress and cold temperatures.

Abstract Twenty-six Alaskan sled dogs were used to study the biochemical and histopathological changes which occur when dog paws are exposed to cold temperatures and physical stress. They were separated into a running group of 20 dogs and a control group of six non-running dogs. Over 2 1/2 days, the running group ran in their natural environment for 170 miles and environmental parameters were recorded. Following the run, an 8-mm díameter skin biopsy specimen was taken from the lateral aspect of the right fore and hind paws of the running and non-running dogs. The skin was evaluated for histopathological changes and the présence of 2, 3-dinor thromboxane B2 (2, 3-dinor TxB2 ). No significant histopathological changes were noted in any of the biopsy specimens. Based on measured elevation of 2, 3-dinor TxB2 , the forepaws experienced more physical stress than the hind paws. Wet snow at higher environmental temperatures caused more paw stress than hard crusted snow at lower environmental temperatures. Resumen Se emplearon veintiséis perros trineo de Alaska para estudiar las alteraciones bioquimicas e histopatológicas ocurridas durante la exposición de las patas a las bajas temperaturas y al estrés fisico. Se dividieron entre un grupo de 20 perros corredores y un grupo control de seis perros no corredores. Durante dos días y medio el grupo de corredores corrió en su ambiente natural 170 millas. Durante la carrera se tomó una biopsia por punch de 8 mm del aspecto lateral de la pata derecha delantera y trasera de los perros corredores y no corredores. Se evaluaron las alteraciones histopatológicas cutáneas y la presencia de tromboxano B2 2, 3-dinor (2, 3-dinor TxB2 ). No se observaron alteraciones histopatológicas significativas en ninguna de las muestras de biopsia. Según la elevación detectada en 2.3-dinor TxB2 , las patas delanteras sufrieron un estrés fisico mayor que las traseras. La nieve húmeda en temperaturas ambientales elevadas causó un estrés mayor que la nieve dura en temperaturas ambientales más bajas. [Bradley, D.M., Swaim, S.F., Vaughn, D.M., Powers, R.D., McGuire, J.A., Reinhart, G.A., Burr, J., Swenson, R.A. Biochemical and histopathological evaluation of changes in sled dog paw skin associated with physical stress and cold temperatures. (Estudio bioquimico e histopatologico de las alteraciones en las patas de perros de trineo asociadas al estrés fisico y por las bajas temperaturas). Veterinary Dermatology 1996; 7: 203-208.] Résumé Vingt six chiens de traineau de l'Alaska fürent utilisés dans une étude évaluant les modifications biochimiques et histologiques survenant lorsque les pattes sont exposées à des températures froides et des stress physiques. lls fürent divisés en un groupe de vingt chiens de course et un groupe de six chiens ne courant pas. Après deux jours et demi, le groupe de course avait parcouru 170 miles dans son environnement naturel, dont les paramètres fürent enregistrés. Après la course, des biopsies de 8 mm de díamètre fürent prises sur les faces latérales des pattes antérieure et postérieure droites des chiens d'attelage et de ceux qui étaient restés au repos. L'évaluation de l'état cutané s'est faite sur les modifications histologiques et la présence de 2, 3-dinor thromboxane B2 (2, 3-dinor TxB2 ). Aucune modification histologique significative n'a été notée dans aucune des biopsies réalisées. Jugé sur l'élévation du 2, 3 TxB2 , les pattes antérieures subissent un stress physique supérieur aux pattes postérieures. La neige humide à temperatures plus élevées cause plus d'agression que la neige dure et crouteuse à des températures plus basses. [Bradley, D.M., Swaim, S.F., Vaughn, D.M., Powers, R.D., McGuire, J.A., Reinhart, G.A., Burr, J., Swenson, R.A. Biochemical and histopathological evaluation of changes in sled dog paw skin associated with physical stress and cold temperatures. (Evaluation des modifications biochimiques et histologiques induites par les stress physiques et le froid au niveau de la peau des pattes de chiens de traineau). Veterinary Dermatology 1996; 7: 203-208.] Zusammenfassung Sechsundzwanzig Alaska-Schlittenhunde wurde für eine Studie über biochemische und histopathologische Veränderungen herangezogen, die an den Pfotenballen auftreten, wenn sie kalten Temperaturen und physischem Streß ausgesetzt sind. Die Hunde wurden in eine Renngruppe von 20 Hunden und eine Kontrollgruppe von sechs Nicht-Rennhunden eingeteilt. Über einen Zeitraum von zweieinhalb Tagen rannte die Renngruppe in lhrer natürlichen Umgebung 170 Mellen, wobei die Umgebungsparamenter aufgezeichnet wurden. Nach dem Rennen wurden Biopsien mit einem Durchmesser von 8 mm von der Lateralseite der rechten Vorder-und Hinterpfote bei den Renn-und Nichtrennhunden entnommen. Die Haut wurde auf histopathologische Veränderungen und die Anwesenheit von 2, 3-dinor-Thromboxan BA (2, 3-dinor TxB2 ) untersucht. Es wurden keine signifikanten histopathologischen Veränderungen bei einer der Biopsien festgestellt. Auf der Basis der gemessenen Erhöhung von 2, 3-dinor TxB2 erfuhren die Vorderpfoten mehr physischen Streß als die Hinterpfoten. Nasser Schnee und höhere Umgebungstemperaturen verursachten mehr Pfotenstreß als harter, verkrusteter Schnee bei niedrigeren Umgebungstemperaturen. [Bradley, D.M., Swaim, S.F., Vaughn, D.M., Powers, R.D., McGuire, J.A., Reinhart, G.A., Burr, J., Swenson, R.A. Biochemical and histopathological evaluation of changes in sled dog paw skin associated with physical stress and cold temperatures (Biochemische und histopathologische Untersuchung von Hautveränderungen an den Pfoten von Schlittenhunden in Verbindung mit physischem Streß und Kälte). Veterinary Dermatology 1996; 7: 203-208.].

Evaluation of Effects of Dietary n-6 to n-3 Fatty Acid Ratios on Leukotriene B Synthesis in Dog Skin and Neutrophils.

Résumé- Les effets d'alimentations supplémentées avec des ratios croissants decides gras polyinsaturés n - 6/n - 3 sur la synthèse de leucotriènes B dans la peau du chien et les neutrophiles sont présentés. Trente chien Beagles ont reçu pendant 2 mois avec une alimentation ayant un ratio n -6/n -3 de 28:1. Des aliments expérimentaux contenant des ratios de 5:1, 10:1, 25:1, 50:1 et 100:1 (six chiens par groupe) ont été administrés ensuite pendant 12 semaines. A la fin des deux mois d'alimentation témoin et au bout de 6 et 12 semaines d'alimentation expérimentale, les concentrations de LTB4 et LTB5 dans la peau et les neutrophiles ont été déterminées. Les neutrophiles de chiens ayant mangé des aliments de ratio 5:1 et 10:1 ont synthétisé 30-33 pourcent moins de LTB4 (P <0,05) et 370-500 pourcent plus de LTB5 (P <0,05) à 6 et 12 semaines, mais le relargage d'anions superoxide était inchangé. La peau des chiens stimulée par un lipopolysaccharide a synthétisé 48 à 62 pourcent moins de LTB4 (P < 0,05) et 48 à 79 pourcent moins de LTB5 (P <0,05) à 12 semaines. [Vaughan, D. M., Reinhart, G. A., Swaim, S. F., Lauten, S. D., Garner, C. A., Boudreaux, M. K., Spano, J. S., Hoffman, C. E., Conner, B. Evaluation of effects of dietary n -6 to n - 3 fatty acid ratios on leukotriéne B synthesis in dog skin and neutrophils. (Evaluation de l'effet du ratio d'acides gras n - 6/n - 3 dans l'alimentation sur la synthèse de leucotriènes B dans la peau du chien et les neutrophiles). Resumen- Evaluamos los efectos producidos por el aumento en la proportion de ácidos grasos poli-insatu-rados n-6 a n-3 en la dieta sobre la sintesis de leucotrienos B en la piel del perro y en los neutrófilos. Se administró durante dos meses una dieta con una proporión 28:1 de ácidos grasos n-6 a n-3 a un grupo de treinta Beagles. Se administraron dietas experimentales con proporciones de 5:1, 10:1, 25:1, 50:1 y 100:1 durante 12 semanas (seis perros por grupo). Se cuantificaron los niveles de leucotrienos B4 y B5 en la piel y en los neutrófilos al final de los dos meses de dieta control y a las 6 y 12 semanas de la dieta-tratamiento. Los neutrófilos de perros con dietas 5:1 y 10:1 sintetizaron 30 a 33% menos leucotrieno B4 (P < 0.05) y 370 a 500% más leucotrieno B5 (P <0.05) a las 6 y 12 semanas pero no alteraron la liberación de aniones superóxido durante la espiracion. La piel de perro estimulada con lipopolisacáridos sintetizó de 48 a 62% menos leucotrieno B4 (P < 0.05) y 48 a 79% más leucotrieno B5 (P < 0.05) a las 12 semanas. [Evaluation of effects of dietary n-6 to n-3 fatty acid ratios on leukotriene B synthesis in dog skin and neutrophils (Effecto de la proporción de ácidos grasos n-6 a n-3 en la dieta sobre la sintesis de leucotrienos B en la piel del perro y en los neutrófilos). Abstract- The effects of diets supplemented with increasing ratios of n-6 to n-3 polyunsaturated fatty acids on leukotriene B synthesis in dog skin and neutrophils were evaluated. Thirty Beagles were conditioned for 2 months on a diet with an n-6 to n-3 fatty acid ratio of 28:1. Experimental diets, containing n-6 to n-3 ratios of 5:1, 10:1, 25:1, 50:1 and 100:1 (six dogs/group), were fed for 12 weeks. At the end of the 2 month control diet period, and again at 6 and 12 weeks of treatment feeding, leukotriene B4 and leukotriene B5 were quantitated in skin and neutrophils. Neutrophils from dogs fed the 5:1 and 10:1 diets synthesized 30-33 per cent less leukotriene B4 (P < 0.05) and 370-500 per cent greater leukotriene B5 (P < 0.05) at 6 and 12 weeks, but had no change in the release of superoxide anions during respiratory burst. Lipopolysaccharide-stimu-lated dog skin synthesized 48-62 per cent less leukotriene B4 (P < 0.05) and 48-79 per cent more leukotriene B5 (P <0.05) at 12 weeks.