Desmopressin in canine mammary carcinoma: Comments on the importance of the administration route

Several years ago, we proposed the haemostatic peptide desmopressin (1-desamino-8-d-arginine vasopressin; dDAVP) as a potential anti-metastatic agent to be used during surgical excision of locally advanced tumours. A prospective randomized study in 28 intact dogs with mammary carcinomas receiving perioperative intravenous dDAVP infusions (1 μg/kg) demonstrated a significant survival benefit in dogs with moderately (grade 2) or poorly differentiated (grade 3) tumours.1 dDAVP is known to exert anti-proliferative and anti-angiogenic effects in laboratory models, by acting on AVPR2 vasopressin receptors present in tumour and endothelial cells. Moreover, dDAVP can induce the release of von Willebrand factor (VWF) from microvascular endothelium into blood circulation. Beyond its critical function in primary haemostasis, VWF plays a protective role against metastatic dissemination. An abrupt increase in VWF blood levels is able to interfere with the arrest of circulating cancer cells at target organs and also to induce apoptosis in micrometastatic foci.2 The article entitled “A prospective randomized trial of desmopressin in canine mammary carcinoma” recently published in Veterinary and Comparative Oncology by Sorenmo et al retested dDAVP as a surgical adjuvant in 24 dogs with mammary carcinomas.3 They reported that few dogs developed metastatic disease in this study, and no significant benefit of perioperative dDAVP administration was observed. We completely agree with the authors in the sense that subgroup comparisons between the high-risk subgroups were very underpowered, since none of the dogs with grade 2 tumours developed metastasis and only one dog with a grade 3 tumour was randomized to receive dDAVP.3 More to the point, all intact dogs underwent ovariohysterectomy as part of their treatment in this study, thus reducing the risk of metastasis and possibly diminishing the impact of perioperative dDAVP on survival. However, it is important to note that Sorenmo et al used a nasal spray formulation of dDAVP administered by the subcutaneous route,3 instead of an intravenous infusion as in our previous study.1 Even though subcutaneous administration is the standard of care in bleeding disorders, it was clearly demonstrated that dDAVP is ineffective by the subcutaneous route in experimental metastasis assays in mice. A clear dose-dependent anti-metastatic action was observed by using the intravenous injection (dDAVP doses ranging from 0.3 to 2 μg/kg), while no significant effects were obtained with similar doses by the subcutaneous route.4 Although a haemostatic factor such as VWF is involved, anti-metastatic effects of dDAVP are not directly associated with the coagulation process.4 VWF is a multifunctional protein and its role in resistance to metastasis is independent of its role in haemostasis,2 probably requiring the rapid peak concentrations associated with high intravenous doses to favour the elimination of early metastatic cells. Finally, we agree with the authors in that a prospective randomized trial in dogs bearing grade 3 mammary tumours should be conducted with the aim of resolving discrepancies between studies. However, in order to confirm the therapeutic benefits of perioperative dDAVP, compound should always be administered using the intravenous route. In this setting, maintenance therapy based on additional postoperative doses of dDAVP, or its synthetic analog with enhanced cytostatic activity [V4Q5]dDAVP,5 could be used to consolidate the effect against dormant metastasis or disseminated tumour cells.Fil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Turic, Esteban. Biogénesis Bagó; ArgentinaFil: Garona, Juan. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Effects of Copper and Zinc Supplementation on Weight Gain and Hematological Parameters in Pre-weaning Calves

Cow-calf operations may be affected by trace mineral deficiencies, particularly copper (Cu) and zinc (Zn) deficiency, which may decrease the calf daily weight gain and alter hematological parameters. We evaluated the effect of Cu and Zn supplementation on pre-weaning calves (n = 40; 92 ± 6 kg initial body weight) from the Salado River basin, Buenos Aires, Argentina. Calves were divided into four groups (n = 10 each) and subcutaneously administered 0.3 mg/kg Cu (Cu group), 1 mg/kg Zn (Zn group), Cu and Zn together (Cu + Zn group), and sterile saline solution (control group) every 40 days for 120 days. Plasma Cu and Zn concentrations, hematological parameters, and weight were recorded every 40 days. A completely randomized 2 × 2 factorial treatment design was used and data were analyzed with a mixed model for repeated measures over time. Cu and Zn were detected in plasma after the second sampling. Cu × Zn interaction was significant (p = 0.09), being Cu concentration higher in the Cu + Zn than in the Cu group. Differences in weight gain (Zn × time interaction; p   0.1). On the other hand, none of the treatments altered any of the hematological parameters assessed (p > 0.1). Our results show the risk of lower weight gain due to Zn deficiency in pre-weaning calves raised in the Salado River basin.Facultad de Ciencias Veterinaria

Effects of parenteral supplementation with minerals and vitamins on oxidative stress and humoral immune response of weaning calves

We aimed to evaluate the effects of injectable mineral and vitamin supplementation on weaning calves subjected to a low-stress (fence-line) weaning system. Seven-month-old Aberdeen Angus female calves (n = 40, 152 ± 11 kg body weight) from a selenium-deficient area of extensive cattle production on natural grass were randomly assigned to two groups (n = 20 each). One group received subcutaneous supplementation with copper, zinc, selenium, manganese and vitamins A and E (SG), and the other was given sterile saline solution (CG). The animals were supplemented twice, seven days before weaning (day −7) and on the day of weaning (day 0), and they were evaluated 30 (+30) and 60 (+60) days after weaning. Total antioxidant status (TAS), selenium-dependent glutathione peroxidase (GPx) activity, body weight, and average daily gain (ADG) were evaluated. Additionally, antibody titers were assessed prior to and after each immunization with a vaccine containing bovine herpes virus type 1 (BoHV-1). On day +30, body weight (p = 0.03) was higher in SG, whereas TAS (p = 0.02) and GPx (p = 0.0038) activity were lower in CG and remained constant in SG. Antibody titers increased in SG and CG following immunization, being higher in SG on days +30 and +60 (p < 0.05). In conclusion, parenteral supplementation of minerals and vitamins with antioxidant effects in a low-stress weaning system prevented the decrease in TAS and GPx activity, improved antibody response and had positive effects on body weight.Fil: Mattioli, Guillermo Alberto. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Departamento de Ciencias Básicas. Laboratorio de Nutrición Mineral y Fisiología Reproductiva; ArgentinaFil: Rosa, Diana Esther. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Departamento de Ciencias Básicas. Laboratorio de Nutrición Mineral y Fisiología Reproductiva; ArgentinaFil: Turic, Esteban. Biogénesis Bagó; ArgentinaFil: Picco, Sebastian Julio. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Departamento de Ciencias Básicas. Laboratorio de Nutrición Mineral y Fisiología Reproductiva; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET- La Plata. Instituto de Genética Veterinaria "Ing. Fernando Noel Dulout". Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Instituto de Genética Veterinaria; ArgentinaFil: Raggio, Santiago José. Biogénesis Bagó; ArgentinaFil: Hamad Minervino, Antonio Humberto. Universidade Federal do Oeste do Pará; BrasilFil: Fazzio, Luis Emilio. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Departamento de Ciencias Básicas. Laboratorio de Nutrición Mineral y Fisiología Reproductiva; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Departamento de Patología. Cátedra de Patología Especial Veterinaria; Argentin

Effect of Injectable Copper and Zinc Supplementation on Weight, Hematological Parameters, and Immune Response in Pre-weaning Beef Calves

Copper (Cu) and zinc (Zn) deficiency may cause poor weight gain, hematological changes, and immune failure in extensive beef cattle breeding systems. Diagnosis of the deficiency is based on plasma Cu and Zn concentrations; however, there are discrepancies regarding data interpretation. Here, plasma Cu and Zn concentrations are discussed as risk markers. We evaluated the effect of parenteral Cu and Zn supplementation on their plasma concentrations, weight gain, hematological parameters, and antibody titers to bovine herpes virus 1 (BoHV-1). Pre-weaning calves (n = 40; 99 ± 8 kg bw) from a typical breeding area of Argentina with background Cu and Zn deficiency were used. They were assigned to two homogeneous groups in a completely randomized design. Calves were subcutaneously injected with 0.3 mg/kg Cu and 1 mg/kg Zn (supplemented group), or saline solution (control), every 40 days during 120 days. Plasma Cu and Zn concentrations, hematological parameters, and weight were recorded. On days 40 and 80 of the trial, calves were vaccinated with inactivated BoHV-1. Antibody immune response was measured on days 80 and 120. Data were analyzed with a mixed model for repeated measures over time. Before treatment, plasma Cu was low and Zn was adequate in both groups. After treatment, plasma Cu increased and remained within a normal range, whereas plasma Zn remained constant. Supplemented animals had higher weight gain (p < 0.01); higher hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin levels (p < 0.05); and higher immune response to BoHV-1 (p < 0.05). Our results suggest that Cu and Zn supplementation improved daily weight gain and the immune response of pre-weaning calves.Facultad de Ciencias Veterinaria

Safety and pharmacokinetic assessments of a novel ivermectin nasal spray formulation in a pig model

Recently published data indicates that high ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray administration may contribute to attaining high drug concentrations in nasopharyngeal tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performances of a novel IVM spray formulation were assessed in a pig model. Piglets received IVM either orally (0.2 mg/kg) or by one or two nasal spray doses. The overall safety, and histopathology of the IVM-spray application site tissues, were assessed. The IVM concentration profiles measured in plasma and respiratory tract tissues after the nasal spray were compared with those achieved after the oral administration. Animals tolerated well the nasal spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in nasopharyngeal and lung tissues. The nasal/oral IVM concentration ratios in nasopharyngeal and lung tissues markedly increased by repeating (12 h apart) the spray application. The fast attainment of high and persistent IVM concentrations in nasopharyngeal tissue is the main advantage of the nasal over the oral route. These original results support the undertaking of future clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the prevention and/or treatment of COVID-19.Fil: Errecalde, Jorge Oscar. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina. INCAM S.A; ArgentinaFil: Lifschitz, Adrian Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Vecchioli, Graciela Isabel. INCAM S.A; ArgentinaFil: Ceballos, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Errecalde, Francisco. INCAM S.A; ArgentinaFil: Ballent, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Marin, Gustavo Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; ArgentinaFil: Daniele, Martin Rafael. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Departamento de Ciencias Básicas. Cátedra de Farmacología, Farmacotecnia y Terapéutica; ArgentinaFil: Turic, Esteban. Biogenesis Bago S.a..; ArgentinaFil: Spitzer, Eduardo. Laboratorio Elea Phoenix S.a.; ArgentinaFil: Toneguzzo, Fernando. Laboratorio Elea Phoenix S.a.; ArgentinaFil: Gold, Silvia. Laboratorio Elea Phoenix S.a.; ArgentinaFil: Krolewiecki, Alejandro Javier. Universidad Nacional de Salta; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alvarez, Luis Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentin

Ivermectin repurposing for COVID-19 therapy: Safety and pharmacokinetic assessment of a novel nasal spray formulation in a pig model

High ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray (N-IVM-spray) administration may contribute to attaining high drug concentrations in nasopharyngeal (NP) tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performance of a new N-IVM spray formulation in a piglet model were assessed. Crossbred piglets (10–12 kg) were treated with either one or two (12 h apart) doses of N-IVM-spray (2 mg, 1 puff/nostril) or orally (0.2 mg/kg). The overall safety of N-IVM-spray was assessed (clinical, haematological, serum biochemical determinations), and histopathology evaluation of the application site tissues performed. The IVM concentration profiles measured in plasma and respiratory tract tissues (nasopharynx and lungs) after the nasal spray treatment (one and two applications) were compared with those achieved after the oral administration. Animals tolerated well the novel N–IVM-spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in NP and lung tissues. Significant increases in IVM concentration profiles in both NP-tissue and lungs were observed after the 2-dose nasal administrations. The nasal/oral IVM concentration ratios in NP and lung tissues (at 6 h post-dose) markedely increased by repeating the spray application. The fast attainment of high and persistent IVM concentrations in NP tissue is the main advantage of the nasal over the oral route. These original results are encouraging to support the undertaking of further clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the treatment and/or prevention of COVID-19.Facultad de Ciencias MédicasFacultad de Ciencias VeterinariasComisión de Investigaciones Científicas de la provincia de Buenos Aire

Pharmacokinetic of Azithromycin in Holstein Lactating Cows

El prototipo de una clase de antibióticos conocido como macrólidos fue introducido en 1952 con el nombre eritromicina. La azitromicina (AZI) es un compuesto semisintético en el cual se ha expandido el anillo lactónico de la eritromicina para formar un compuesto con una estructura anular de 15 miembros que posee en humanos una mayor tolerancia gástrica, mejor perfil farmacocinético, acumulación en células inflamatorias y un espectro de actividad mayor. Estas características hacen pensar que la azitromicina pueda tener un futuro promisorio en medicina veterinaria para ciertas infecciones del bovino como las producidas en la glándula mamaria. El objetivo de este trabajo consistió en estudiar el comportamiento farmacocinético de AZI en sangre y leche luego de administración por diferentes vías y en vacas lecheras sanas y con mastitis. Las concentraciones en sangre y leche fueron determinadas por método microbiológico y analizadas por el modelo farmacocinético descriptivo no compartimental. El comportamiento observado luego de administración por cualquiera de las vías analizadas fue típico de los macrólidos con bajas concentraciones en plasma y concentraciones muy altas en leche y tejidos blandos; un gran volumen de distribución y una prolongada fase de eliminación tanto en leche como en sangre. El hecho de que AZI tiende a acumularse en células inflamatorias, ha tenido incidencia cinética en los resultados obtenidos tras su administración, especialmente en la administración intramamaria. Dado su comportamiento farmacocinético estudiado y descripto en este trabajo AZI demostró ser una interesante herramienta potencial para las infecciones de los tejidos blandos el bovino, aunque esto debería ser complementado con estudios de eficacia.The prototype of the macrolide class of antibiotics was introduced in 1952 under the name of Erythromycin. Azithromycin (AZI) is a semisynthetic compound in which the lactone ring has been expanded to a 15-member structure and is considered the prototype of new macrolide structures identified as azalides. In human medicine, azithromycin has an improved pharmacokinetic profile, shows an expanded/enhanced antimicrobial spectrum over erythromycin, and the incidence of gastrointestinal-related effects are significantly lower, providing a useful alternative to erythromycin. In veterinary medicine AZI could possess advantages for the treatment of certain bovine infections such as those produced in the mammary gland. The objective of this paper was to study its pharmacokinetic behavior in blood and milk following administration by different routes, both in healthy cows and with mastitis. The blood and milk concentrations were determined by the microbiological method and analyzed using a non-compartmental pharmacokinetic descriptive model. The results observed after its administration by any of the analyzed routes was typical of the macrolides, with low plasma concentrations and very high maximum concentrations (Cmax) in milk and soft tissues; a great volume of distribution and a prolonged terminal half-life both in blood and milk. The fact that AZI tends to accumulate in inflammatory cells, has a kinetic incidence in the results, especially after intramammary administration. Due to the described pharmacokinetic behavior, AZI proved to be an interesting tool with a potential for infections in the soft tissues of the cow, although this should be backed by efficacy trials.Facultad de Ciencias Veterinaria

Pharmacokinetic of Azithromycin in Holstein Lactating Cows

El prototipo de una clase de antibióticos conocido como macrólidos fue introducido en 1952 con el nombre eritromicina. La azitromicina (AZI) es un compuesto semisintético en el cual se ha expandido el anillo lactónico de la eritromicina para formar un compuesto con una estructura anular de 15 miembros que posee en humanos una mayor tolerancia gástrica, mejor perfil farmacocinético, acumulación en células inflamatorias y un espectro de actividad mayor. Estas características hacen pensar que la azitromicina pueda tener un futuro promisorio en medicina veterinaria para ciertas infecciones del bovino como las producidas en la glándula mamaria. El objetivo de este trabajo consistió en estudiar el comportamiento farmacocinético de AZI en sangre y leche luego de administración por diferentes vías y en vacas lecheras sanas y con mastitis. Las concentraciones en sangre y leche fueron determinadas por método microbiológico y analizadas por el modelo farmacocinético descriptivo no compartimental. El comportamiento observado luego de administración por cualquiera de las vías analizadas fue típico de los macrólidos con bajas concentraciones en plasma y concentraciones muy altas en leche y tejidos blandos; un gran volumen de distribución y una prolongada fase de eliminación tanto en leche como en sangre. El hecho de que AZI tiende a acumularse en células inflamatorias, ha tenido incidencia cinética en los resultados obtenidos tras su administración, especialmente en la administración intramamaria. Dado su comportamiento farmacocinético estudiado y descripto en este trabajo AZI demostró ser una interesante herramienta potencial para las infecciones de los tejidos blandos el bovino, aunque esto debería ser complementado con estudios de eficacia.The prototype of the macrolide class of antibiotics was introduced in 1952 under the name of Erythromycin. Azithromycin (AZI) is a semisynthetic compound in which the lactone ring has been expanded to a 15-member structure and is considered the prototype of new macrolide structures identified as azalides. In human medicine, azithromycin has an improved pharmacokinetic profile, shows an expanded/enhanced antimicrobial spectrum over erythromycin, and the incidence of gastrointestinal-related effects are significantly lower, providing a useful alternative to erythromycin. In veterinary medicine AZI could possess advantages for the treatment of certain bovine infections such as those produced in the mammary gland. The objective of this paper was to study its pharmacokinetic behavior in blood and milk following administration by different routes, both in healthy cows and with mastitis. The blood and milk concentrations were determined by the microbiological method and analyzed using a non-compartmental pharmacokinetic descriptive model. The results observed after its administration by any of the analyzed routes was typical of the macrolides, with low plasma concentrations and very high maximum concentrations (Cmax) in milk and soft tissues; a great volume of distribution and a prolonged terminal half-life both in blood and milk. The fact that AZI tends to accumulate in inflammatory cells, has a kinetic incidence in the results, especially after intramammary administration. Due to the described pharmacokinetic behavior, AZI proved to be an interesting tool with a potential for infections in the soft tissues of the cow, although this should be backed by efficacy trials.Facultad de Ciencias Veterinaria

Desmopressin in canine mammary carcinoma: Comments on the importance of the administration route

Several years ago, we proposed the haemostatic peptide desmopressin (1-desamino-8-d-arginine vasopressin; dDAVP) as a potential anti-metastatic agent to be used during surgical excision of locally advanced tumours. A prospective randomized study in 28 intact dogs with mammary carcinomas receiving perioperative intravenous dDAVP infusions (1 μg/kg) demonstrated a significant survival benefit in dogs with moderately (grade 2) or poorly differentiated (grade 3) tumours.1 dDAVP is known to exert anti-proliferative and anti-angiogenic effects in laboratory models, by acting on AVPR2 vasopressin receptors present in tumour and endothelial cells. Moreover, dDAVP can induce the release of von Willebrand factor (VWF) from microvascular endothelium into blood circulation. Beyond its critical function in primary haemostasis, VWF plays a protective role against metastatic dissemination. An abrupt increase in VWF blood levels is able to interfere with the arrest of circulating cancer cells at target organs and also to induce apoptosis in micrometastatic foci.2 The article entitled “A prospective randomized trial of desmopressin in canine mammary carcinoma” recently published in Veterinary and Comparative Oncology by Sorenmo et al retested dDAVP as a surgical adjuvant in 24 dogs with mammary carcinomas.3 They reported that few dogs developed metastatic disease in this study, and no significant benefit of perioperative dDAVP administration was observed. We completely agree with the authors in the sense that subgroup comparisons between the high-risk subgroups were very underpowered, since none of the dogs with grade 2 tumours developed metastasis and only one dog with a grade 3 tumour was randomized to receive dDAVP.3 More to the point, all intact dogs underwent ovariohysterectomy as part of their treatment in this study, thus reducing the risk of metastasis and possibly diminishing the impact of perioperative dDAVP on survival. However, it is important to note that Sorenmo et al used a nasal spray formulation of dDAVP administered by the subcutaneous route,3 instead of an intravenous infusion as in our previous study.1 Even though subcutaneous administration is the standard of care in bleeding disorders, it was clearly demonstrated that dDAVP is ineffective by the subcutaneous route in experimental metastasis assays in mice. A clear dose-dependent anti-metastatic action was observed by using the intravenous injection (dDAVP doses ranging from 0.3 to 2 μg/kg), while no significant effects were obtained with similar doses by the subcutaneous route.4 Although a haemostatic factor such as VWF is involved, anti-metastatic effects of dDAVP are not directly associated with the coagulation process.4 VWF is a multifunctional protein and its role in resistance to metastasis is independent of its role in haemostasis,2 probably requiring the rapid peak concentrations associated with high intravenous doses to favour the elimination of early metastatic cells. Finally, we agree with the authors in that a prospective randomized trial in dogs bearing grade 3 mammary tumours should be conducted with the aim of resolving discrepancies between studies. However, in order to confirm the therapeutic benefits of perioperative dDAVP, compound should always be administered using the intravenous route. In this setting, maintenance therapy based on additional postoperative doses of dDAVP, or its synthetic analog with enhanced cytostatic activity [V4Q5]dDAVP,5 could be used to consolidate the effect against dormant metastasis or disseminated tumour cells.Fil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Turic, Esteban. Biogénesis Bagó; ArgentinaFil: Garona, Juan. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin