Cannabinoids CB2 Receptors, One New Promising Drug Target for Chronic and Degenerative Pain Conditions in Equine Veterinary Patients.

Osteoarticular equine disease is a common cause of malady; in general, its therapy is supported on steroids and nonsteroidal anti-inflammatories. Nevertheless, many side effects may develop when these drugs are administered. Nowadays, the use of new alternatives for this pathology attention is demanded; in that sense, cannabinoid CB2 agonists may represent a novel alternative. Cannabinoid belongs to a group of molecules known by their psychoactive properties; they are synthetized by the Cannabis sativa plant, better known as marijuana. The aim of this study was to contribute to understand the pharmacology of cannabinoid CB2 receptors and its potential utilization on equine veterinary patients with a chronic degenerative painful condition. In animals, two main receptors for cannabinoids are recognized, the cannabinoid receptor type 1 and the cannabinoid receptor type 2. Once they are activated, both receptors exert a wide range of physiological responses, as nociception modulation. Recently, it has been proposed the use of synthetic cannabinoid type 2 receptor agonists; those receptors looks to confer antinociceptive properties but without the undesired psychoactive side effects; for that reason, veterinary patients, whit chronical degenerative diseases as osteoarthritis may alleviate one of the most common symptom, the pain, which in some cases for several reasons, as patient individualities, or side effects produced for more conventional treatments cannot be attended in the best way.

Visceral branches of the abdominal aorta in the New Zealand rabbit: ten different patterns / Ramas viscerales de la aorta abdominal en el conejo neozelandés: diez patrones de presentación

The abdominal aorta of the rabbit has been in the focus of research to develop new platforms of training diagnostic and therapeutic protocols; and for testing endovascular devices and materials, however, few descriptions of the anatomy of the abdominal aorta and its emerging visceral branches has been reported on the scientific literature for this specie. Anatomical variations are common and should have in mind during research and clinical trials. The aim of this study was to describe the different patterns that can occur in the visceral branches arising from the abdominal aorta in the rabbit.

La aorta abdominal del conejo ha sido objeto de estudio e investigación para desarrollar nuevas plataformas de entrenamiento para protocolos diagnósticos y terapéuticos así como para probar las virtudes de materiales y equipos endovasculares, sin embargo, existen muy pocas descripciones en la literatura de las ramas viscerales que emergen de la aorta abdominal en esta especie. Las variaciones anatómicas son eventos de ocurrencia común y por lo tanto deben ser considerados para realizar investigación y ensayos clínicos. El objetivo del presente estudio ha sido describir los diferentes patrones que pueden presentar las ramas viscerales que emergen de la aorta abdominal en el conejo.

Modelo virtual tridimensional de la articulación cubital del perro a partir de cortes plastinados ultradelgados / Three-dimensional virtual model of the elbow joint of the dog by means of ultrathin plastinated slices

La articulación cubital del perro es de tipo compuesta, formada por el cóndilo del húmero, la cabeza del radio y la escotadura troclear de la ulna. Esta articulación es propensa a padecer enfermedades del desarrollo, lesiones traumáticas y degenerativas. La corrección de estos padecimientos suele ser quirúrgica, sin embargo, el planteamiento de la cirugía resulta difícil debido a la complejidad estructural de esta articulación. Los modelos anatómicos tridimensionales (3D) obtenidos de los cortes seriados mediante tomografía computarizada han probado ser eficaces en el planteamiento de los abordajes quirúrgicos, sin embargo tiene limitaciones técnicas en la identificación de los tejidos blandos. Los cortes ultradelgados (1 mm) obtenidos mediante plastinación permiten realizar descripciones anatómicas detalladas de regiones anatómicas complejas y también pueden ser usadas para realizar reconstrucciones 3D. El objetivo del presente trabajo, ha sido obtener una reconstrucción 3D de las estructuras anatómicas que conforman el codo del perro a partir de cortes plastinados ultradelgados.

The dog's elbow joint is a very complex structure formed between the humeral condyle, the radial head and the ulnar trochlear notch. This joint is prone to suffer growth disorders, traumatic injuries, and degenerative conditions. All these problems used to be solved by surgical means, nevertheless, the surgical plan, results in a complex decision making process related with the aforementioned joint characteristics, three dimensional (3D) anatomical models from computed tomography have proven to be useful in the surgical approach, nevertheless the image technique is at some point limited, mainly identifying soft tissues. Ultrathin plastinated slices (1 mm) allows to perform very detailed descriptions of complex structures and 3D reconstructions as well. The aim of this work, was to obtain a 3D reconstruction of ultrathin plastinated elbow joint in the dog.

Aromatic esters of progesterone as 5alpha-reductase and prostate growth inhibitors.

The aim of this study was to determine the biological activity of 4 steroidal derivatives (9a, 9b and 10a, 10b) prepared from the commercially available 17alpha acetoxyprogesterone, where 9a, 9b, have the Delta(4)-3-oxo structure and 10a and 10b an epoxy group at C-4 and C-5. These steroids were tested as inhibitors of 5alpha-reductase enzyme, which is present in androgen-dependent tissues and converts testosterone to its more active reduced metabolite dihydrotestosterone. The pharmacological effect of these steroids was demonstrated by the significant decrease of the weight of the prostate gland of gonadectomized hamsters treated with testosterone plus finasteride or with steroids 10a and 10b. For the studies in vitro the IC(50) values were determined by measuring the steroid concentration that inhibits 50% of the activity of-5alpha-reductase. In this study we also determined the capacity of these steroids to bind to the androgen receptor present in the rat prostate cytosol. The results from this work indicated that compounds 9a, 9b, 10a, and 10b inhibited the 5alpha reductase activity with IC(50) values of 360, 370, 13 and 4.9 nM respectively. However these steroids did not bind to the androgen receptors since none competed with labeled mibolerone. Steroid 10b, an epoxy steroidal derivative containing bromine atom in the ester moiety, was the most active inhibitor of 5alpha-reductase enzyme, present in human prostate homogenates with an IC(50) value of 4.9 nM and also showed in vivo pharmacological activity since it decreased the weight of the prostate from hamsters treated with testosterone in a similar way as finasteride.

In vivo and in vitro effect of novel 4,16-pregnadiene-6,20-dione derivatives, as 5alpha-reductase inhibitors.

In this study, we report the synthesis and biological evaluation of several new 3-substituted pregna-4,16-diene-6,20-dione derivatives (11a-11d). These compounds were prepared from the commercially available 16-dehydropregnenolone acetate. The biological effect of these steroids was demonstrated in in vivo and in vitro experiments. In the in vivo experiments, we measured the activity of the 11a-11d on the weight of the prostate gland of gonadectomized hamsters treated with testosterone plus finasteride or with the new steroids. For the studies in vitro, we determined the IC50 values by measuring the steroid concentration that inhibits 50% of the activity of 5alpha-reductase present in human prostate. In order to study the mechanism of action of 11a-11d, we also determined the capacity of these steroids to bind to the androgen receptor (AR) present in the rat prostate cytosol using labeled mibolerone as a tracer. The results from this work indicated that compounds 11a-11d significantly decreased the weight of the prostate as compared to testosterone treated animals and this reduction of the weight of the prostate was comparable to that produced by the finasteride. On the other hand 11a-11d exhibited a high inhibitory activity for the human 5alpha-reductase enzyme with IC50 values of 1.4 x 10(-8), 1.8 x 10(-9), 1.0 x 10(-8) and 4 x 10(-5) respectively. However the IC50 value of 11a (1.8 x 10(-9)) was the only one lower than that of finasteride (8.5 x 10(-9)). Nevertheless this compound did not show a higher potency in vivo as compared to that of compounds 11b-11d. The competition analysis for the androgen receptor indicated that the IC50 value of non-labeled mibolerone used in this experiment was 1nM, whereas steroids 10, 11a-11d did not inhibit the labeled mibolerone binding to the androgen receptor. On the other hand, steroid 10 did not show any activities in vitro or in vivo, and for this reason these steroidal derivatives (11a-11d) cannot be considered as prodrugs of compound 10. In conclusion, the compounds containing chlorine 11a, bromine 11b, iodine 11c atoms, and 11d (without any substituent in the ester moiety) at C-3 produce a significant decrease of the prostate weight in castrated animals treated with T and inhibits the activity of the 5alpha-reductase. Apparently the presence of the halogen atoms in compounds 11a-11c enhances the inhibitory activity for the 5alpha-reductase enzyme.

Biological activity of novel progesterone derivatives having a bulky ester side chains at C-3.

Antiandrogens are widely used agents for the treatment of androgen dependent diseases as inhibitors of androgen receptors (AR) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of the structure of the ligand in relation with the nuclear co-repressors. In the present study, we investigated the relationship between logP (the partition coefficient) of four pregnane derivatives 9a-9d and their biological activity. For this purpose, we determined the relative binding affinity (RBA) of steroids 9a-9d to androgen receptor (AR) obtained from rat prostate cytosol, using labeled mibolerone (MIB) as ligand. The IC(50) value of each compound was calculated according to the plots of concentration versus percentage of binding. The in vivo effect of 9a-9d was determined on the weight of the prostate and seminal vesicles from castrated hamsters treated with dihydrotestosterone. The four compounds bind to the androgen receptor with different relative binding affinity (RBA). Compound 9d having a logP of 4.17 showed the highest RBA>100% as compared to compound 9a having a logP of 2.92 which exhibited a RBA of only 2.85%. These data show a very good correlation between the lipophilicity of these compounds represented by logP and the percentage of RBA. The in vivo experiments showed that all new compound 9a-9d reduced the weight of the prostate gland as well as the seminal vesicles. Steroids 9c and 9d having a logP of 3.75 and 4.17, respectively, showed the highest antiandrogenic effect.

Steroids with a carbamate function at C-17, a novel class of inhibitors for human and hamster steroid 5alpha-reductase.

In order to study the biological activity of the two novel steroidal carbamates derivatives: 8a and 8b, we determined the concentration of both compounds that inhibit the 50% of the activity of human prostate 5alpha-reductase enzyme, as well as the in vivo effect of these compounds in the weight of hamster prostate and flank organs diameter size. We determined also, the capacity of these steroids to bind to the androgen receptors present in the rat prostate cytosol. Furthermore the activity of these compounds on the mRNA expression of glycerol 3-phosphate acyl transferase (GPAT) in flank organs was analyzed by RT-PCR. This enzyme induces the triglycerides synthesis, which is increased by T in flank organs. The results from this study indicated that steroids 8a and 8b inhibited the human 5alpha-reductase activity. Compound 8b, which contains a bromine atom in the molecule, decreased the inhibitory effect of the human 5alpha-reductase activity, whereas steroid 8a, which lacks a halogen atom did not show any decrease in the activity of this enzyme. The competition studies demonstrated that 8a and 8b did not inhibit mibolerone binding to the androgen receptor present in the rat prostate cytosol. However, the in vivo activity of both steroids was similar; steroids 8a and 8b had a tendency to decrease the weight of the hamster prostate although this parameter was not statistically significant. These compounds also significantly reduced the diameter of the pigmented spot of hamster flank organs, which are androgen dependent skin's pilosebaceous structures. Steroids 8a and 8b, decreased the transcription of mRNA encoding for GPAT in intact hamster's flank organs topically treated in a similar way as in gonadectomized non-treated animals. These results suggest that mRNA encoding for GPAT is induced by DHT in this tissue.