N-adamantyl-anthranil amide derivatives: New selective ligands for the cannabinoid receptor subtype 2 (CB2R).

Cannabinoid type 2 receptor (CB2R) is a G-protein-coupled receptor that, together with Cannabinoid type 1 receptor (CB1R), endogenous cannabinoids and enzymes responsible for their synthesis and degradation, forms the EndoCannabinoid System (ECS). In the last decade, several studies have shown that CB2R is overexpressed in activated central nervous system (CNS) microglia cells, in disorders based on an inflammatory state, such as neurodegenerative diseases, neuropathic pain, and cancer. For this reason, the anti-inflammatory and immune-modulatory potentials of CB2R ligands are emerging as a novel therapeutic approach. The design of selective ligands is however hampered by the high sequence homology of transmembrane domains of CB1R and CB2R. Based on a recent three-arm pharmacophore hypothesis and latest CB2R crystal structures, we designed, synthesized, and evaluated a series of new N-adamantyl-anthranil amide derivatives as CB2R selective ligands. Interestingly, this new class of compounds displayed a high affinity for human CB2R along with an excellent selectivity respect to CB1R. In this respect, compounds exhibiting the best pharmacodynamic profile in terms of CB2R affinity were also evaluated for the functional behavior and molecular docking simulations provided a sound rationale by highlighting the relevance of the arm 1 substitution to prompt CB2R action. Moreover, the modulation of the pro- and anti-inflammatory cytokines production was also investigated to exert the ability of the best compounds to modulate the inflammatory cascade.

Bcr-Abl Allosteric Inhibitors: Where We Are and Where We Are Going to.

The fusion oncoprotein Bcr-Abl is an aberrant tyrosine kinase responsible for chronic myeloid leukemia and acute lymphoblastic leukemia. The auto-inhibition regulatory module observed in the progenitor kinase c-Abl is lost in the aberrant Bcr-Abl, because of the lack of the N-myristoylated cap able to bind the myristoyl binding pocket also conserved in the Bcr-Abl kinase domain. A way to overcome the occurrence of resistance phenomena frequently observed for Bcr-Abl orthosteric drugs is the rational design of allosteric ligands approaching the so-called myristoyl binding pocket. The discovery of these allosteric inhibitors although very difficult and extremely challenging, represents a valuable option to minimize drug resistance, mostly due to the occurrence of mutations more frequently affecting orthosteric pockets, and to enhance target selectivity with lower off-target effects. In this perspective, we will elucidate at a molecular level the structural bases behind the Bcr-Abl allosteric control and will show how artificial intelligence can be effective to drive the automated de novo design towards off-patent regions of the chemical space.

Bcr-Abl Tyrosine Kinase Inhibitors in the Treatment of Pediatric CML.

The therapeutic approach to Chronic Myeloid Leukemia (CML) has changed since the advent of the tyrosine kinase inhibitor (TKI) imatinib, which was then followed by the second generation TKIs dasatinib, nilotinib, and, finally, by ponatinib, a third-generation drug. At present, these therapeutic options represent the first-line treatment for adults. Based on clinical experience, imatinb, dasatinib, and nilotinib have been approved for children even though the studies that were concerned with efficacy and safety toward pediatric patients are still awaiting more specific and high-quality data. In this scenario, it is of utmost importance to prospectively validate data extrapolated from adult studies to set a standard therapeutic management for pediatric CML by employing appropriate formulations on the basis of pediatric clinical trials, which allow a careful monitoring of TKI-induced adverse effects especially in growing children exposed to long-term therapy.

Evaluation of the urodynamic and hemodynamic effects of orally administered phenylpropanolamine and ephedrine in female dogs.

OBJECTIVE: To compare the urodynamic and hemodynamic effects of different dosages of phenylpropanolamine and ephedrine and determine effective dosages in increasing urethral resistance in female dogs. ANIMALS: 20 sexually intact female Beagles. PROCEDURE: Dogs were allocated into 4 groups and received phenylpropanolamine once, twice, or 3 times daily, or ephedrine twice daily, for 14 days. On days 0, 7, and 14, urethral pressure profiles were performed while dogs were anesthetized with propofol. Variables recorded included maximum urethral pressure, maximum urethral closure pressure, integrated pressure, functional profile length, anatomic profile length, plateau distance, distance before maximum urethral pressure, and maximum meatus pressure. Arterial and central venous pressures were measured before anesthetic induction and 10 and 35 minutes after induction. RESULTS: Administration of phenylpropanolamine once daily or ephedrine twice daily significantly increased maximum urethral pressure and maximum urethral closure pressure. Values for integrated pressure were significantly increased after 14 days of once-daily administration of phenylpropanolamine. Variables did not change significantly from day 7 to day 14. Diastolic and mean arterial blood pressures increased significantly during the treatment periods, and arterial pressure decreased during propofol infusion. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of phenylpropanolamine once daily or ephedrine twice daily increased urethral resistance in clinically normal dogs and may be recommended for management of urethral sphincter mechanism incompetence. Treatment efficacy may be assessed after 1 week. Dogs with concurrent cardiovascular disease should be monitored for blood pressure while receiving alpha-adrenergic agents because of the effects on diastolic and mean arterial pressure.

Use of autogenous fascia lata graft for perineal herniorrhaphy in dogs.

OBJECTIVE: To evaluate the effectiveness of a herniorrhaphy technique, using an autogenous fascia lata graft (FLG) for perineal hernia (PH) repair in dogs. STUDY DESIGN: Prospective clinical study. ANIMALS: Twelve dogs with PH. METHOD: PHs were repaired with FLG harvested from the dog's ipsilateral thigh and sutured directly into the perineal defect. Correction of associated conditions, and castration were performed. Surgical time, pain, inflammation, pattern of defecation, lameness, hospitalization time, postoperative complications, and owner satisfaction were recorded. Histopathologic examination was performed in 1 dog euthanatized 10 months after repair. RESULTS: Hernia did not recur (mean follow-up, 5.8 months). Lameness was the most frequent minor complication, and was resolved within a few days. Transient rectal prolapse occurred in 2 dogs with bilateral PH. The mean (+/-SD) hospitalization was 1.8+/-0.9 days, and the surgical time was 76.5+/-9.8 minutes. Histopathologic examination in 1 dog revealed perfect integration of FLG into adjacent tissues without substantial tissue reaction. CONCLUSIONS: FLG reconstruction of PH is a simple, effective method of treatment. CLINICAL RELEVANCE: FLG can be used without major complications for primary repair of PH, as an augmentation procedure when the internal obturator muscle is thin or friable, or when herniation has recurred after another repair technique.