Antidepressant and anxiolytic profiles of newly synthesized arginine vasopressin V1B receptor antagonists: TASP0233278 and TASP0390325.

BACKGROUND AND PURPOSE: Vasopressin V1B receptor antagonists may be effective for the treatment of depression and anxiety and the objective of this study was to characterize the pharmacological profiles of two newly synthesized arginine vasopressin receptor 1B (V1B receptor) antagonists, TASP0233278 and TASP0390325. EXPERIMENTAL APPROACH: We investigated the in vitro profiles of TASP0233278 and TASP0390325. In addition, the effect of TASP0390325 on the increase in plasma adrenocorticotropic hormone (ACTH) levels induced by corticotropin-releasing factor (CRF)/desmopressin (dDAVP) was investigated. We also investigated the antidepressant and anxiolytic profiles of TASP0233278 and TASP0390325 in animal models. KEY RESULTS: Both TASP0233278 and TASP0390325 showed a high affinity and potent antagonist activity for V1B receptors. Oral administration of TASP0390325 antagonized the increase in plasma ACTH levels induced by CRF/dDAVP in rats, indicating that TASP0390325 blocks the anterior pituitary V1B receptor in vivo. Oral administration of TASP0233278 or TASP0390325 also exerted antidepressant effects in two models of depression (a forced swimming test and an olfactory bulbectomy model). Moreover, TASP0233278 improved depressive-like behaviour induced by repeated treatment with corticosterone, a model that has been shown to be resistant to treatment with currently prescribed antidepressants. In addition to depression models, TASP0233278 or TASP0390325 exerted anxiolytic effects in several anxiety models (social interaction, elevated plus-maze, stress-induced hyperthermia, separation-induced ultrasonic vocalization and sodium lactate-induced panic-like responses in panic-prone rats). CONCLUSION: TASP0233278 and TASP0390325 are potent and orally active V1B receptor antagonists with antidepressant and anxiolytic activities in rodents.

Revisional bariatric surgery: perioperative morbidity is determined by type of procedure.

BACKGROUND: Revisional bariatric procedures are on the rise. The higher complexity of these procedures has been reported to lead to increased risk of complications. The objective of our study was to compare the perioperative risk profile of revisional bariatric surgery with primary bariatric surgery in our experience. METHODS: A prospectively maintained database of all patients undergoing bariatric surgery by three fellowship-trained bariatric surgeons from June 2005 to January 2013 at a center of excellence was reviewed. Patient demographics, type of initial and revisional operation, number of prior gastric surgeries, indications for revision, postoperative morbidity and mortality, length of stay, 30-day readmissions, and reoperations were recorded. These outcomes were compared between revisional and primary procedures by the Mann-Whitney or Chi square tests. RESULTS: Of 1,556 patients undergoing bariatric surgery, 102 patients (6.5%) underwent revisional procedures during the study period. Indications for revisions included inadequate weight loss in 67, failed fundoplications with recurrent gastroesophageal reflux disease in 29, and other in 6 cases. Revisional bariatric procedures belonged into four categories: band to sleeve gastrectomy (n = 23), band to Roux-en-Y gastric bypass (n = 25), fundoplication to bypass (n = 29), and other (n = 25). Revisional procedures were associated with higher rates of readmissions and overall morbidity but no differences in leak rates and mortality compared with primary procedures. Band revisions had similar length of stay with primary procedures and had fewer complications compared with other revisions. Patients undergoing fundoplication to bypass revisions were older, had a higher number of prior gastric procedures, and the highest morbidity (40%) and reoperation (20%) rates. CONCLUSIONS: In experienced hands, many revisional bariatric procedures can be accomplished safely, with excellent perioperative outcomes that are similar to primary procedures. As the complexity of the revisional procedure and number of prior surgeries increases, however, so does the perioperative morbidity, with fundoplication revisions to gastric bypass representing the highest risk group.

Staged hernia repair preceded by gastric bypass for the treatment of morbidly obese patients with complex ventral hernias.

BACKGROUND: Obesity may be the most predominant risk factor for recurrence following ventral hernia repair. This is secondary to significantly increased intra-abdominal pressures, higher rates of wound complications, and the technical difficulties encountered due to obesity. Medically managed weight loss prior to surgery is difficult. One potential strategy is to provide a surgical means to correct patient weight prior to hernia repair. METHODS: After institutional review board approval, we reviewed the medical records of all patients who underwent gastric bypass surgery prior to the definitive repair of a complex ventral hernia at our medical center. RESULTS: Twenty-seven morbidly obese patients with an average of 3.7 (range 1-10) failed ventral hernia repairs underwent gastric bypass prior to definitive ventral hernia repair. Twenty-two of the gastric bypasses were open operations and five were laparoscopic. The patients' average pre-bypass body mass index (BMI) was 51 kg/m2 (range 39-69 kg/m2), which decreased to an average of 33 kg/m2 (range 25-37 kg/m2) at the time of hernia repair at a mean of 1.3 years (range 0.9-3.1 years) after gastric bypass. Seven patients had hernia repair at the same time as their gastric bypass (four sutured, three biologic mesh), all of which recurred. Of the 27 patients, 19 had an open hernia repair and eight had a laparoscopic repair. Panniculectomy was performed concurrently in 15 patients who had an open repair. Prior to formal hernia repair, one patient required an urgent operation to repair a hernia incarceration and a small-bowel obstruction 11 months after gastric bypass. The average hernia and mesh size was 203 cm2 (range 24-1,350 cm2) and 1,040 cm2 (range 400-2,700 cm2), respectively. There have been no recurrences at an average follow-up of 20 months (range 2 months-5 years). CONCLUSION: Gastric bypass prior to staged ventral hernia repair in morbidly obese patients with complex ventral hernias is a safe and definitive method to effect weight loss and facilitate a durable hernia repair with a possible reduced risk of recurrence.

In vitro infectability of prosthetic mesh by methicillin-resistant Staphylococcus aureus.

Although mesh use is important for effective herniorrhaphy in adults, prosthetic infections can cause serious morbidity. Bacterial adherence to the mesh is a known precursor to prosthetic infection. We compared the ability of common mesh prosthetics to resist bacterial adherence. The meshes studied included polypropylene (Marlex, expanded polytetrafluoroethylene (PTFE) with and without silver chlorhexidine coating (DualMesh Plus and Dualmesh) composite meshes (Composix E/X, Proceed, and Parietex Composite) and lightweight polypropylene meshes (TiMesh, Ultrapro, and Vypro). Fifteen samples of each mesh type were individually inoculated with a suspension of 10(8 )methicillin-resistant Staphylococcus aureus (MRSA) in tryptic soy broth. After incubation at 37 degrees C for 1 h, the mesh pieces were then removed and serially washed. The colony-forming units (CFU) of MRSA present in the initial inoculum, at the end of the 1-h warm-water bath (broth count), and the pooled washes (wash count), were determined using serial dilutions and spot plating. The bacteria not accounted for in the broth or wash counts were considered adhered to the mesh. Samples of each mesh type were also analyzed using scanning electron microscopy (SEM). Data are presented as the mean percentage adherence with ANOVA and Tukey's test used to determine significance (P<0.05). The DualMesh Plus mesh had no detectable MRSA in the broth or the pooled wash samples. Dualmesh had less adherence compared with Marlex, Proceed, and Vypro (P<0.05). Conversely, Vypro had a statistically higher adherence (96%, P<0.05) as compared to TiMesh, Ultrapro, Composix E/X, and Parietex Composite. SEM confirmed bacterial adherence to all the mesh types except DualMesh Plus. The ability of a biomaterial to resist infection has an important clinical significance. DualMesh Plus, due to its antimicrobial coating, is the only mesh type of the nine tested that demonstrated a bactericidal property. Standard PTFE (Dualmesh) also had less bacterial adherence. Vypro demonstrated an increase in bacterial adherence; this was possibly due to the multifilament polyglactin 910 weaved within the prolene component of the mesh.

Total syntheses of beta-carboline alkaloids, (R)-(-)-pyridindolol K1, (R)-(-)-pyridindolol K2, and (R)-(-)-pyridindolol.

The total syntheses of beta-carboline alkaloids, (R)-(-)-pyridindolols (1, 5, and 6) are described. The two key steps involved are (1) a thermal electrocyclic reaction of the 3-alkenylindole-2-aldoxime 10 and (2) a thermal cyclization of 3-alkynylindole-2-aldoxime 11 to construct the beta-carboline N-oxides 8, which upon heating with acetic anhydride and sequential treatment with trifluoromethanesulfonic anhydride gave the triflates 18. The Stille coupling reaction of 18 with vinylstannane, followed by cleavage of MOM ether, afforded the 1-ethenyl-3-hydroxymethyl-beta-carboline (7a). Subsequent acetylation of 7a yielded the acetate 7b, which was subjected to the Sharpless asymmetric 1,2-dihydroxylation by AD-mix-beta to produce (R)-(-)-pyridindolol K2 (6). Selective acetylation of 6 was effected by Ac(2)O and collidine to form (R)-(-)-pyridindolol K1 (5). By contrast, hydrolysis of 6 provided (R)-(-)-pyridindolol (1).

Total syntheses of novel cytocidal beta-carboline alkaloids, oxopropalines D and G.

A new type of beta-carboline nucleus, N-methoxymethyl-4-methyl-beta-carboline (4) was synthesized by thermal electrocyclic reaction of a 1-azahexatriene system, involving the indole 2,3-bond. The key compound N-methoxymethyl-1-methoxycarbonyl-4-methyl-beta-carboline (2) was then prepared in a four-step sequence. The total synthesis of oxopropaline G (1e) was achieved from this key compound in four steps. Furthermore, the enantioselective total syntheses of (+)-oxopropaline D (1c) and its enantiomer were also achieved by application of the Sharpless oxidation-procedure in nine steps from 2.

Divergent secretory behavior of the opposite ends of aggrecan.

The proteoglycan, aggrecan has a globular domain, G1, at the N terminus and a different globular domain, G3, at the C terminus. Aggrecan produced by mutant nanomelic chickens is truncated due to a premature stop codon and consequently lacks G3 and a minor portion of its chondroitin sulfate domain (Li, H., Schwartz, N. B., and Vertel, B. M.(1993) J. Biol. Chem. 268, 23504-23511). The mutant protein is retained in the endoplasmic reticulum and fails to enter the Golgi stacks (Vertel, B. M., Walters, L. M., Grier, B., Maine, N. , and Goetinck, P. F.(1993) J. Cell Sci. 104, 939-948). The homozygous mutant is lethal because of failure of chondrogenesis and osteogenesis, while the heterozygous mutant is dwarfed. To further elucidate the pathogenetic mechanisms underlying nanomelia and to determine if G1 and G3 are themselves secreted, we expressed them in transfected host cells. Expression was performed in wild type Chinese hamster ovary (CHO) cells and in mutant CHO cells which are unable to link glycosaminoglycan (GAG) chains to core proteins. We compared: (a) secretion of expressed G1 and G3 constructs containing contiguous GAG chain consensus sites and (b) GAG chain modification of the secreted proteins. We find that: 1) G3 is 24-100 times more rapidly secreted than G1; 2) secreted G3 contains contiguous chondroitin sulfate GAG chains, while secreted G1 lacks contiguous GAG chains; 3) G3 secretion is not coupled to xylosylation of contiguous GAG chain consensus sites. These results imply that G1 and G3 intrinsically differ in passage through the cell secretory route.