Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia.

We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.

Consensus conference on the stapled transanal rectal resection (STARR) for disordered defaecation.

An international working party was convened in Rome, Italy on 16-17 June, 2005, with the purpose of developing a consensus on the application of the circular stapling instrument to the treatment of certain rectal conditions, the so-called Stapled Transanal Rectal Resection (STARR). Since the procedure has been submitted to only limited objective analysis it was felt prudent to hold a meeting of interested individuals for the purpose of evaluating the current status and to make conclusions and recommendations concerning the applicability of this new approach.

Stapled haemorrhoidopexy: a consensus position paper by an international working party - indications, contra-indications and technique.

An international working party with experience in the performance of an alternative haemorrhoid operation through the use of the circular stapler was convened for the purpose of developing a consensus as to the criteria for undertaking this procedure. The agenda consisted of first, naming the operation; second, the indications and contra-indications for its performance; and third, the preferred surgical technique. Among the recommendations for individuals who plan to embark on this surgery are that experience with anorectal surgery and an understanding of anorectal anatomy are requisites; experience with circular stapling devices is essential; and the surgeon must attend a formal course which should include lectures, videos, the application of the instrument in models, and observation of the operation as performed by a surgeon recognized by his or her peers-leading ultimately to undertaking the procedure while being observed by an experienced surgeon. Following satisfactory completion of the above, independent responsibility should be determined by an individual's department of surgery.

History of laparoscopy.

The history of laparoscopic surgery demonstrates how a close interaction between technology and medical-surgical innovators permitted its ultimate development. Similar revolutions have occurred in information and communication technology and in molecular biology. Within less than 2 decades, surgical management has moved from a disease-oriented approach to one that is more patient-oriented. While the past decade was characterized by the issue of what could be accomplished laparoscopically, the future will focus on the question of which operations should really be performed by this approach.

The WAND local anesthetic delivery system: a more pleasant experience for anal anesthesia.

PURPOSE: The WAND is a computer-controlled local anesthetic delivery system. Its use has been proven to be more comfortable for dental patients. The purpose of this study is to explore its applicability to anal procedures. Our hypothesis is that the WAND will provide greater comfort during anesthesia delivery while achieving the same anesthetic effect as traditional syringe technique. METHODS: Twenty patients with painless anal pathology were randomized to receive anal anesthesia using either the WAND or traditional syringe technique to a randomly selected half of the anoderm (right or left). The opposite side was then anesthetized by the alternate method, allowing patients to act as their own control. Objective and subjective pain scores were obtained from the patient after each mode of delivery. An independent observer interpreted the patient's tolerance by giving a subjective pain score. The volume of anesthetic used was recorded. Adequacy of anesthesia was tested by a pinch test. RESULTS: Sixteen (80 percent) of the 20 patients preferred the use of the WAND. Objective and subjective pain scores per the patients and subjective pain scores per the observer were significantly lower for the WAND than for traditional syringe technique (P < 0.05). The mean volume of local anesthetic used with the WAND was 1.7 ml compared with 3.2 ml for traditional syringe technique (P < 0.005). Anesthesia achieved with the WAND was as good as that achieved with traditional syringe technique when the pinch test was used. CONCLUSION: The WAND is as effective as the traditional syringe technique in the delivery of anal anesthesia while providing a more comfortable experience for the patient.

Intestinal stomas in Crohn's disease.

Stomal construction is as important as the establishment of hemostasis. Appropriate preoperative assessment and adherence to accepted construction techniques usually will avoid stomal complications. In patients who suffer adverse consequences, accurate assessment and appropriate management principles are essential to properly address the problem.

Double-blind comparison of single-dose alatrofloxacin and cefotetan as prophylaxis of infection following elective colorectal surgery. Trovafloxacin Surgical Group.

BACKGROUND: Alatrofloxacin, the prodrug of trovafloxacin, is a novel fluoroquinolone antimicrobial agent with a broad spectrum, including activity against gram-positive and gram-negative aerobes and anaerobes. Its pharmacokinetic properties (long half-life, excellent tissue distribution, and good safety profile) suggest a role in surgical prophylaxis. This prospective, multicenter, double-blind trial compared alatrofloxacin with cefotetan, an approved drug for surgical prophylaxis, in reducing postoperative infections. METHODS: The efficacy and safety of a single 200-mg intravenous dose of alatrofloxacin were compared to a single 2-g intravenous dose of cefotetan in 492 patients undergoing elective colorectal surgery. The efficacy of alatrofloxacin as a prophylaxis for wound, intra-abdominal, or remote-site postoperative infectious complications was compared with cefotetan in 317 clinically evaluable patients; 161 received alatrofloxacin and 156 received cefotetan. The patients were monitored for infections and safety for 30 days postoperatively. RESULTS: No statistically significant between-treatment difference was detected in successful clinical response rates at the end of the study (72% for each group). The incidence of primary wound infections at the time of hospital discharge was also similar: 21% in patients treated with alatrofloxacin and 18% in those treated with cefotetan. Safety, established by the incidence of adverse events, did not differ statistically between the groups. CONCLUSIONS: A single intravenous dose of alatrofloxacin given within 4 hours prior to surgery was as effective as an intravenous dose of cefotetan in the prevention of postoperative infectious complications in patients undergoing elective colorectal surgery. The safety profiles of the two medications were similar.

Synthesis and oral efficacy of a 4-(butylethylamino)pyrrolo[2,3-d]pyrimidine: a centrally active corticotropin-releasing factor1 receptor antagonist.

The syntheses of a centrally active nonpeptide CRF1 receptor antagonist 2, butylethyl[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine (CP-154,526), and its analogs 11-14 and [3H]-2 are reported. The in vitro CRF1 receptor binding affinity in the series 2, the pharmacokinetic properties of 2 in rats, and the anxiolytic-like effects of orally administered 2 are presented.

Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives.

The erbB-2 oncogene encodes a transmembrane protein tyrosine kinase which plays a pivotal role in signal transduction and has been implicated when overexpressed in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the quinoid moiety of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2 (FRE/erbB-2). Specifically, dosed intraperitoneally at 100 mg/kg, 17-(allylamino)-17-demethoxygeldanamycin and other 17-amino analogs were effective at reducing p185 phosphotyrosine in subcutaneous flank FRE/erbB-2 tumors. Modifications to the 17-19-positions of the quinone ring revealed a broad structure-activity relationship in vitro.

erbB-2 oncogene inhibition by geldanamycin derivatives: synthesis, mechanism of action, and structure-activity relationships.

Overexpression of the erbB-2 oncogene has been linked to poor prognosis in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the ansa ring of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2. Functional group modification in the ansa ring was performed stereoselectively and regiospecifically without the need for protection strategies. Essential functional groups that were required for anti-erbB-2 activity were the 7-carbamate and the 2,3-double bond. Modification of the functional groups at the other positions was permitted. Structure-activity relationships are described for 1-5-, 7-9-, 11-, 15-, and 22-substituted geldanamycins.

Immunoscintigraphy with 111In-satumomab pendetide in patients with colorectal adenocarcinoma: performance and impact on clinical management.

PURPOSE: The role of immunoscintigraphy with 111In-satumomab pendetide in the medical and/or surgical management of colorectal cancer patients was evaluated in a multicenter trial. METHODS: This 103 patient study population included 46 individuals with rising serum carcinoembryonic antigen levels and otherwise negative diagnostic evaluation, 29 patients with known recurrence, presumed to be isolated and resectable, and 28 patients for whom standard diagnostic tests provided equivocal information. RESULTS: No adverse reactions were noted following intravenous administration of 1 mg of satumomab pendetide radiolabeled with approximately 5 mCi of 111In. Thirty percent of patients developed human anti-mouse antibodies postinfusion. In the 84 patients for whom correlation with histopathologic, diagnostic, and/or clinical findings was available, antibody imaging demonstrated a sensitivity of 73 percent in patients with confirmed tumor (36/49) and negative results for all 35 patients with no evidence of malignancy. Occult disease was detected in 18 patients. CONCLUSION: 111In-satumomab pendetide immunoscintigraphy was helpful in the medical and/or surgical management of 45 (44 percent) patients and provided information unavailable from other diagnostic modalities.

Principles of surgical technique in the treatment of carcinoma of the large bowel.

The principles of surgical technique for the operative management of colon cancer are described. With the background of the evolution of anastomotic alternatives, the methods for reestablishing intestinal continuity and the approach to the treatment of complicated presentations of colonic cancer are reviewed. While one may construe this paper to have a certain author bias, I have tried to present diverse options where pertinent, but there should be little question as to where my opinion lies.

Prospective, randomized trial of the biofragmentable anastomosis ring. The BAR Investigational Group.

A randomized trial was undertaken to compare the biofragmental anastomotic ring (BAR) with conventional intraperitoneal colorectal anastomotic techniques. Patients were randomized into one of two schemes: BAR versus sutured or BAR versus stapled anastomosis. There were 782 patients entered into the study and 283 patients (36%) had a sutured anastomosis, 104 patients (13%) had a stapled anastomosis, and 395 (51%) had the BAR. Comparison of the BAR with combined suture and stapled controls revealed no significant differences in wound complication, abscess rate, bleeding, anastomotic leaks, ileus, obstruction, or deaths. There were no differences in return of bowel function, return to normal diet, or hospital stay. Intraoperative difficulties occurred in 46 BAR patients (17%), and this was significantly higher (p less than 0.001) than for sutured (3%) but not for stapled anastomoses (11%). The occurrence of these problems did not adversely effect the outcome. The data suggest that the BAR is a safe, satisfactory alternative to sutured or stapled colorectal anastomoses.