Novel antagonists of the 5-HT3 receptor. Synthesis and structure-activity relationships of (2-alkoxybenzoyl)ureas.

A series of benzoylureas derived from bicycle amines were prepared and evaluated for 5-HT3 antagonist activity on the rat isolated vagus nerve. From among these compounds, those analogues which were ortho substituted by an alkoxy group on the benzoyl function were shown to be potent 5-HT3 antagonists with similar or greater potency than the standard agent ondansetron. NMR and X-ray crystallography studies showed these o-alkoxy compounds to exist as a planar, hydrogen-bonded, tricyclic ring system. In molecular modeling studies on endo-N-[[(8-methyl-8-azabicyclo[3.2.1]octan-3-yl-amino] carbonyl]-2-(cyclopropylmethoxy)benzamide (30) the central hydrogen-bonded ring was able to mimic an aromatic ring present in previously reported 5-HT3 antagonists.     

The Diabetes Treatment Satisfaction Questionnaire change version (DTSQc) evaluated in insulin glargine trials shows greater responsiveness to improvements than the original DTSQ

Background  

The results of using status measures to identify any changes in treatment satisfaction strongly suggest a need for specific change instruments designed to overcome the ceiling effects frequently observed at baseline. Status measures may leave little room to show improvement in situations where baseline ceiling effects are observed. A change version of the DTSQ (DTSQc) is compared here with the original status (now called DTSQs) version to test the instruments' comparative ability to demonstrate change.     

Management of pressure ulcers.

PURPOSE: Wound healing, the epidemiology and staging of pressure ulcers, and pressure ulcer prevention and treatment are discussed. SUMMARY: The principal event leading to the formation of pressure ulcers appears to be a consistent interruption in blood supply to the skin. Several known risk factors exist and can be attributed to patient-specific variables and wound-specific conditions. Initial management should include removal of the source of pressure, a comprehensive assessment of the patient, and proper staging of the ulcer. Preparation of the wound for treatment is essential and can have a significant impact on healing. While the patient's nutritional status is thought to affect wound healing, only an increased protein content in the diet has been demonstrated to have a benefit. Specialized wound dressings are available for pressure ulcers of all stages and drainage characteristics. With wide variation in cost and in application regimens, a direct cost-effectiveness comparison of commercially available dressing products is difficult. Many of the growth factors commonly present in healing wounds have been synthesized and evaluated as treatments. Although topical platelet-derived growth factor has demonstrated benefit in some studies, its use remains controversial. To date, no topical growth factors carry FDA-approved labeling for use in the treatment of pressure ulcers. Human skin equivalents mark the latest advancement in therapy. Certain species of bacteria have been associated with poorly healing ulcers and may warrant intervention with either local or systemic antibiotic therapy. CONCLUSION: No pharmacologic intervention has been conclusively shown to be effective for pressure ulcers. The cornerstones of therapy remain elimination of the source of pressure or friction and appropriate wound care. usa.     

Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 (n=867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 (n=1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P=0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.     

On the dual structure of the auditory brainstem response in dogs.

OBJECTIVE: To use the over-complete discrete wavelet transform (OCDWT) to further examine the dual structure of auditory brainstem response (ABR) in the dog. METHODS: ABR waveforms recorded from 20 adult dogs at supra-threshold (90 and 70dBnHL) and threshold (0-15dBSL) levels were decomposed using a six level OCDWT and reconstructed at individual scales (frequency ranges) A6 (0-391Hz), D6 (391-781Hz), and D5 (781-1563Hz). RESULTS: At supra-threshold stimulus levels, the A6 scale (0-391Hz) showed a large amplitude waveform with its prominent wave corresponding in latency with ABR waves II/III; the D6 scale (391-781Hz) showed a small amplitude waveform with its first four waves corresponding in latency to ABR waves I, II/III, V, and VI; and the D5 scale (781-1563Hz) showed a large amplitude, multiple peaked waveform with its first six waves corresponding in latency to ABR waves I, II, III, IV, V, and VI. At threshold stimulus levels (0-15dBSL), the A6 scale (0-391Hz) continued to show a relatively large amplitude waveform, but both the D6 and D5 scales (391-781 and 781-1563Hz, respectively) now showed relatively small amplitude waveforms. CONCLUSIONS: A dual structure exists within the ABR of the dog, but its relative structure changes with stimulus level. SIGNIFICANCE: The ABR in the dog differs from that in the human both in the relative contributions made by its different frequency components, and the way these components change with stimulus level.     

Minimal displacement of novel self-anchoring catheters suitable for temporary prostate implants.

Catheters were developed that can be fixed in the prostate gland by self-expanding parts for use in PDR brachytherapy. Daily CT-scans were made to investigate the magnitude of catheter displacement. The mean absolute displacement during the 3 day treatment was 1.2 mm. The resulting minor alterations in dose-volume parameters were of no clinical importance.     

Remotely inserted venous occlusion catheters for the control of venous haemorrhage.

This paper describes the use of venous occlusion catheters inserted via the long saphenous vein or its tribularies for control of major retroperitoneal venous haemorrhage. The technique has been applied successfully in 10 cases of trauma and aortocaval fistula. Exposure and insertion are simple and quick and a measure of control is obtained before exposure of the injury which can then be completely repaired before deflation of the balloon and withdrawal of the catheter.     

ARTHROSCOPIC REMOVAL OF ACRYLIC CEMENT FROM UNREDUCED HIP PROSTHESIS

A case is reported in which entrapped polymethylmethacrylate following traumatic dislocation of a total hip replacement prevented complete reduction. A combined arthroscopic and fluoroscopic technique was used to remove the entrapped polymethylmethacrylate. Manipulation of the total hip prosthesis was done after removal of polymethylmethacrylate to minimize mechanical abrasion. This technique allows direct visual assessment of the articulating surfaces as well as the mechanical stability of the prosthesis. The morbidity related to the procedure is minimal and a short rehabilitation period is the major advantage.     

Activation of the Ha-, Ki-, and N-ras genes in chemically induced liver tumors from CD-1 mice.

We compared the profile of ras gene mutations in spontaneous CD-1 mouse liver tumors with that found in liver tumors that were induced by a single i.p. injection of either 7,12-dimethylbenz(a)anthracene (DMBA), 4-aminoazobenzene, N-hydroxy-2-acetylaminofluorene, or N-nitrosodiethylamine. By direct sequencing of polymerase chain reaction-amplified tumor DNA, the carcinogen-induced tumors were found to have much higher frequencies of ras gene activation than spontaneous tumors. Furthermore, each carcinogen caused specific types of ras mutations not detected in spontaneous tumors, including several novel mutations not previously associated with either the carcinogen or mouse hepatocarcinogenesis. For example, the model compound DMBA is known to cause predominantly A to T transversions in Ha-ras codon 61 in mouse skin and mammary tumors, consistent with the ability of DMBA to form bulky adducts with adenosine. Our results demonstrate that the predominant mutation caused by DMBA in mouse liver tumors is a G to C transversion in Ki-ras codon 13 (DMBA is also known to form guanosine adducts), illustrating the influence of both chemical- and tissue-specific factors in determining the type of ras gene mutations in a tumor. 4-Aminoazobenzene and N-hydroxy-2-acetylaminofluorene also caused the Ki-ras codon 13 mutation. In addition, we found that N-nitrosodiethylamine, 4-aminoazobenzene, and N-hydroxy-2-acetylaminofluorene all caused G to T transversions in the N-ras gene (codons 12 or 13). This is the first demonstration of N-ras mutations in mouse liver tumors, establishing a role for the N-ras gene in mouse liver carcinogenesis. Finally, comparison of the ras mutations detected in the direct tumor analysis with those detected after NIH3T3 cell transfection indicates that spontaneous ras mutations (in Ha-ras codon 61) are often present in only a small fraction of the tumor cells, raising the possibility that they may sometimes occur as a late event in CD-1 mouse hepatocarcinogenesis.