Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1.

The alarming reduction in drug effectiveness against bacterial infections has created an urgent need for the development of new antibacterial agents that circumvent bacterial resistance mechanisms. We report here a series of DNA gyrase and topoisomerase IV inhibitors that demonstrate potent activity against a range of Gram-positive and selected Gram-negative organisms, including clinically-relevant and drug-resistant strains. In part 1, we present a detailed structure activity relationship (SAR) analysis that led to the discovery of our previously disclosed compound, REDX05931, which has a minimum inhibitory concentration (MIC) of 0.06 µg mL-1 against fluoroquinolone-resistant Staphylococcus aureus. Although in vitro hERG and CYP inhibition precluded further development, it validates a rational design approach to address this urgent unmet medical need and provides a scaffold for further optimisation, which is presented in part 2.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 2.

Building on our previously-reported novel tricyclic topoisomerase inhibitors (NTTIs), we disclose the discovery of REDX07965, which has an MIC90 of 0.5 µg mL-1 against Staphylococcus aureus, favourable in vitro pharmacokinetic properties, selectivity versus human topoisomerase II and an acceptable toxicity profile. The results herein validate a rational design approach to address the urgent unmet medical need for novel antibiotics.

Tension-free vaginal tape: 162 cases in a district general hospital.

From March 1999 to July 2002 a prospective study was carried out of 162 consecutive cases of urodynamically confirmed stress and mixed incontinence who underwent the tension-free vaginal tape (TVT) procedure. Patients were followed up at 6 weeks and 6 months and with a quality of life questionnaire at 1 year. The intraoperative complication rate was 7.6% and the postoperative complication rate was 18.8%. The subjective cure rate for patients suffering from urodynamic stress incontinence was 85%, with a further 11% experiencing significant improvement in their symptoms. The subjective cure rate for patients with mixed incontinence was 88%, with a further 9% experiencing significant improvement. The TVT procedure appears to be safe and effective for both stress and mixed incontinence for up to three years in a district general hospital. Complications in the short term are uncommon and can be managed easily.

The infusion trial of micturition.

OBJECTIVE: To compare three methods for a trial of micturition (TOM) (the midnight removal of the catheter, dawn removal, and a new infusion method) in a randomized prospective study. PATIENTS AND METHODS: A total of 118 consecutive patients who had undergone transurethral resection of the prostate (TURP) or bladder neck incision (BNI) underwent TOM by one of the three methods. In the infusion method, the bladder was filled at a fast-drip rate via the catheter from a bag of normal saline connected by an intravenous supply set. The catheter was then removed, the patient voided and the volume was measured. From the volume of saline remaining, it was possible to calculate the residual volume in the patient. RESULTS: The infusion TOM took a mean 13 h less than the other two methods, which were statistically indistinguishable. CONCLUSION: The infusion TOM is safe and simple, is quick to carry out and can be performed at any time. It establishes the completeness of bladder emptying, which helps in the assessment of voiding.

Does ethamsylate reduce haemorrhage in transurethral prostatectomy?

A double-blind, randomised trial of 44 consecutive patients undergoing transurethral prostatectomy demonstrated that ethamsylate (Dicynene) did not reduce blood loss during either the operative or the post- operative periods.