First Phase 1 Double-Blind, Placebo-Controlled, Randomized Rectal Microbicide Trial Using UC781 Gel with a Novel Index of Ex Vivo Efficacy

Objectives: Successful control of the HIV/AIDS pandemic requires reduction of HIV-1 transmission at sexually-exposed mucosae. No prevention studies of the higher-risk rectal compartment exist. We report the first-in-field Phase 1 trial of a rectally-applied, vaginally-formulated microbicide gel with the RT-inhibitor UC781 measuring clinical and mucosal safety, acceptability and plasma drug levels. A first-in-Phase 1 assessment of preliminary pharmacodynamics was included by measuring changes in ex vivo HIV-1 suppression in rectal biopsy tissue after exposure to product in vivo. Methods: HIV-1 seronegative, sexually-abstinent men and women (N = 36) were randomized in a double-blind, placebo-controlled trial comparing UC781 gel at two concentrations (0.1%, 0.25%) with placebo gel (1:1:1). Baseline, single-dose exposure and a separate, 7-day at-home dosing were assessed. Safety and acceptability were primary endpoints. Changes in colorectal mucosal markers and UC781 plasma drug levels were secondary endpoints; ex vivo biopsy infectibility was an ancillary endpoint. Results: All 36 subjects enrolled completed the 7-14 week trial (100% retention) including 3 flexible sigmoidoscopies, each with 28 biopsies (14 at 10 cm; 14 at 30 cm). There were 81 Grade 1 adverse events (AEs) and 8 Grade 2; no Grade 3, 4 or procedure-related AEs were reported. Acceptability was high, including likelihood of future use. No changes in mucosal immunoinflammatory markers were identified. Plasma levels of UC781 were not detected. Ex vivo infection of biopsies using two titers of HIV-1 BaL showed marked suppression of p24 in tissues exposed in vivo to 0.25% UC781; strong trends of suppression were seen with the lower 0.1% UC781 concentration. Conclusions: Single and 7-day topical rectal exposure to both concentrations of UC781 were safe with no significant AEs, high acceptability, no detected plasma drug levels and no significant mucosal changes. Ex vivo biopsy infections demonstrated marked suppression of HIV infectibility, identifying a potential early biomarker of efficacy. (Registered at ClinicalTrials.gov; #NCT00408538). © 2011 Anton et al

Giant cell tumour of the sacrum: a suggested algorithm for treatment

To investigate the outcome of our management of patients with giant cell tumour of the sacrum and draw lessons from this. A retrospective review of medical records and scans for all patients treated at our unit over the past 20 years with a giant cell tumour of the sacrum. Of the 517 patients treated at our unit for giant cell tumour over the past 20 years, only 9 (1.7%) had a giant cell tumour in the sacrum. Six were female, three male with a mean age of 34 (range 15–52). All, but two tumours involved the entire sacrum and there was only one purely distal to S3. The mean size was 10 cm and the most common symptom was back or buttock pain. Five had abnormal neurology at diagnosis, but only one presented with cauda equina syndrome. The first four patients were treated by curettage alone, but two patients had intraoperative cardiac arrests and although both survived all subsequent curettages were preceded by embolisation of the feeding vessels. Of the seven patients who had curettage, three developed local recurrence, but all were controlled with a combination of further embolisation, surgery or radiotherapy. One patient elected for treatment with radiotherapy and another had excision of the tumour distal to S3. All the patients are alive and only two patients have worse neurology than at presentation, one being impotent and one with stress incontinence. Three patients required spinopelvic fusion for sacral collapse. All patients are mobile and active at a follow-up between 2 and 21 years. Giant cell tumour of the sacrum can be controlled with conservative surgery rather than subtotal sacrectomy. The excision of small distal tumours is the preferred option, but for larger and more extensive tumours conservative management may well avoid morbidity whilst still controlling the tumour. Embolisation and curettage are the preferred first option with radiotherapy as a possible adjunct. Spinopelvic fusion may be needed when the sacrum collapses

Mapping of drug-related problems among older adults conciliating medical and pharmaceutical approaches

PURPOSE: To lay the fundamentals of drug-related problems (DRPs) in older adults, and to organize them according to a logical process conciliating medical and pharmaceutical approaches, to better identify the causes and consequences of DRPs. MATERIALS AND METHODS: A narrative overview. RESULTS: The causes of DRPs may be intentional or unintentional. They lie in poor prescription, poor adherence, medication errors (MEs) and substance use disorders (SUD). Poor prescription encompasses sub-optimal or off-label drug choice; this choice is either intentional or unintentional, often within a polypharmacy context and not taking sufficiently into account the patient's clinical condition. Poor adherence is often the consequence of a complicated administration schedule. This review shows that MEs are not the most frequent causes of DRPs. SUD are little studied in older adults and needs to be more investigated because the use of psychoactive substances among older people is frequent. Prescribers, pharmacists, nurses, patients, and caregivers all play a role in different causes of DRPs. The potential deleterious outcomes of DRPs result from adverse drug reactions and therapeutic failures. These can lead to a negative benefit-risk ratio for a given treatment regimen. DISCUSSION/CONCLUSION: Interdisciplinary pharmacotherapy programs show significant clinical impacts in preventing or resolving adverse drug events and, suboptimal responses. New technologies also seem to be interesting solutions to prevent MEs. Better communication between healthcare professionals, patients and their caregivers would ensure greater safety and effectiveness of treatments