PubMed Health⌕ Search

Biomedical subjects

Michael Chancellor

Publications and source records attributed to Michael Chancellor.

7 recordsLinked to original sources
PubMed2004

Sustained intravesical drug delivery using thermosensitive hydrogel.

PURPOSE: Direct instillation of drug solutions into the bladder through a urethral catheter (i.e., intravesical therapy) evades systemic adverse effects of drugs used for bladder diseases. However, conventional vehicles for these drugs fail to extend duration of drug exposure in the bladder beyond the first voiding of urine postinstillation. The current study seeks to overcome the aforementioned inherent limitation of intravesical drug administration by using thermosensitive hydrogel as a matrix for sustained intravesical drug delivery. METHODS: Under halothane anesthesia, normal adult female Sprague-Dawley rats were catheterized with PE-50 tubing to instill either 0.02% w/v solution of fluorescein isothiocyanate (FITC) or the same amount of FITC in a 30% w/v dispersion of thermosensitive [Poly(ethylene glycol)-Poly[lactic acid-co-glycolic acid]-Poly(ethylene glycol)) (PEG-PLGA-PEG) polymer in a 0.1 M phosphate buffer. After instillations, rats were kept in metabolic cages for urine collection. Fluorescence emanating from FITC was measured in the urine at various time points up to 24 h after instillation. A rat model of cyclophosphamide-induced cystitis was chosen for the efficacy study using misoprostol as a model drug entrapped in the thermosensitive hydrogel in place of FITC. Efficacy of hydrogel containing misoprostol was compared against rat groups instilled with saline, hydrogel, and misoprostol independently. RESULTS: Prolonged drug exposure to the bladder afforded by hydrogel was evident from the time course of FITC elimination in the urine and by the green fluorescence of FITC seen at the bladder surface when isolated 24 h after instillation. Rats instilled with free FITC voided almost all of the fluorescence in the urine within the first 8 h, whereas rats instilled with hydrogel encapsulated FITC showed sustained release up to 24 h after instillation. Using a cyclophosphamide-induced cystitis model, rats instilled with misoprostol, a synthetic PGE1 analog, showed significantly reduced frequency of urine voiding (p < 0.05) as compared to the rats instilled with saline. Histological examination of the urothelium showed near normal morphology in rats instilled with misoprostol in hydrogel, whereas extensive tissue damage was observed in rats instilled with saline. CONCLUSION: Our study showed that PEG-PLGA-PEG polymer could be used as a viable sustained drug delivery system for intravesical therapy of diseases of the bladder such as cystitis using misoprostol.

Animals↗
PubMed2002

Technique of combined pubovaginal sling and cystocele repair using a single piece of cadaveric dermal graft.

OBJECTIVES: To investigate the feasibility of using a single piece of cadaveric dermal allograft for the repair of stress urinary incontinence (SUI) with concurrent cystocele. METHODS: Nineteen patients with combined SUI and symptomatic grade III cystoceles were treated. Eleven of 19 patients had undergone prior repairs for SUI. All patients underwent a combined pubovaginal sling procedure and cystocele repair using a single piece of cadaveric dermal allograft (3 x 7 cm). The single strip of dermal graft was placed in a longitudinal direction along the anterior vagina. The distal segment of the allograft supported the urethra, and the proximal portion supported the central cystocele defect and was sutured to the pubocervical fascia. The mean follow-up was 28 +/- 4 months and patients were monitored by physical examination, videourodynamic studies, and completion of the bladder bothersome visual analog scale. RESULTS: Of the 19 patients, 1 developed an acute infection and failure of the graft after presenting with fever, discharge, dysuria, and incontinence. The autolysed graft was removed, and she subsequently underwent successful autologous fascial repair. Of the remaining 18 patients, 17 were cured of their SUI, including 10 who had had prior repairs, and 16 had no recurrence of cystocele and 2 had asymptomatic grade I and II cystoceles. One patient developed de novo detrusor instability that was successfully treated with anticholinergic medication. No cases of urethral obstruction occurred. CONCLUSIONS: Although the follow-up was short, the use of a single piece of cadaveric dermal graft slings for concomitant pubovaginal sling and cystocele repair is feasible and simple to perform. At more than 2 years of follow-up, documented by videourodynamic studies, neither urethral obstruction nor symptomatic cystocele recurrence was found.

Adult↗
PubMed2002

Bacterial toxin N-formyl-methionyl-leucyl-phenylalanine acutely contracts human and rabbit detrusor through the release of eicosanoids.

PURPOSE: Uropathogenic bacteria that secrete N-formylmethionyl oligopeptides such as N-formyl-methionyl-leucyl-phenylalanine (f-MLP) are a common cause of urinary tract infections. We determined the in vitro effects of f-MLP on human and rabbit detrusor as well as its mechanism and site of action. MATERIALS AND METHODS: Reverse transcriptase-polymerase chain reaction was used to investigate cyclooxygenase-2 messenger RNA within the rabbit detrusor. Standard mechanical organ bath recording techniques were used to measure contractile activity from rabbit and human detrusor muscle strips. Immunohistochemistry was performed using macrophage specific antibodies (human BerMAC3 and rabbit RAM11) on detrusor whole mount specimens. RESULTS: Muscle activity recorded from human and rabbit detrusor showed that f-MLP caused contracture of the detrusor, which was completely blocked by indomethacin and partially blocked by individual cyclooxygenase-1 and cyclooxygenase-2 selective inhibitors. Exposure of the detrusor to exogenous prostaglandins indicated that f-MLP released an effective concentration of more than 1 microM. from an endogenous source. Immunohistochemical staining of the human (BerMAC3) and rabbit (RAM11) bladder demonstrated a dense network of resident macrophages lying within the detrusor muscle bundles, which are known to secrete prostaglandins during the activation of specific f-MLP receptors. CONCLUSIONS: Bacterial derived f-MLP contracts the detrusor through the release of eicosanoids from resident macrophages. These data suggest that bacterial activation of the resident macrophage network could participate in causing the symptoms of bacterial cystitis.

Animals↗
PubMedDate not supplied

Intravesical antisense therapy for cystitis using TAT-peptide nucleic acid conjugates.

The present study investigated the potential of intravesical instillation for localized reduction of NGF (nerve growth factor) expression in the urinary bladder. Overexpression of NGF has been linked to the pathogenesis of interstitial cystitis (IC). A minimum free energy algorithm was used to predict suitable regions in mRNA of rat betaNGF, which can be targeted for an antisense approach. The candidate antisense oligos were evaluated for their ability to reduce NGF expression in vitro by cotransfecting HEK293 cells with NGF cDNA. A single oligonucleotide ODN sequence was chosen for testing in an acute cystitis model in rat induced by cyclophosphamide. Overexpression of NGF is known to mediate inflammation of bladder in this model. For improved stability, antisense ODN was replaced with antisense peptide nucleic acid (PNA) and its penetration into bladder was facilitated by tethering TAT peptide sequence. Rat bladders were instilled with either antisense or its scrambled control prior to cystitis induction. Cystometrograms performed on rats under urethane anaesthesia exhibited bladder contraction frequency that was significantly decreased in the antisense treated rats than rats treated with the control. NGF immunoreactivity was also decreased in the urothelium of the antisense treated bladders. Our findings demonstrate the feasibility of using TAT-PNA conjugates for intravesical antisense therapy.

Administration, Intravesical↗
PubMedDate not supplied

Recent advances in intravesical drug/gene delivery.

Targeting of drugs administered systemically relies on the higher affinity of ligands for specific receptors to obtain selectivity in drug response. However, achieving the same goal inside the bladder is much easier with an intelligent pharmaceutical approach that restricts drug effects by exploiting the pelvic anatomical architecture of the human body. This regional therapy involves placement of drugs directly into the bladder through a urethral catheter. It is obvious that drug administration by this route holds advantage in chemotherapy of superficial bladder cancer, and it has now become the most widely used treatment modality for this ailment. In recent years, the intravesical route has also been exploited either as an adjunct to an oral regimen or as a second-line treatment for neurogenic bladder. (Lamm, D. L.; Griffith, J. G. Semin. Urol. 1992, 10, 39-44. Igawa, Y.; Satoh, T.; Mizusawa, H.; Seki, S.; Kato, H.; Ishizuka, O.; Nishizawa, O. BJU Int. 2003, 91, 637-641.) Instillation of DNA via this route using different vectors has been able to restrict the transgene expression in organs other than bladder. The present review article will discuss the shortcomings of the current options available for intravesical drug delivery (IDD) and lay a perspective for future developments in this field.

Administration, Intravesical↗