Formulation and evaluation of simvastatin cubosomal nanoparticles for assessing its wound healing effect.

Wound healing is one of the most challenging medical circumstances for patients. Pathogens can infect wounds, resulting in tissue damage, inflammation, and disruption of the healing process. Simvastatin was investigated recently, as a wound healing agent that may supersede the present therapies for wounds. Our goal in this paper is to focus on formulation of simvastatin cubosomes for topical delivery, as a potential approach to improve simvastatin skin permeation. By this technique its wound healing effect could be improved. Cubosomes were prepared using the top-down method and the prepared cubosomes were characterized by several techniques. The most optimal simvastatin cubosomal formulation was then included in a cubogel dosage form using different gelling agents. The results showed that the average particle size of the prepared cubosomes was 113.90 ± 0.58 nm, the entrapment efficiency was 93.95 ± 0.49% and a sustained simvastatin release was achieved. The optimized formula of simvastatin cubogel displayed pseudoplastic rheological behavior. This same formula achieved enhancement in drug permeation through excised rat skin compared to free simvastatin hydrogel with flux values of 46.18 ± 2.12 mcg cm-2 h-1 and 25.92 ± 3.45 mcg cm-2 h-1 respectively. Based on the in-vivo rat studies results, this study proved a promising potential of simvastatin cubosomes as wound healing remedy.

Colon-targeting of progesterone using hybrid polymeric microspheres improves its bioavailability and in vivo biological efficacy.

This study aims to enhance progesterone (PG) oral bioavailability via its incorporation into hybrid colon-targeted pectin/NaCMC microspheres (MS) cross-linked with Zn2+ and Al3+. The MS were characterized for particle morphology, encapsulation efficiency, swelling behavior, drug release, mucoadhesivity and colon-specific degradability. Response-surface methodology was adopted to optimize the fabrication conditions. Enhancement of in vivo drug performance was evaluated through pharmacokinetic and pharmacodynamic studies. The optimized formulation was typically spherical with a mean diameter of 1031 µm and drug entrapment efficiency of 88.8%. This formulation exhibited pH-dependent swelling, negligible drug release in simulated gastric fluid and sustained-release pattern in simulated small intestinal fluid with a mean t50% of 26.5 h. It also showed prolonged and preferential adhesion to rat colonic mucosa, as well as expedited degradation in presence of rat caecal contents. The MS significantly increased the area under the curve and mean residence time by 1.8 and 2.3-fold, respectively compared to the free drug. Orally administered MS showed ~10 times increase in myometrial thickness compared with the drug suspension and elicited uterine responses very similar to that obtained parenterally. These results confirm the ability of this new carrier system to improve the oral bioavailability of PG and attain adequate clinical efficacy.

Amidated pectin/sodium carboxymethylcellulose microspheres as a new carrier for colonic drug targeting: Development and optimization by factorial design.

The colon is a promising site for drug targeting owing to its long transit time and mild proteolytic activity. The aim of this study was to prepare new low methoxy amidated pectin/NaCMC microspheres cross-linked by a mixture of Zn(2+) and Al(3+) ions and test their potential for colonic targeting of progesterone. A 2(4) factorial design was carried out to optimize the preparation conditions. High drug entrapment efficiency (82-99%) was obtained and it increased with increasing drug concentration but decreased with increasing polymer concentration. Drug release rate was directly proportional to the microsphere drug content and inversely related to Al(3+) ion concentration. Drug release was minimal during the first 3h but was significantly improved in the presence of 1% rat caecal contents, confirming the microsphere potential for colonic delivery. The microspheres achieved >2.3-fold enhancement of colonic progesterone permeability. These results confirm the viability of the produced microspheres as colon-targeted drug delivery vehicle.

Development and in vitro/in vivo evaluation of Zn-pectinate microparticles reinforced with chitosan for the colonic delivery of progesterone.

The colon is a promising target for drug delivery owing to its long transit time of up to 78 h, which is likely to increase the time available for drug absorption. Progesterone has a short elimination half-life and undergoes extensive first-pass metabolism, which results in very low oral bioavailability (∼25%). To overcome these shortcomings, we developed an oral multiparticulate system for the colonic delivery of progesterone. Zn-pectinate/chitosan microparticles were prepared by ionotropic gelation and characterized for their size, shape, weight, drug entrapment efficiency, mucoadhesion and swelling behavior. The effect of cross-linking pH, cross-linking time and chitosan concentration on progesterone release were also studied. Spherical microparticles having a diameter of 580-720 µm were obtained. Drug entrapment efficiency of ∼75-100% was obtained depending on the microparticle composition. Microparticle mucoadhesive properties were dependent on the pectin concentration, as well as the cross-linking pH. Progesterone release in simulated gastric fluids was minimal (3-9%), followed by burst release at pH 6.8 and a sustained phase at pH 7.4. The in vivo study revealed that the microparticles significantly increased progesterone residence time in the plasma and increased its relative bioavailability to ∼168%, compared to the drug alone. This study confirms the potential of Zn-pectinate/chitosan microparticles as a colon-specific drug delivery system able to enhance the oral bioavailability of progesterone or similar drugs.

Preparation and in vitro/in vivo evaluation of the buccal bioadhesive properties of slow-release tablets containing miconazole nitrate.

Slow-release buccal bioadhesive tablets of miconazole nitrate were prepared by using polymer mixtures of buccoadhesive materials such as hydroxypropylmethylcellulose, sodium carboxymethylcellulose, carbopol 934p, and sodium alginate. The physicochemical properties, swelling index, microenvironment pH, in vitro drug release, in vivo buccoadhesion time, and miconazole salivary concentrations of the prepared tablets were shown to be dependent on the type and composition of the buccoadhesive materials used. The dissolution of miconazole from all the prepared tablets into phosphate buffer (pH 6.8) was controlled and followed non-Fickian release mechanisms. All the prepared tablets gave reasonable buccoadhesion time (2.45-3.65 hr). Infrared spectroscopy and differential scan calorimetry studies revealed the absence of significant interactions between miconazole nitrate and the selected buccoadhesive materials. Duration of the antifungal activity as measured by the inhibition zone of Candida albicans by extracted human saliva was significantly longer (p < 0.05), compared with commercial miconazole oral gel (Daktaren oral gel). Based on the results obtained, the prepared slow-release buccoadhesive tablets of miconazole would markedly prolong the duration of the antifungal activity with more patient convenience.

Laparoscopic radical cystectomy with intracorporeal ileal conduit diversion: five cases with a 2-year follow-up.

OBJECTIVE: To assess the feasibility and intermediate-term outcome of laparoscopic radical cystectomy (LRC) with ileal conduit urinary diversion in patients with organ-confined muscle-invasive carcinoma of the urinary bladder, the entire procedure undertaken intracorporeally only using laparoscopic techniques. PATIENTS AND METHODS: Five patients (four men and one woman) underwent LRC with intracorporeal ileal conduit diversion in February 2000, using a six-port transperitoneal technique. LRC, ileal conduit exclusion, restoration of ileo-ileal continuity, and bilateral stented uretero-ileal anastomoses were completed intracorporeally in all patients. The follow-up data up to 2 years are reported. RESULTS: All procedures were completed laparoscopically with no open conversion or intraoperative complications. The mean duration of surgery was 7.5 h; the blood loss was 360 mL and no patient required perioperative blood transfusion. The mean (range) hospital stay was 7 (6-22) days; the specimen weight was 225-400 g. The surgical margins of the bladder specimen were negative in each patient. One patient developed intestinal obstruction after surgery, requiring a diverting ileostomy for 12 weeks. At a follow-up of 2 years, two patients died, both from unrelated causes (myocardial infarction and septicaemia from pulmonary infection in one each). The three surviving patients are asymptomatic with normal upper tracts and no evidence of local recurrence or metastatic disease. CONCLUSION: LRC with ileal conduit diversion undertaken completely intracorporeally is a feasible option for muscle-invasive organ-confined carcinoma of the urinary bladder, with good outcomes over a 2-year follow-up.

Laparoscopic bladder flap ureteral reimplantation: survival porcine study.

PURPOSE: The bladder or Boari flap is a useful technique for ureteroneocystostomy when the distal ureter is too short to reach the bladder without undue tension. We report our experience with laparoscopic Boari flap ureteroneocystostomy in the chronic porcine model. MATERIALS AND METHODS: Six female farm pigs underwent unilateral laparoscopic Boari bladder flap ureteroneocystostomy. Refluxing direct ureteral reimplantation was performed in the initial 3 animals. In the next 3 animals a submucosal tunnel was formed to achieve nonrefluxing ureteroneocystostomy into the Boari flap. The animals were sacrificed 6 weeks after surgery. At sacrifice ascending cystography, ipsilateral antegrade pyelography and autopsy examination of the ureteroneocystostomy site was performed. RESULTS: No intraoperative or postoperative complications were noted. Average operative time was 140 minutes. Postoperatively serum creatinine and hemoglobin were normal in all pigs. All 3 animals with direct ureteroneocystostomy into the Boari flap had free reflux into the kidney and all 3 with a submucosal tunnel reimplant had no reflux on ascending cystography and free drainage on antegrade pyelography. Autopsy confirmed a patent anastomotic site in all 6 cases. CONCLUSIONS: Laparoscopic ureteroneocystostomy using the Boari bladder flap technique is feasible. Our survival porcine model confirms the successful application of the refluxing and nonrefluxing technique of ureteral reimplantation. Clinical application of the technique has the potential to decrease patient morbidity associated with traditional open surgery.

Laparoscopic repair of renal artery aneurysm.

PURPOSE: We describe technical considerations of the laparoscopic repair of a renal artery aneurysm. MATERIALS AND METHODS: A 57-year-old woman presented with a 3 cm. aneurysm of the distal left main renal artery at its bifurcation. Using a purely laparoscopic 4-port transperitoneal technique the aneurysm was completely mobilized from its location behind the renal vein. Its 3 feeding vessels were controlled individually with bulldog clamps. The aneurysm sac was bivalved and precisely trimmed to conform with the diameter of the main renal artery. Vascular reconstruction was performed with running freehand laparoscopic suturing and intracorporeal knot tying using 4-zero polypropylene suture. RESULTS: Warm ischemia time was 31 minutes, total operative time was 4.2 hours, blood loss was 100 cc and hospital stay was 2 days. Postoperatively renal scan showed improved perfusion and renal arteriography confirmed adequate repair of the aneurysm. CONCLUSIONS: Laparoscopic repair of the renal artery aneurysm is feasible. To our knowledge we present the initial clinical report of laparoscopic renovascular surgery in the literature.

Laparoscopic intracorporeally constructed ileal conduit after porcine cystoprostatectomy.

PURPOSE: We present our technique of laparoscopic ileal conduit creation after cystoprostatectomy in a porcine model performed in a completely intracorporeal manner. METHODS AND METHODS: After developing the technique in 5 acute animals laparoscopic cystoprostatectomy with intracorporeally performed ileal conduit urinary diversion was performed in 10 surviving male pigs. A 5-port transperitoneal technique was used. All steps of the technique applied during open surgery were duplicated intracorporeally. Specifically cystectomy, isolation of an ileal conduit, restoration of bowel continuity and mucosa-to-mucosa stented bilateral ileoureteral anastomosis formation were performed by exclusively intracorporeal laparoscopic techniques. RESULTS: Surgery was successful in all 10 study animals without intraoperative or immediate postoperative complications. Blood loss was minimal and average operative time was 200 minutes. Stenosis of the end ileal stoma specifically at the skin level was noted in 6 animals. Three deaths occurred 2 to 3 weeks postoperatively. At sacrifice renal function was normal in all surviving animals. No ileo-ureteral anastomotic strictures were noted on pre-sacrifice radiography of the loop or at autopsy examination of the anastomotic sites. CONCLUSIONS: Laparoscopic ileal conduit urinary diversion after cystoprostatectomy may be performed completely intracorporeally in the porcine model. Clinical application of this technique is imminent.

Laparoscopic orthotopic ileal neobladder.

BACKGROUND AND PURPOSE: Orthotopic ileal neobladder is currently the preferred continent urinary diversion in suitable patients undergoing radical cystectomy for muscle-invasive bladder cancer. To our knowledge, presented herein is the initial report of laparoscopic orthotopic ileal neobladder following cystectomy that was performed completely intracorporeally in a porcine model. MATERIALS AND METHODS: The laparoscopic technique was developed in seven pigs. Subsequently, a long-term survival study was performed in 12 consecutive animals. Laparoscopic cystectomy was performed, preserving the urethral sphincter. An ileal segment of 35 cm (first three animals), 45 cm (next four), or 55 cm (final five animals) with adequate mesentery was isolated; and ileal continuity was restored intracorporeally by a stapled anastomosis. Ileal detubularization for construction of an ileal neobladder, urethroileal anastomosis, and bilateral stented ileoureteral anastomoses to a tubular Studer limb extension were all created completely intracorporeally using only laparoscopic free-hand suturing and knot-tying. Biochemical data (preoperative and serial postoperative hemoglobin, renal panel, blood gases), radiologic studies (intravenous urogram, retrograde pouchgram), functional measures (neobladder urodynamics, Whitaker pressure-flow study of both ureters), and microscopic evaluation of the neobladder and ureteroileal and urethroileal anastomotic sites were obtained to evaluate the long-term functional and anatomic outcome. RESULTS: Completely intracorporeal laparoscopic construction of an ileal orthotopic neobladder was successful in all 12 animals without intraoperative or early postoperative complications or open conversion. The mean operating time was 5.4 hours (range 4.5-6.5 hours), and the blood loss was minimal. All study pigs survived their predetermined follow-up period, ranging from 1 to 3 months. Late complications occurred in three animals: one port-site abscess and two cases of E. coli pyelonephritis and azotemia, leading to one death at 2 months. The mean serum creatinine concentrations were 1.33 mg/dL, 1.61 mg/dL, and 1.55 mg/dL at 1, 2, and 3 months, respectively. The mean neobladder capacity was 420 mL (range 250-700 mL) with pressures < or = 20 cm H2O (range 17-20 cm H2O). Pre-euthanasia Whitaker testing confirmed excellent drainage in all 24 ureters. No ileoureteral or ileourethral anastomotic strictures or leaks were noted on intravenous urography, retrograde pouchgram, or postmortem physical calibration of the anastomotic sites. Histologic examination confirmed excellent healing without obvious fibrosis. CONCLUSION: Laparoscopic construction of an orthotopic neobladder is feasible. The anatomic and functional outcome is excellent and comparable to that of open surgery. Clinical application is imminent.

Ischemic nephropathy. Epidemiology and clinical implications.

Renal dysfunction secondary to stenosis of the renal arteries is an entity that is underdiagnosed but becoming increasingly recognized. This condition probably accounts for a large number of patients in dialysis programs. Hypertension is not an essential component of this disease. Progression of renal artery stenosis with deterioration of renal function is the natural course. This progression can be reversed with surgical or percutaneous revascularization of the ischemic kidneys with a high degree of success in preserving or restoring kidney function.

Laparoscopic urinary diversion.

Urinary diversion, in conjunction with cystectomy or as an isolated procedure, has traditionally been performed using open surgical technique. Laparoscopic urinary diversion has only recently been reported. We review the available literature on laparoscopic urinary diversion and present some of the experimental and clinical studies that have attempted to overcome the technical difficulties of the procedure. In addition, the indications, results, and future directions of laparoscopic urinary diversion are discussed.

Laparoscopic radical cystoprostatectomy with ileal conduit performed completely intracorporeally: the initial 2 cases.

OBJECTIVES: To present the initial 2 patients who underwent laparoscopic radical cystoprostatectomy, bilateral pelvic lymphadenectomy, and ileal conduit urinary diversion, with the entire procedure performed exclusively by intracorporeal laparoscopic techniques. METHODS: Two male patients, 78 and 70 years old, with muscle-invasive, organ-confined, transitional cell carcinoma of the urinary bladder underwent the procedure. The entire procedure, including radical cystoprostatectomy, pelvic node dissection, isolation of the ileal loop, restoration of bowel continuity with stapled side-to-side ileoileal anastomosis, retroperitoneal transfer of the left ureter to the right side, and bilateral stented ileoureteral anastomoses were all performed exclusively by intracorporeal laparoscopic techniques. Free-hand laparoscopic suturing and in situ knot-tying techniques were used exclusively. RESULTS: The surgical time was 11.5 hours in the first patient and 10 hours in the second. The respective blood loss was 1200 mL and 1000 mL. In both patients, ambulation resumed on postoperative day 2, bowel sounds on day 3, and oral intake on day 4; the hospital stay was 6 days. Narcotic analgesia comprised 108.3 mg and 16.5 mg of morphine sulfate equivalent, respectively. Pathologic examination revealed pT4N0M0 (prostate) and pT2bN0M0 transitional cell carcinoma of the bladder with the surgical margins negative for cancer in both patients. No intraoperative or postoperative complications occurred in either patient. CONCLUSIONS: To our knowledge, this is the initial report of laparoscopic radical cystoprostatectomy with intracorporeal ileal conduit urinary diversion. We believe that with further experience and refinement in the operative technique, laparoscopic radical cystoprostatectomy with ileal conduit urinary diversion may become an attractive treatment option for selected candidates with localized muscle-invasive bladder cancer.

No difference in biochemical failure rates with or without pelvic lymph node dissection during radical prostatectomy in low-risk patients.

OBJECTIVES: To detect the short-term differences in biochemical relapse-free rates between patients with and without pelvic lymph node dissection (PLND). Recently, a trend has begun to omit PLND in patients undergoing radical prostatectomy considered at low risk of pelvic lymph node metastases. METHODS: The records of 1152 consecutive radical prostatectomy cases were reviewed. A total of 575 patients with favorable tumor characteristics (prostate-specific antigen [PSA] 10 ng/mL or less, Gleason score 6 or less, and clinical Stage T1 or T2) who were not receiving adjuvant or neoadjuvant therapy were divided into two groups according to whether PLND was performed (PLND group, n = 372) or omitted (no PLND group, n = 203). Proportional hazards were used to analyze the effect of age, race, family history, stage, biopsy Gleason score, initial PSA, PLND, and pathologic findings on the likelihood of biochemical failure. Biochemical failure-free survival for each group was estimated by Kaplan-Meier analysis. The mean follow-up was 38 months (range 1 to 141). RESULTS: The actuarial 4-year biochemical relapse-free rate for the PLND versus no PLND groups was 91% and 97%, respectively (P = 0.16). On multivariate analysis, PLND was not an independent predictor of outcome (P = 0.24). CONCLUSIONS: The results of our study indicate that the omission of PLND in patients with favorable tumor characteristics does not adversely affect biochemical relapse rates.

Retroperitoneal minilaparoscopic nephrectomy in the rat model.

OBJECTIVES: Development of small animal models for laparoscopic surgery is important for basic pathophysiologic and oncologic studies, instrument development, and surgical training. Although transperitoneal laparoscopy has been described in the rat, the technical feasibility of the retroperitoneoscopic approach for major renal surgery has not been reported previously. Herein, we describe the development of a rat model for retroperitoneal minilaparoscopic nephrectomy. METHODS: Sixteen male Sprague-Dawley rats underwent a three-port bilateral retroperitoneoscopic nephrectomy using 2 and 3-mm instruments and optics exclusively. After developing the technique in 10 animals, the study was conducted in 6 animals. Following retroperitoneal balloon dilation and CO(2) pneumoretroperitoneum (mean 4.5 mm Hg), nephrectomy was accomplished by intracorporeal en bloc ligation of the renal pedicle. To prevent peritoneal entry, the anterior surface of the kidney was mobilized subcapsularly. Volume of the created retroperitoneal space and peritoneal integrity were confirmed by a contrast x-ray study. Intraperitoneal pressure was monitored constantly during the procedure. RESULTS: Mean surgical time was 74.5 minutes (range 60 to 95) and estimated blood loss was less than 1 mL. Mean volume of the retroperitoneal space was 8.4 mL after initial balloon dilation, and 11.5 mL after nephrectomy. Mean weight of the excised kidneys was 1. 4 g. Inadvertent peritoneotomy occurred during 3 of 12 study nephrectomies. Complications included renal artery hemorrhage leading to death in 1 animal and renal vein injury in 1 animal. CONCLUSIONS: Laparoscopic retroperitoneal nephrectomy in the rat model is technically feasible. This novel small animal model can be used for further studies of the retroperitoneal laparoscopic approach.

Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year followup.

PURPOSE: Partial nephrectomy is effective for renal cell carcinoma when preservation of renal function is a concern. We present the 10-year followup of patients treated with nephron sparing surgery at our institution. MATERIALS AND METHODS: Partial nephrectomy was performed in 107 patients with localized sporadic renal cell carcinoma before December 1988. Tumors were symptomatic in 73 patients (68%) and indications for surgery were imperative in 96 (90%). Of the patients 42 (39%) had renal insufficiency preoperatively. All patients were followed a minimum of 10 years or until death. RESULTS: At the end of the followup interval 32 patients (30%) had no evidence of recurrence, 28 (26%) died of metastatic renal cell carcinoma and 46 (42%) died of unrelated causes. Cancer specific survival was 88.2% at 5 and 73% at 10 years, and was significantly affected by tumor stage, symptoms, tumor laterality and tumor size. Long-term renal function was stable in 52 patients (49%). CONCLUSIONS: Partial nephrectomy is effective for localized renal cell carcinoma, providing long-term tumor control with preservation of renal function.

A technique of transrectal ultrasound guided transperineal random prostate biopsy in patients with ulcerative colitis and an ileal pouch.

PURPOSE: Prostate biopsy in patients with rectal disease may present a difficult urological problem. We describe a useful technique for the accurate guidance of transperineal random prostate biopsy in patients with colorectal disease. MATERIALS AND METHODS: Biopsy was required in a patient with ulcerative colitis and an ileal pouch who had chronic pouchitis. Biopsy through the pouch was avoided by performing random transperineal prostate biopsies using the ultrasound grid and stabilizing platform used for prostate brachytherapy. RESULTS: Accurate random sampling of the prostate was accomplished. Multiple cores of prostatic tissue were successfully obtained. CONCLUSIONS: Random transperineal biopsy of the prostate was accurately performed under transrectal ultrasound guidance. With the increasing availability of brachytherapy equipment we believe that this method may be used for prostate biopsy in patients with rectal disease.

Nephron sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence and TNM staging.

PURPOSE: We studied the impact of tumor size on patient survival and tumor recurrence following nephron sparing surgery for localized sporadic renal cell carcinoma. In addition, we evaluated the usefulness of the new TNM staging system in which T1 versus T2 tumor status is delineated by tumor size 7 or less versus more than 7 cm., respectively. MATERIALS AND METHODS: The results of nephron sparing surgery for localized sporadic renal cell carcinoma in 485 patients treated before 1997 were reviewed. Patients were divided into groups according to tumor size as 1--2.5 or less (142), 2--2.5 to 4.0 (168), 3--more than 4 to 7 (125) and 4--more than 7 cm (50). Mean postoperative followup was 47 months. RESULTS: Overall and cancer specific 5-year survival for the entire series was 81 and 92%, respectively. Of 44 patients with recurrent renal cell carcinoma 16 (3.2%) had local recurrence and 28 (5.8%) had metastatic disease. There was no difference in 5-year cancer specific survival or tumor recurrence between groups 1 and 2 or groups 3 and 4. However, these outcome measures were significantly more favorable in groups 1 and 2 combined (tumors 4 cm. or less) compared to groups 3 and 4 combined (tumors more than 4 cm.) (p = 0.001). CONCLUSIONS: Following nephron sparing surgery for localized sporadic renal cell carcinoma cancer-free survival is significantly better in patients with tumors 4 cm. or less compared to those with larger tumors. The usefulness of the current TNM staging system can be improved by subdividing T1 tumors into T1a (4 cm. or less) and T1b (4 to 7 cm.).

Review of Cleveland Clinic experience with penile fracture.

OBJECTIVES: Fracture of the penis is an uncommon injury that results from trauma to the erect penis, usually during sexual intercourse. In some cases, the urethra is injured as well. To determine the outcome of immediate surgical management, we reviewed the cases of 8 patients with fracture of the penis who presented to the Cleveland Clinic from 1992 to 1998. METHODS: Trauma was encountered during intercourse in all our patients. A concomitant urethral injury was found in 3 cases (38%); 1 was a complete disruption, and the other 2 were partial injuries. Patients were treated with immediate surgical exploration and repair, with preoperative urethrography in patients suspected of having a urethral injury. RESULTS: All patients had a successful outcome, with preservation of sexual function and without significant penile curvature. Patients with urethral injuries reported normal voiding without the need for additional procedures. CONCLUSIONS: Immediate surgical repair offers complete recovery for patients with penile fracture in most cases, even in the presence of urethral injury. We present our recommendations for treatment of this condition.