Angiotensin-(1-7) administration reduces oxidative stress in diabetic bone marrow.

Diabetics have an increased risk of developing cardiovascular disease, in part due to oxidative stress, resulting in endothelial nitric oxide synthase (eNOS) dysfunction. Studies have demonstrated that angiotensin-(1-7) [Ang-(1-7)] can activate eNOS activity. Because the bone marrow is a primary source of a number of progenitors important in physiological homeostasis and healing, the goal of this study was to evaluate the in vivo effects of Ang-(1-7) treatment on oxidative stress and the ensuing nitrative stress in diabetic bone marrow and its potential pathways. BKS.Cg-Dock7(m) +/+ Lepr(db)/J mice and their heterozygous controls were administered Ang-(1-7) alone or combined with A-779, losartan, PD123,319, nitro-l-arginine methyl ester, or icatibant sc for 14 d. The bone marrow was then collected to measure nitric oxide levels, eNOS phosphorylation, and expression of nitric oxide synthase, superoxide dismutase, and p22-phox. Nitric oxide levels in the bone marrow were significantly decreased in diabetic mice, and Ang-(1-7) treatment was able to significantly increase these measures (P < 0.01). This effect was blocked by the coadministration of PD123,319, A-779, nitro-l-arginine methyl ester, and icatibant. In addition, Ang-(1-7) treatment reversed the paradoxical increase in eNOS and neuronal nitric oxide synthase expression and decreased the phosphorylation of eNOS at Thr495 seen in diabetic mice. Ang-(1-7) also reversed diabetes-induced production of reactive oxygen species by decreasing p22-phox expression and increasing superoxide dismutase 3 expression, leading to a significant reduction in 3-nitrotyrosine formation in diabetic bone marrow (P < 0.05). Our findings demonstrate that Ang-(1-7) administration decreases diabetes-induced oxidative stress in the bone marrow and modifies pathways involved in eNOS dysfunction.

Clinical evaluation of a viscoelastic gel for reduction of adhesions following gynaecological surgery by laparoscopy in Europe.

BACKGROUND: Commonly used adhesion prevention devices either cannot be applied or are difficult to use via laparoscopy. A viscoelastic gel was developed specifically for adhesion prophylaxis during minimally invasive surgery. METHODS: Randomized, third party-blinded, parallel-group design conducted at four centres. Patients (18-46 years old) underwent laparoscopic surgery with second look 6-10 weeks later. Viscoelastic gel coated adnexa and adjacent tissues. Blinded reviews of videotapes were quantified by American Fertility Society (AFS) adhesion scores. RESULTS: In 25 treatment patients, surgery was performed on 45 adnexa. Coverage of surgical sites at risk for adhesions was typically accomplished with approximately 15 ml of viscoelastic gel which was delivered in approximately 90 s. In 24 control patients, surgery alone was performed on 41 adnexa. Treated adnexa showed a decrease in AFS score (11.9-9.1). In contrast, control adnexa showed an increase in AFS score (8.8-15.8). This difference in second-look AFS scores (42% reduction) is significant (P<0.01). Ninety-three per cent of treated adnexa did not have a worse adhesion score in contrast to 56% of control adnexa. Combining scores into prognostic categories also show significant treatment effect of the viscoelastic gel (P<0.01). CONCLUSION: Viscoelastic gel was easy to use via laparoscopy and produced significant reduction in adnexal adhesions. It provides benefits to patients undergoing gynaecological surgery.

Effects of intraperitoneal 4% icodextrin solution on the healing of bowel anastomoses and laparotomy incisions in rabbits.

OBJECTIVE: Peri-operative lavage and postoperative instillation of a 4% icodextrin solution reduces de novo formation and reformation of peritoneal adhesions following abdominal surgery. This experimental study evaluated the effects of 4% icodextrin treatment on the healing of bowel anastomoses and laparotomy incisions. MATERIALS AND METHODS: Female New Zealand White rabbits (weight 2.21-2.77 kg) were randomised by ascending weight to one of 3 surgical treatments, each with 2 termination points (6 groups of 8 animals). The treatments were anastomotic bowel surgery alone or with lavage and postoperative instillation of either 4% icodextrin solution or Lactated Ringer's Solution (LRS). The solutions were coded A and B by the supplier, so that the study personnel were blinded to their identity. After the abdomen was opened, 30 ml of solution A or B was instilled and removed by aspiration prior to surgery. The ascending colon was then transected 5 cm aboral to the ileocaecal junction and the ends anastomosed. During surgery, 5 ml of the solution was applied 4 times at the surgical site, and a further 30 ml was administered and aspirated as a postoperative lavage. Just prior to closure of the abdominal wall, 50 ml of the solution was administered as a postoperative instillate. Duplicate treatment groups were terminated 7 and 21 days after surgery and the anastomotic sites inspected for adhesion and/or abscess formation. In 6 animals per group, an 8-12 cm length of colon including the anastomotic site was removed for measurement of bursting pressure, and a section of the abdominal wall including the incision line was tested for breaking strength. The other 2 animals per group provided tissue for histological analysis of wound healing at the bowel and incision sites. RESULTS: There was no significant difference between the 3 treatment groups for any parameter (P > 0.05). Compared with the surgical control at either day 7 or 21 after surgery, the administration of solutions A or B did not affect the formation of abscesses or adhesions, the bursting strength of the bowel, or the tear strength of the abdominal wall incision. Histological assessment of the quality of wound healing showed no differences between treatment groups in inflammatory cell infiltration, fibroblast density, blood vessel formation or collagen maturity. CONCLUSIONS: The use of a 4% icodextrin solution for peri-operative lavage and postoperative instillation in a rabbit model of bowel anastomotic healing did not result in any difference from either LRS treated or untreated surgical controls.

A randomized, controlled pilot study of the safety and efficacy of 4% icodextrin solution in the reduction of adhesions following laparoscopic gynaecological surgery.

BACKGROUND: Adhesion-related readmissions are frequent sequelae to gynaecological surgery. Attempts to prevent adhesions by separating healing peritoneal surfaces include site-specific barriers and hydroflotation by instilled solutions. Rapid absorption limits the effectiveness of solutions such as Ringer's lactated saline (RLS). This pilot study assessed the safety, tolerability and preliminary effectiveness of a non-viscous, iso-osmolar solution of 4% icodextrin, an alpha-1,4 glucose polymer with prolonged intraperitoneal residence, in reducing adhesions after laparoscopic gynaecological surgery. METHODS: Women aged > or = 18 years, requiring laparoscopic adnexal surgery (n = 62), were entered into a randomized, open-label, assessor-blinded, multicentre study to compare 4% icodextrin with RLS. Treatments were coded in blocks of four with equal randomization to each group, and pre-allocated to consecutively numbered patients. At least 100 ml per 30 min was used for intra-operative lavage, with 1 l instilled post-operatively. Per protocol analysis included all eligible patients (n = 53); reformation analysis required one or more baseline adhesion (n = 42). Incidence, extent and severity of post-operative adhesions were assessed at second-look laparoscopy after 6-12 weeks. Procedures were video-taped for third party, blinded assessment. RESULTS: Safety and tolerability (laboratory variables, adverse events, clinical follow-up) were good with no difference between treatments. A shift analysis of incidence-ranked adhesions (n = 53) showed apparent improvements in more patients with icodextrin than RLS (37 versus 15%; not significant). Adhesion score reduction (n = 42) was more frequent in icodextrin- than RLS-treated patients: incidence (52 versus 32%), extent (52 versus 47%), and severity (65 versus 37%). Despite greater baseline adhesions, median reformation was less after icodextrin (24%) than RLS (60%). The pilot study group sizes were not powered for statistical significance. CONCLUSIONS: In this preliminary study, 4% icodextrin lavage plus instillation was well tolerated and reduced adhesion formation and reformation following laparoscopic gynaecological surgery. A Phase III pivotal study is currently in progress.

Peritoneal repair and post-surgical adhesion formation.

It was shown in 1919 that peritoneal healing differs from that of skin. When a defect is made in the parietal peritoneum the entire surface becomes epithelialized simultaneously and not gradually from the borders as in epidermalization of skin wounds. While multiplication and migration of mesothelial cells from the margin of the wound may play a small part in the regenerative process, it cannot play a major role, since new mesothelium develops in the centre of a large wound at the same time as it develops in the centre of a smaller one. Development of intraperitoneal adhesions is a dynamic process whereby surgically traumatized tissues in apposition bind through fibrin bridges which become organized by wound repair cells, often supporting a rich vascular supply as well as neuronal elements.

Reduction of postsurgical adhesions with Intergel adhesion prevention solution: a multicenter study of safety and efficacy after conservative gynecologic surgery.

OBJECTIVE: To assess the safety and efficacy of the Intergel adhesion prevention solution, a 0.5% ferric hyaluronate gel, in reducing adhesions in patients undergoing peritoneal cavity surgery by laparotomy with a planned second-look laparoscopy. DESIGN: Randomized, third-party blinded, placebo-controlled, parallel group. SETTING: Eleven centers in the United States, and five centers in Europe. PATIENT(S): Women aged 18-46 years who wanted to retain their fertility. INTERVENTION(S): Patients received 300 mL of Intergel solution (n = 143) or lactated Ringer's solution (n = 138) as an intraperitoneal instillate at the completion of surgery. MAIN OUTCOME MEASURE(S): At second-look laparoscopy 6-12 weeks later, the presence of adhesions was evaluated at 24 abdominal sites. RESULT(S): Patients treated with Intergel solution (n = 131) had significantly less adhesions compared to controls (n = 134). Adhesion extent and severity were also significantly reduced. The American Fertility Society score for adnexal adhesions was reduced 59% in the patients in whom the Intergel solution was used. The safety profile of the patients treated with the Intergel solution was comparable to those treated with lactated Ringer's solution. CONCLUSION(S): The Intergel solution was safe and highly efficacious in reducing the number, severity, and extent of adhesions throughout the abdomen after peritoneal cavity surgery.

Reduction of post-surgical adhesions with ferric hyaluronate gel: a European study.

BACKGROUND: The objective of this study was to assess the safety and efficacy of a 0.5% ferric hyaluronate gel, in reducing adhesions in patients undergoing peritoneal cavity surgery by laparotomy, with a planned 'second-look' laparoscopy. METHODS: The study was a randomized (by computer-generated schedule), third party blinded, placebo-controlled, parallel-group design conducted at five centres in Europe. Females aged 18-46 years received 300 ml ferric hyaluronate (n = 38) or lactated Ringer's (n = 39) as an intraperitoneal instillate at the completion of surgery. At second-look 6-12 weeks later, the presence of adhesions was evaluated at 24 abdominal sites. RESULTS: Patients treated with ferric hyaluronate had significantly fewer adhesions compared with controls. When adhesions formed, they were significantly less extensive and less severe in the treated group. The American Fertility Society score for adnexal adhesions was reduced by 69% in the treatment group compared with controls. The safety profile of ferric hyaluronate-treated patients was comparable with those treated with lactated Ringer's solution. CONCLUSIONS: In conclusion, ferric hyaluronate was safe and highly efficacious in reducing the number, severity and extent of adhesions throughout the abdomen following peritoneal cavity surgery.

Effect of angiotensin II on hematopoietic progenitor cell proliferation.

Angiotensin II (AII) induced the proliferation of hematopoietic progenitor cells (HPC) isolated from murine bone marrow or human cord blood. The formation of colonies with more than 50 cells increased approximately five-sevenfold in cultures of murine lineage-negative (Lin(-)) bone marrow cells both in the presence (day 10) and absence (day 13) of colony-stimulating factors (CSF). This could be blocked with addition of Losartan, an antagonist of AIITR1. The increase in proliferation of early hematopoietic progenitors (Lin(-)Sca l(+) cells) by AII was approximately threefold and occurred only in the presence of CSF, suggesting that AII may affect mesenchymal stromal cells to induce CSF production and might directly affect early HPC. These in vitro studies were replicated with human HPC isolated from cord blood. AII also accelerated the proliferation and formation of colony-forming units (CFU)-granulocyte/erythroid/macrophage/megakaryocyte and CFU-granulocyte/macrophage colonies by CD34(+)CD38(-) enriched progenitors but only in the presence of CSF. Additional studies also indicated that AII can act to increase proliferation in suspension culture. Exposure of CD34(+) cells to AII in suspension culture, prior to placement in a semisolid medium with erythropoietin, increased the formation of colonies with more than 50 cells and erythroid progenitors approximately five- and 20-fold, respectively. Further, mRNA for the AT1a receptor was expressed by human bone marrow CD34(+)CD38(-) cells, CD34(+)CD38(-) cells, and lymphocytes, but not mature myeloid cells. Similarly, mRNA for the AT1a receptor was expressed on human stromal cell clones, offering further support to the hypothesis that AII acts partially through the mesenchymal compartment of the bone marrow. These data suggest that AII may be a factor which stimulates the proliferation of hematopoietic progenitors.

Angiotensin II increases host resistance to peritonitis.

Studies by other laboratories have shown that angiotensin II (AII) can affect the function of cells which comprise the immune system. In the present study, the effect of AII on the function of peritoneal macrophages and peripheral blood monocytes was assessed. In vitro exposure (4 h prior to assay) of peritoneal macrophages from mice and rats to AII increased the percentage of cells that phagocytosed opsonized yeast and the number of yeast per macrophage. Furthermore, AII increased the respiratory burst capacity of peritoneal macrophages from mice and rats and peripheral blood mononuclear cells from humans. Because of these observations, the effect of AII on host resistance to bacterial infection was assessed. Intraperitoneal administration of AII was shown to increase host resistance (reduced abscess formation) in an animal model of bacterial peritonitis. Studies were then conducted to assess whether parenteral administration of AII, a clinically relevant route, could affect peritoneal host resistance in a manner similar to that observed after peritoneal administration. These studies showed that subcutaneous administration of AII throughout the postinfection interval increased the level of host resistance to bacterial peritonitis. Furthermore, in a study which compared AII and Neupogen, an agent approved for use for the reduction of febrile neutropenia after myeloablative therapy, daily subcutaneous administration of AII reduced abscess size and incidence, whereas Neupogen did not have any therapeutic benefit in this model. These data suggest that AII may be of therapeutic benefit as an immunomodulatory agent.

Effect of oxiplex* films (PEO/CMC) on adhesion formation and reformation in rabbit models and on peritoneal infection in a rat model.

OBJECTIVE: To assess the efficacy of Oxiplex (FzioMed, Inc., San Luis Obispo, CA) barriers. DESIGN: Film of polyethylene oxide and carboxymethylcellulose (Oxiplex) were tested for strength and tissue adherence. Films were selected for evaluation in models for biocompatability and adherence. Three films were selected for evaluation in efficacy studies, and one was evaluated for effects on bacterial peritonitis. Handling characteristics of Oxiplex film were evaluated via laparoscopy. SETTING: University laboratory. PATIENT(S): Rabbits, rats, pigs. INTERVENTION(S): Placement of Oxiplex prototypes at the site of injury. MAIN OUTCOME MEASURE(S): Mechanical properties, biocompatibility, tissue adherence, adhesion development, infection potentiation, and device handling. RESULT(S): Mechanical tests indicated that tensile strength and elongation were inversely correlated. All films tested had excellent tissue adherence properties. Selected films, based on residence time and biocompatibility, prevented adhesion formation in all animals and were highly efficacious in preventing adhesion reformation. The optimal Oxiplex prototype prevented adhesion reformation in 91% of the animals. This Oxiplex film, dyed to allow visualization, prevented adhesion reformation and did not affect bacterial peritonitis. In a laparoscopic model, the Oxiplex film, delivered in FilmSert forceps, via a 5.0-mm trocar, rapidly unfurled and could be easily applied to tissue with strong adherence. CONCLUSION(S): These data show development of an adhesion prevention material that is tissue adherent, can be placed via laparoscopy, and does not affect host resistance.

Reduction of retrosternal and pericardial adhesions with rapidly resorbable polymer films.

BACKGROUND: The formation of postoperative cardiac adhesions makes a repeat sternotomy time consuming and dangerous. Many attempts have been made to solve this problem by using either drugs to inhibit fibrinolytic activity or different types of pericardial substitutes. The results have not been satisfactory. METHODS: The efficacy of bioresorbable film prototypes made of polyethylene glycol (EO) and polylactic acid (LA) (EO/LA = 1.5, 2.5, and 3.0) in the prevention of adhesions after cardiac operations in canine models was tested. After desiccation and abrasion of the epicardium, a transparent bioresorbable film was placed over the heart. The pericardium was closed to allow intrapericardial adhesions (n = 32) or left open and attached to the chest wall to induce retrosternal adhesions (n = 17). Postoperative recovery was similar among the groups. Retrosternal and pericardial adhesions were evaluated at necropsy 3 weeks later by assessing area, tenacity, and density of the adhesions. RESULTS: In the control dogs, tenacious, dense adhesions were observed. In contrast, adhesion formation was reduced at all sites covered by the films. The bioresorbable films were efficacious in the reduction of adhesion formation between epicardium and pericardium or between epicardium and sternum after cardiac operation. The EO/LA 1.5 film most effectively prevented the early adhesions. CONCLUSIONS: The bioresorbable films (EO/LA = 1.5, 2.5, and 3.0) significantly reduced adhesion formation, with EO/LA = 1.5 (Repel CV) being optimal. As the barrier was rapidly resorbed, the capsule formation induced by permanent barriers was avoided.

Reduction of adhesion formation by intraperitoneal administration of Arg-Gly-Asp-containing peptides.

OBJECTIVE: To evaluate the ability of a variety of peptides containing the Arg-Gly-Asp (RGD) sequence to reduce the formation of intraperitoneal adhesions in a rabbit model. DESIGN: Prospective, randomized, double-blinded study. SETTING: University-based laboratory. ANIMAL(S): New Zealand white rabbits. INTERVENTION(S): Administration of RGD-containing peptides. MAIN OUTCOME MEASURE(S): Reduction of adhesion information. RESULT(S): In initial studies, two RGD-containing peptides (3 or a 10 amino acid peptides) were administered via Alzet miniosmotic pump to the site of injury. Administration of either of these peptides significantly reduced adhesion formation, but the larger peptide was more efficacious and reduced variability in the response. Further studies then were conducted with RGD-containing peptides five to six amino acids in length. Administration of these peptides also significantly reduced adhesion formation in a standard rabbit model. Administration of three of these peptides in a viscous vehicle at the end of surgery was also effective in reducing adhesion formation. CONCLUSION(S): The most effective combination tested was RGD-containing peptide Gly-dser-Arg-Gly-Asp-Ser-Pro in a viscous, cremophor-containing vehicle. These studies demonstrate that administration of an RGD-containing peptide was effective in reducing adhesion formation in this model.

Reduction of adhesion formation by intraperitoneal administration of various anti-inflammatory agents.

Adhesion formation is a major source of postoperative morbidity and mortality. Therefore, the reduction of postoperative adhesion formation would be of clinical benefit. Various modalities have been shown to reduce adhesion formation, including fibrinolytic enzymes, nonsteroidal anti-inflammatory drugs, and barriers that reduce the apposition of sites of potential adhesion formation. In this report, the ability of three compounds with different mechanisms of action, all-trans-retinoic acid, quinacrine, and dipyridamole, to reduce the formation of intraperitoneal adhesions was examined in two rabbit models. In the sidewall model, the medicaments were administered via an Alzet miniosmotic pump for the entire postoperative interval. With all three agents, there was a reduction in the area of the sidewall injury that was involved in adhesions to the cecum and the bowel at both doses tested. In the same model, quinacrine also reduced the area of the sidewall injury that was involved in adhesions to the cecum and the bowel. At the higher concentrations of quinacrine, there was a deposition and walling off of the quinacrine at the site of delivery. In the double uterine horn model (DUH), the medicaments were administered via an Alzet miniosmotic pump to the area of injury for either 1, 2, 3, or 7 days. Administration of all three compounds for as little as 24 h after surgery significantly reduced the extent of adhesion formation. However, there was a further reduction in the amount of adhesion when the retinoic acid or dipyridamole was administered for 72 h postoperatively. However, when the quinacrine was administered for longer times postoperatively, the amount of adhesion reduction observed was less. These studies demonstrate that postoperative administration of retinoic acid, quinacrine, or dipyridamole to the site of injury reduced the formation of postoperative adhesions in two animal models.

Reduction of adhesion formation in rabbits by intraperitoneal administration of lazaroid formulations.

Adhesion formation is a major source of postoperative morbidity and mortality. In this study, the ability of a variety of lazaroid formulations [the antioxidant 21-aminosteroid PNU74006F (tirilazad) and the non-steroidal 2-methylaminochroman derivative PNU83,836E] to reduce i.p. adhesion formation in three rabbit models was examined. In initial studies, PNU83836E was administered via Alzet miniosmotic pump to the site of injury. In the sidewall and double uterine horn models, PNU83,836E was administered via Alzet miniosmotic pump for the entire postoperative interval. In the sidewall model, there was a dose-dependent reduction in the area of the sidewall injury that was involved in adhesions. In the double uterine horn model, PNU83,836E was administered via Alzet miniosmotic pump to the area of injury for 1, 2, 3 or 7 days. Administration for as little as 24 h after surgery significantly reduced the extent of adhesion formation and the reduction was increased if it was administered for longer. Further studies were conducted in which various lazaroid formulations were administered as a bolus at the end of surgery. In both the sidewall and double uterine horn models, administration of either PNU83,386E (in citrate buffer) or PNU74006F (in cyclodextrin or lipid emulsion vehicles) at the end of surgery reduced adhesion formation. Administration of a bolus of PNU74006F 10 min prior to initiation of surgery with or without additional treatment at the end of surgery further increased its efficacy in the reduction of adhesion formation. Administration of a minimum of 1.5 mg before and after surgery (3 mg total) was required for maximal efficacy. These studies demonstrate that pre- and postoperative administration of either a steroidal (PNU74006F) or non-steroidal (PNU83,836E) lazaroid intraperitoneally reduced the formation and reformation of postoperative adhesions in three animal models.

Prevention of retrosternal adhesion formation in a rabbit model using bioresorbable films of polyethylene glycol and polylactic acid.

The purpose of this study was to test the efficacy of three bioresorbable films of polyethylene glycol (EO) and polylactic acid (LA) (EO/LA = 1.5, 2.5, and 3.0) in the prevention of adhesion formation between the epicardium and the sternum (retrosternal adhesions) in a rabbit model. Retrosternal adhesions were generated by sternotomy, pericardiotomy, and abrasion of the anterior epicardium. The adhesion barrier was placed between the epicardium and the sternum and sutured to the edge of the pericardium. Epicardial adhesions were evaluated 14-20 days later by assessing the area of the epicardium covered by adhesions. In the control rabbits, tenacious adhesions were observed between sternum and the central portion of epicardium (portion exposed through the pericardiotomy) which were difficult to dissect. When a bioresorbable film was placed over the pericardium, adhesion formation at the central strip of the epicardium (area between the sternum and the epicardium exposed through the pericardium) could be reduced or prevented. At this site, the areas of adhesion formation were 0% (EO/LA = 1.5), 8.4 +/- 2.8% (EO/LA = 2.5), and 5.6 +/- 4.7% (EO/LA = 3.0) of the central strip, significantly less than that observed in the control group, 78.0 +/- 5.8% (P < 0.01). At the anterior left and right and posterior apex of the heart (sites where the film was not placed), there were no differences between control and treatment groups. The films were completely resorbed at the time of necropsy in group EO/LA = 2.5 and 3.0. Small pieces of film were observed in group EO/LA = 1.5. In conclusion, the bioresorbable films [EO/LA = 1.5 (REPEL-CV), 2.5, or 3.0] were efficacious in the reduction of retrosternal adhesions to the epicardium.

Clinical evaluation of 0.5% ferric hyaluronate adhesion prevention gel for the reduction of adhesions following peritoneal cavity surgery: open-label pilot study.

The objective of this study was to assess the safety and to make a preliminary assessment of the efficacy of 0.5% ferric hyaluronate adhesion prevention gel in reducing adhesions in patients undergoing peritoneal cavity surgery by laparotomy, with a planned 'second-look' laparoscopy. The study was a randomized, open-label, placebo-controlled, parallel-group design in patients desirous of fertility at the Women's and Children's Hospital, Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles, California. Female patients aged 24 to 41 years received 300 ml 0.5% ferric hyaluronate adhesion prevention gel or lactated Ringer's solution as an intraperitoneal instillate at the completion of the laparotomy procedure. At second-look laparoscopy 4-12 weeks after the laparotomy, the presence of adhesions was evaluated. Haematology and serum chemistry were determined throughout the study interval. All patients tolerated the procedures well and did not manifest any serious adverse events. At second-look laparoscopy, patients treated with 0.5% ferric hyaluronate adhesion prevention gel had significantly fewer adhesions than control patients. When adhesions did form, they were significantly less extensive and less severe in patients who received 0.5% ferric hyaluronate adhesion prevention gel. In conclusion, 0.5% ferric hyaluronate adhesion prevention gel was safe and highly efficacious in the reduction of the number, severity and extent of adhesions throughout the entire abdomen following peritoneal cavity surgery.

Histologic alterations in dermal repair after thermal injury effects of topical angiotensin II.

Previously, we determined that quantitative assessment of epithelialization of the burn site could be performed using quantitative immunohistochemistry with an antibody to the protein cyclin. In this study, the effect of administration of angiotensin II (AII) on two histologic parameters of healing-the number of vascular channels at the burn site and the number of cells proliferating in hair follicles at the edge of the burn and within the burn-were evaluated. Beginning on day 4, vascular channels were noted within the burn site. Significantly more channels were noted in the burns treated with AII than those treated with placebo. With the exception of 3 postinjury days, this increase continued through day 17. Thereafter, the number of vascular channels peaked, and no differences were noted between control and treated burns. The number of cells proliferating in the hair follicle was also evaluated. At the edge of the burn, on average, 126 cells per microscope field (10x) were undergoing proliferation in the AII-treated burn on days 1 through 16 after burn injury. This is approximately a 50% increase over the number of cells proliferating in the placebo-treated burns. On day 12 (approximately 5 days before that observed in control burns), this AII-dependent proliferative response began to increase and peaked on day 19 at a level comparable to control. Thereafter, the proliferative response remained at this level through day 28. Within the area of the burn on days 1 through 15, 21 cells per medium power field on average (approximately 50% more than control) were undergoing proliferation. As on the edge of the burn, an AII-dependent increase in the number of cells proliferating in the hair follicles was observed during the latter phase of healing (on day 16 after the initiation of injury). However, unlike the edge of the burn, administration of AII led to a continued increase (approximately 50%) in the number of cells per field undergoing proliferation. AII increased neovascularization and cellular proliferation after burn injury. Through an increase in these two cellular events, AII may in turn accelerate healing of tissues after thermal injury.

Reduction of adhesion formation by postoperative administration of ionically cross-linked hyaluronic acid.

OBJECTIVE: To examine the efficacy of various formulations of hyaluronic acid (HA), including HA ionically cross-linked with trivalent iron, in animal models of adhesion formation. DESIGN: Hyaluronic acid formulation of varying concentrations and cross-linked densities were prepared and evaluated in a rabbit uterine horn model and a rabbit sidewall model. SETTING: ETHICON, Inc., Somerville, New Jersey. SUBJECT(S): New Zealand White rabbits. INTERVENTION(S): Test formulations were applied as intraperitoneal instillates after surgery. MAIN OUTCOME MEASURE(S): Adhesion formation was assessed at 7 and 14 days (sidewall and uterine horn model, respectively). RESULT(S): Hyaluronic acid that was not ionically cross-linked was ineffective in reducing adhesions in these models even at high viscosity, whereas the ionically cross-linked formulations of HA with trivalent iron were highly effective. Efficacy improved with increased levels of ionic cross-linking. Flowable gels, which could be delivered readily by syringe and cannula, also were effective when administered at a site remote from injury and with saline present. CONCLUSION(S): Whereas previous studies show that HA was effective in reducing adhesions peripheral to the site of injury, HA ionically cross-linked with trivalent iron was effective in reducing adhesions at all sites. From these studies, a formulation of HA ionically cross-linked with trivalent iron, 0.5% Ferric Hyaluronate Gel (LUBRICOAT; ETHICON, Inc., Somerville, NJ), was identified for subsequent clinical evaluations.

Expression of cyclin protein after thermal skin injury in a guinea pig model.

In this study, an immunohistochemical stain for cyclin was used to quantitate proliferating elements in hair follicles at the edge of and within thermal burn areas. Biopsy specimens from thermal injury in the guinea pig (day 1 through day 28) were sectioned and stained with MIB-1 antibody, which recognizes cyclin, a protein expressed during epithelial cell proliferation. At the edge of the burn, 89 +/- 6.1 (SD) cells per medium power field (x 10, mpf) were MIB-1-positive on days 1 through 16. On day 17, the number of positive cells increased, reaching peak values on days 20 to 28 (271 +/- 12.7 cells/mpf). Within the burn, minimal staining was observed from day 1 to day 15 (12.7 +/- 1.6 cells/mpf). Thereafter the number of MIB-1-positive cells increased and plateaued with an average of 96.4 +/- 9.0 cells/mpf on days 20 through 28. In conclusion, immunohistochemical staining of dermal biopsy specimens with MIB-1 antibody may provide a quantitative method for the evaluation of tissue damage and healing after thermal injury.

Clinical problem of intraperitoneal postsurgical adhesion formation following general surgery and the use of adhesion prevention barriers.

Because of multiple studies demonstrating barrier efficacy, adhesion prevention adjuvants have received widespread acceptance in appropriate surgical settings. Many investigators are incorporating adhesion prevention barriers into their routine clinical practice and are achieving good results. Although both Seprafilm and Interceed barriers were shown to be safe and effective in all human clinical trials, their use did not eliminate adhesions in all patients. Efficacy of these barriers is limited to surgical situations in which the area in question can be completely covered. Physician acceptance is constrained by technical difficulties, including the need for hemostasis and removal of excess peritoneal fluid (Interceed), as well as limitations in application and handling properties within the surgical field (Seprafilm).