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.

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.

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.

Reduction of adhesion formation with hyaluronic acid after peritoneal surgery in rabbits.

OBJECTIVE: To examine the effect of hyaluronic acid, a high-molecular-weight glucosaminoglycan found in the extracellular matrix, on the formation of adhesions, a major source of postoperative complications. DESIGN: The ability of hyaluronic acid to reduce adhesion formation was evaluated using a standardized rabbit model. The material was administered i.p. at the end of surgery. SETTING: University laboratory. ANIMAL(S): New Zealand White female rabbits. INTERVENTION(S): Intraperitoneal administration of various formulations of hyaluronic acid at the end of surgery. MAIN OUTCOME MEASURE(S): One week after surgery, a second laparotomy was performed and the extent of adhesion formation was determined. RESULT(S): Five separate molecular weight ranges of hyaluronic acid representing eight viscosities between 1,000 and 12,000 centipoise (CPS) were shown to reduce adhesion formation in this model. All volumes, 1 to 30 mL, of hyaluronic acid tested reduced adhesion formation. In addition, the low-viscosity, low-molecular-weight hyaluronic acid significantly reduced adhesion formation when added to the trauma site or when injected at a site remote from the trauma area. CONCLUSION(S): This study showed that hyaluronic acid administered at the end of surgery reduced adhesion formation.

Prevention of adhesion formation with intraperitoneal administration of tolmetin and hyaluronic acid.

Adhesion formation after peritoneal surgery is a major source of postoperative complications and pain. Previous studies showed that intraperitoneal administration of the nonsteroidal anti-inflammatory drug tolmetin reduced adhesion formation after two types of peritoneal surgery. The effect of tolmetin combined with hyaluronic acid (HA), a high-molecular-weight glucosaminoglycan found in the extracellular matrix, on the formation of adhesions was examined. In this study, the effect of tolmetin in HA on adhesion formation was evaluated in a standardized rabbit model. The medicament was administered intraperitoneally at the end of surgery. One week after surgery, a second laparotomy was performed and the extent of adhesion formation was determined. A range of molecular weights (7.5 x 10(5)-2 x 10(6) Da) and viscosities (1000-25,000 centapoise) of HA in combination with tolmetin was effective in reducing adhesion formation. However, low viscosity HA solutions in combination with tolmetin, 0.5-2.0 mg/mL, were most efficacious in reducing adhesion formation. These data suggest that HA, in combination with tolmetin, acts as an effective carrier to reduce adhesion formation in the abdominal cavity after surgery.

Time-dependent effect of tolmetin sodium in a rabbit uterine adhesion model.

Tolmetin is a nonsteroidal anti-inflammatory drug (NSAID) that reduces adhesion formation in several animal models after a single intraperitoneal (i.p.) dose delivered at the time of surgery. We set out to determine the period during which tolmetin could prevent adhesions. Adhesions were induced in New Zealand White rabbits (2-3 kg) by abrading the uterine horns and removing their mesouterine vasculature. Tolmetin sodium (1 mg/5 ml saline) was given at various times relative to the start of surgery as a single dose i.p. One week later adhesions were assessed using a standard scoring system (0 = no adhesions; 1 = light adhesions involving both uterine horns; 2 = more tenacious adhesions to bowel or bladder; 3 = tenacious adhesions to bowel and bladder partly immobilizing the uterus; 4 = completely fixed horns adherent to bowel and bladder). Scores were arranged in ascending rank order. Mean rank positions were calculated for each group and compared against controls (Dunnett's multiple comparison). Tolmetin sodium was most effective when administered within 1 hour of surgery. Mild effects could still be observed after 4 hours and the effect diminished after 24 hours. When these effects are compared to the temporal biochemical and cellular effects of tolmetin obtained in related studies, the data support the hypothesis that tolmetin reduces adhesions at least in part by modulating fibrinolytic activity of resident macrophages and macrophages present in the early postsurgical period.

Intraperitoneal tolmetin prevents postsurgical adhesion formation in rabbits.

Previous studies showed that drugs that suppress prostaglandin synthesis were able to prevent adhesion formation following surgical trauma to the peritoneum. In our study, this premise was extended to examine the effects of various delivery systems on the ability of a nonsteriodal antiinflammatory drug, tolmetin, to prevent intraperitoneal adhesion formation after a standardized injury to the peritoneum. Continuous delivery of small amounts of tolmetin directly to the injury site following parietal peritoneal injury led to a significant reduction in the number and severity of adhesions formed. A single intraperitoneal injection of tolmetin in 5% Tween, however, required a relatively higher concentration of drugs to prevent adhesion formation. In a follow-up study of abrasion and devascularization of both uterine horns, the acid form of tolmetin was shown to be more potent than the sodium salt for the prevention of adhesion formation.

DBCP and testicular effects in chemical workers: an epidemiological survey in Midland, Michigan.

The agriculturally important nematocide 1,2-dibromo-3-chloropropane (DBCP) has been implicated as a cause of human male sterility. A survey at the Michigan Division of The Dow Chemical Company included measurements of semen samples, testicular size, and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone in 232 chemical workers with past potential exposures to DBCP and in 97 nonexposed comparison employees. Potentially exposed groups showed significantly higher, although not abnormal, mean levels of FSH and LH. In the subgroup with the highest potential exposure ending subsequent to 1972, greater duration of exposure correlated with lower sperm count, higher FSH level, and smaller testicular volume. Mean values for this latter time-divided subgroup were not abnormal. The findings are consistent with a testicular effect of DBCP and also with reversibility of that effect over time.