Synthesis and biological evaluation of NK1 antagonists derived from L-tryptophan.

The 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan (3), which was derived from the screening lead N-ethyl-L-tryptophan benzyl ester, has been used as a starting point to identify high-affinity substance P receptor antagonists with improved in vivo activity. Altering the ester moiety to an amide or ether led to a substantial loss in binding affinity, but conversion to a ketone provided compounds with affinity comparable to the equivalent esters. A homochiral synthesis of the key intermediate amino ketone 15 was developed which allows its preparation on a large scale. From this intermediate a range of amine-containing acylamino derivatives were prepared with affinity optimized in the morpholinylbutyramide 161 which has an IC50 of 0.17 nM at the human NK1 receptor. In addition to improving affinity, the amino group also provided aqueous solubility for a number of these derivatives. When tested in vivo the quinuclidine derivative L-737,488 (16i) was found to be an orally active (ID50 = 1.8 mg/kg) inhibitor of substance P-induced dermal extravasation in the guinea pig.

Tryptophan-derived NK1 antagonists: conformationally constrained heterocyclic bioisosteres of the ester linkage.

The 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan 1 (L-732,138) has been identified previously as a potent and selective substance P receptor antagonist. A series of analogs which introduced a 6-membered heterocyclic ring into the backbone of this structure were prepared for evaluation as bioisosteric replacements of the ester linkage of 1. The 2,5-dioxopiperazine 2 had very weak receptor affinity, but 2-oxopiperazine 5 exhibited modest activity. Examination of the conformations accessible to the substituents on these templates led to exploration of the corresponding 5-membered heterocyclic rings. This study culminated in the identification of oxazolidinedione 14 as a suitable ester mimic in terms of the retention of good NK1 binding affinity.

Should antibiotic prophylaxis be used routinely in clean surgical procedures: a tentative yes.

BACKGROUND: The incidence of surgical site infection (SSI) after clean surgical procedure has traditionally been regarded as too low for routine antibiotic prophylaxis. But we now know that host factors may increase the risk of SSI to as high as 20%. We assessed the value of prophylactic cefotaxime in patients stratified for risk of SSI in a randomized double-blind trial. METHODS: Patients admitted for clean elective operations were enrolled, stratified for risk by National Nosocomial Infection Survey criteria, and randomized to receive intravenous cefotaxime 2 gm or placebo on call for operation. They were followed for 4 to 6 weeks for SSI diagnosed by Centers for Disease Control and Prevention criteria. RESULTS: Analysis of 775 patients showed that the 378 evaluable patients who received cefotaxime had 70% fewer SSI than those who did not--Mantel-Haenszel risk ratio (MH-RR) 0.31; 95% confidence intervals (CI) 0.11 to 0.83. Benefit was clear in the 616 low risk patients--0.97% versus 3.9% SSI (MH-RR 0.25, CI 0.07 to 0.87, p = 0.018), but only a trend was seen in 136 high risk patients--2.8% versus 6.1% SSI (MH-RR 0.48, CI 0.09 to 2.5). CONCLUSIONS: The results indicate clear benefit for routine antibiotic prophylaxis in clean surgical procedures. High risk patients need more study.

Necrotizing soft-tissue infections.

Necrotizing soft-tissue infections have been widely recognized for over a century, but they remain a challenging problem in clinical infectious disease. Patterns of disease are clearly apparent, but most are polymicrobial and derive increased virulence from synergy between bacteria. Early recognition and prompt surgical drainage are the keys to successful treatment. Edema extending beyond the area of erythema, skin vesicles, crepitus or air in the subcutaneous tissues, and absence of lymphangitis and lymphadenitis are markers of necrotizing infections, particularly when they occur in patients with serious underlying disease. Empiric broad-spectrum antibiotics, prophylactic heparin, and nutritional therapy are important adjuncts to aggressive "stepwise" surgical debridement. A knowledge of patterns of disease can aid in fine-tuning treatment to decrease morbidity.

Biliary bacteria, antibiotic use, and wound infection in surgery of the gallbladder and common bile duct.

That clinical risk groups predict postoperative infection in biliary operations has recently been challenged. To reevaluate the risk of infection, we studied 215 patients stratified by clinical risk factors. Of 100 patients having simple "low-risk" cholecystectomy, 11 had positive bile cultures (90% pure), and one with sterile bile got a staphylococcal wound infection (WI). Among 92 "high-risk" patients with acute cholecystitis, obstructive jaundice, or choledochal stones, 42 had positive bile cultures (44% pure, 12% anaerobes). One of 52 patients who received preoperative cefazolin got a staphylococcal WI, but ten of 40 patients without antibiotic therapy developed WIs, nine caused by organisms that also grew from the bile. Of 23 patients with obstructive cholangitis, 22 had positive bile cultures (88% mixed, 23% anaerobes). Despite antibiotic therapy, four developed WIs caused by these organisms. The concept of clinical risk factors is validated.

Simple elective cholecystectomy: to drain or not.

We performed a large single-center prospective randomized controlled study to assess the role of peritoneal drainage in simple elective cholecystectomy. In 248 patients, drains were omitted; 122 patients had closed suction drains and 124 had Penrose drains. There were no deaths, and no patient required reoperation or drainage of a subhepatic collection. Wound infections occurred in eight patients with drains and in six patients without. Most infections were staphylococcal. Postoperative pulmonary complications and hospital stays were similar in patients with and without drains. Statistical analysis of the 10 available prospective controlled randomized studies (1,920 patients) by the method of odds ratios supported our findings. Simple elective cholecystectomy is safe without peritoneal drainage, but short-term drains do not increase morbidity.

Discriminate use of antibiotic prophylaxis in gastroduodenal surgery.

In a prospective study of 107 patients undergoing surgery for gastroduodenal disease, antibiotics were withheld from a group of 24 patients defined preoperatively to be at low risk of developing postoperative infections; no wound infection occurred in this group. Perioperative cephaloridine was randomized among the remaining patients (high risk). Wound infections developed in 11 of 42 patients who did not receive cephaloridine, but in none of the 41 patients who were given cephaloridine (p less than 0.02). Coliform bacteria were grown only from swabs of the stomach mucosa of patients in the high risk group and were the main cause of wound infections. Severe preoperative lymphocytopenia was frequently associated with the development of serious postoperative sepsis. The results validate a policy of restricting antibiotic prophylaxis in gastroduodenal operations to patients at high risk of postoperative infection and suggest a new risk factor--the preoperative blood lymphocyte count.

Cephalosporin therapy in intraabdominal infections. A multicenter randomized, comparative study of cefotetan, moxalactam, and cefoxitin.

Three broad-spectrum cephalosporins (cefotetan, moxalactam, and cefoxitin) proved effective in this randomized, prospective trial for treatment of 303 surgical patients with moderately severe regional peritonitis.

Severe coagulopathy following insertion of the LeVeen shunt: a potentially fatal complication.

Four patients who underwent insertion of the LeVeen shunt for treatment of medically intractable hepatic ascites had coagulation changes. Peritoneo-venous shunting was associated with a mild coagulopathy in two patients, simulating disseminated intravascular coagulation or primary fibrinolysis. The coagulopathy was severe in two patients and life-threatening in one of these. Postoperative coagulopathy may be detected by careful monitoring of coagulation indices and the risk of its development parallels the severity of liver disease.

Albumin: role and discriminative use in surgery.

Exogenous human serum albumin (HSA) is generally used empirically and its role in surgery is poorly defined. The function and kinetics of HSA in the body are reviewed to provide rational guidelines for its use in surgery. Starling's law of transcapillary exchange is important, especially when applied to the capillary beds of the skin and subcutaneous tissue, skeletal muscle, lungs and intestines; but it overestimates the importance of maintaining oncotic pressure in the two situations where HSA is clinically beneficial--hypovolemia and plasma volume sequestration. In hypovolemia, the harmful effects of protein dilution by massive crystalloid resuscitation are minimized initially by "edema safety factors", such as reduced oncotic pressure of interstitial fluid and increased flow of lymph, and subsequently by intravascular protein refill from extravascular sites. But in severe hypovolemia, albumin should be given early, with sufficient isotonic saline, to reduce the total volume of crystalloid required. In the first 24 hours of plasma volume sequestration, albumin infused intravenously may be lost from excessively permeable capillaries; but later, hyperoncotic HSA is useful to restore the plasma volume and to reduce interstitial edema.

Soft tissue infections.

Soft tissue infections vary widely in their nature and severity, and their nomenclature is confusing. A clear approach to management must allow rapid identification and treatment of the diffuse necrotizing infections because they are life-threatening. This review classifies soft tissue infections by their degree of localization and the presence of tissue necrosis. Most focal nonnecrotizing infections start in the skin or adnexae and are easily recognized and readily treated by local measures. Patients with cellulitis, the commonest diffuse nonnecrotizing infection, should be stratified from mild to severe and complicated and then treated with oral or systemic antibiotics. Focal necrotizing infections are relatively uncommon, but they are readily diagnosed on sight and effectively managed by local debridement and systemic antibiotics. In contrast, diffuse necrotizing infections may masquerade in many forms, delaying diagnosis and treatment. Edema out of proportion to erythema, subcutaneous gas, and skin vesicles are important markers. Aggressive sequential debridement and broad-spectrum intravenous antibiotics revised after 48 hours provide the best strategy for management.

Wound infection after gastroduodenal operations: a 10-year review.

A review of 444 gastric operations performed over a 10-year period revealed striking differences in wound infection rates when the operations were categorized according to the major indication for surgery. On this basis, low-intermediate- and high-risk groups were recognized. A subsequent prospective randomized study confirmed the predictive value of this categorization and showed that the administration perioperatively of prophylactic systemic antibiotics in high-risk patients will protect them from postoperative wound infection.

Knitted polypropylene (Marlex) mesh in the repair of incisional hernias.

In 50 consecutive patients, large incisional hernias or those difficult to manage were repaired by suture imbrication of the hernial sac and extrafascial onlay fixation of Marlex mesh. Seromas developed in three and wound infection in two. The use of closed suction drains for all patients and antibiotic prophylaxis before and after operation for patients with antecedent wound infections may prevent these complications. In the follow-up period (mean of 2.6 years), lateral recurrence of the hernias occurred in three patients, but there has been no recurrence in the last 2 years. The method of repair is simple and effective.