Tolerability, pharmacokinetics and concentration-dependent hemodynamic effects of oral CF101, an A3 adenosine receptor agonist, in healthy young men.

OBJECTIVES: To assess safety, tolerability, pharmacokinetics and hemodynamic effects of oral CF 101, an A3 adenosine receptor (A3AR) agonist, in healthy men. METHODS: One single and 1 repeated dose, parallel-group, ascending dose, double-blind and placebo-controlled study in normal volunteers. In the single dose study, n = 15 subjects received 1, 5 or 10 mg oral CF101; in each group 1 subject received placebo, the remainder active CF101. In the repeat-dose study, n = 28 subjects received repeated 12-hourly oral doses of CF 101 (2, 3, 4 or 5 mg) for 7 days, in each group 2 subjects received placebo, the remainder active CF101. TEST MATERIALS: Single-dose study: CF101 in 30% Cremophor RH40. Multiple-dose sudy: CF101 in 0.5% methylcellulose suspension. Both studies: the corresponding vehicles were used as placebos. Galenicals were prepared remotely from the clinical study site to ensure double-blind nature of the study. RESULTS TOLERABILITY: Single doses up to 5 mg CF101 were safe and well-tolerated. However, the single dose of 10 mg CF101 was associated with flushing, tachycardia, nausea and vomiting, which were viewed as dose-limiting in normal volunteers. Single doses of CF101 (as well as the first of the multiple doses) were associated with increases in heart rate (8 - 24 beats/min after 5 mg and 18 - 55 beats/min after 10 mg). Multiple doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. However, the 5 mg multiple-dose group reported headache, drowsiness, hot flushes and dizziness on standing; this declined with dosing duration and was not dose-limiting in this study. Adverse events were commonest near t(max). RESULTS PHARMACOKINETICS: For oral CF101, the t(max) was always 1 - 2 h post-dose and t 1/2 about 9 h, in both the single- and multiple-dose studies. For a single 5 mg dose (mean +/- SD) C(max) = 81.6 +/- 23.6 ng/ml in the single dose study, and 63.6 +/- 22.0 ng/ml after the first of the multiple doses; AUC if was 904.0 +/- 221.9 ng.h/ml and 596.1 +/- 196.6 ng.h/ml for the 2 studies, respectively. After 7 days of multiple dosing there was little change, and AUC(0-24h) = 601.0 +/- 163.6 ng.h/ml. These pharmacokinetic parameters were linearly proportional to dose in the other treatment groups. RESULTS PHARMACODYNAMICS: Increases in heart rate were related to plasma concentration and evident only in the upper range of concentrations observed. There were no changes on ECG monitoring beyond sinus tachycardia, and, in particular, no evidence of PR prolongation in any subject (n = 43). In comparison with single doses, this response was almost absent after 7 days of dosing. Leucocytosis (increases up to about 1.5 x 10(9)/l after 5 and 10 mg) was similarly transient and reversible after multiple dosing. CONCLUSIONS: Single oral doses up to 5 mg CF101 and repeated doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. Multiple-dose CF101 pharmacokinetics were unchanged and predictable from single-dose estimates, and were linearly proportional to dose. Increases in heart rate and neutrophil count were reversible during multiple dosing and were not dose-limiting in the repeat dose study. CF101 warrants further study for its efficacy in treating human disease.

Early gastric cancer and Helicobacter pylori: 34 years of experience at Charity Hospital in New Orleans.

Good survival rates have been reported for resected early gastric adenocarcinoma (EGC) in patients found via screening procedures. However, the prevalence of Helicobacter pylori in EGC in unscreened populations is unclear. The major purpose of this investigation was to analyze the clinical experience and incidence of H. pylori in unscreened patients presenting with EGC at Charity Hospital over a 34-year period. From 1963 through 1997, the tumor registry at Charity Hospital compiled data on 2497 patients evaluated for gastric carcinoma. Of these patients, 26 (1%) had lesions that were confined to the mucosa or submucosa, i.e., T1N0M0 (American Joint Commission on Cancer classification). Pathology specimens and medical records were retrieved for confirmation of diagnosis and retrospective analysis for H. pylori. H. pylori was analyzed by Steiner staining and immunohistochemistry using a polyclonal antibody. EGC was detected in 12 men and 14 women with a mean age of 62 years. Upper gastrointestinal X-ray studies were performed on 19 of the 26 patients and failed to conclusively demonstrate a lesion in any case. Endoscopy was performed on 22 patients, and preoperative biopsies were positive in 95 per cent of these. Operative procedures included 2 local excisions and 22 subtotal and 2 total gastrectomies. No extended nodal dissections were performed. Microscopic evaluation revealed lesions limited to the mucosa in 63 per cent of cases and involving the submucosa in 37 per cent of the cases. Of the 14 patients evaluable of H. pylori, 79 per cent were positive for the bacterium. The status of 2 patients is unknown, and only 1 patient died of the original gastric cancer, for a disease-free survival of 96 per cent. The 5-year and 10-year overall survival rates were calculated to be 50 per cent and 21 per cent, respectively, when all causes of death were taken into consideration. Median follow-up of the survivors was 64 months. Resection of early gastric carcinoma in unscreened patients without extended lymphadenectomy yielded excellent results. H. pylori was present in 79 per cent of cases. These data suggest an association between H. pylori and EGC. Whether H. pylori infection is an etiologic factor in gastric cancer remains an area of active research.

Surgical management of chronic pain from chronic pancreatitis.

Chronic pain from chronic pancreatitis remains a difficult clinical problem. We present the results of surgical attempts to control this pain. For the past 3 years, all patients with chronic pancreatitis and pain requiring high-dose narcotics or hospitalization for pain control were evaluated by the following algorithm. Any anatomic pathology causing ductal dilatation was surgically addressed first (Puestow's procedure, pseudocyst drainage, or sphincteroplasty). If there was no evidence of ductal dilatation, or if pain recurred postoperatively, denervation procedures were performed (splenopancreatic flap, thorascopic sympathectomy, or resection). Pain recurrence was defined as the need for further hospitalization or reoperation. Data were analyzed by comparison of two proportions. Follow-up averaged 26 months. Thirty-seven patients underwent 44 operations solely in an attempt to control pain; 62 per cent were male, and 70 per cent had chronic alcoholic pancreatitis. Our results show that surgical management provides relief in 68 per cent of patients, and no one procedure is clearly superior to others.

Management of penetrating colon injuries. A prospective randomized trial.

Fifty-six patients with penetrating colon injuries were entered into a randomized prospective study. Management of the colon injury was not dependent on the number of associated injuries, amount of fecal contamination, shock, or blood requirements. Twenty-eight patients were treated with primary repair or resection and anastomosis and 28 patients were treated by diversion (24 colostomy, 3 ileostomy, 1 jejunostomy). The average Penetrating Abdominal Trauma Index score was 23.9 for the diversion group and 26 for the primary repair group. There were five (17.9%) septic-related complications in the diversion group. This included four intra-abdominal abscesses and one subcutaneous wound infection. There were six (21.4%) septic-related complications in the primary repair group. This included one wound infection, two positive blood cultures, and three intra-abdominal abscesses. There were no episodes of suture line failure in the primary repair/anastomosis group. The authors conclude that, independent of associated risk factors, primary repair or resection and anastomosis should be considered for treatment of all patients in the civilian population with penetrating colon wounds.

Germfree animals and technics in surgical research.

Germfree animals have been reared to a size, weight, and age permitting the performance of major surgical procedures and the pursuit of a variety of surgical research problems. Germfree dogs have been maintained in the isolator system through three generations, indicating that life, reproduction, and growth are all possible in the absence of microbial contamination. The value of the germfree approach to surgical problems has been utilized in studies of a variety of gastrointestinal problems, shock, cancer, immunology, burns, wound healing, and in direct patient application. Patients have been maintained in isolator environments for prevention of infection, for operative procedures, for treatment of extensive burns, and for management of immune-suppressed individuals. We conclude that germfree animals and germfree technics provide a valuable addition to the armamentarium of the surgeon in both research and clinical applications.

Adenocarcinoma of the stomach: a review of 35 years and 1,710 cases.

The records of 1,710 patients with adenocarcinoma of the stomach treated at Charity Hospital over a 35-year period were reviewed to note any trends which might help in understanding the decreasing incidence and poor prognosis of the disease. The yearly number of gastric cancer patients has dropped from 234/100,000 in the 1950's to 195/100,000 in the 1960's to 108/100,000 patients in the last decade. The percentage of affected white males is decreasing at a rate equal to the increasing frequency of black female patients, while the ratios for black males and white females remain constant. The median age rose from 61.5 years to 66 years over the study period. The operability rate decreased from 82.4% to 72.8% and the resectability rate was 49%. Subtotal gastrectomy was the most common procedure, but radical subtotal gastrectomy gave the best 5-year survival. There are fewer lesions of the antrum today, but the highest number of 5-year survivors had antral lesions. Long-term survival of patients with lesions of the cardia improved from zero in the first 25 years to 14% in the last decade. For the last 2 decades, patients with stage III and IV lesions comprised one-half of the 5-year survivors. Our overall 5-year survival was 7.9%, but in the last decade it was 8.9%. Our 5-year survival for all patients who underwent a resection was 17.9%, but increased to 24.8% for the last decade. These improvements, in combination with a decrease in incidence, have dropped the overall mortality from gastric cancer.

Overview of pancreatic cancer, 1989.

Pancreatic cancer remains a leading cause of death from cancer. Its incidence is rising throughout the world, not solely because of improved diagnostic techniques. Diagnosis is followed relatively rapidly by the demise of the patient, and reasons for this rapid course have been sought. Both patient and physician delay play roles in this course. In addition, spread of the lesion outside the confines of the pancreas is usually present at the time of diagnosis. Symptoms, age and sex distribution, pathologic types, location within the pancreas, and physical findings are discussed. The various diagnostic techniques are evaluated and compared. Choices of operations are discussed, including risks associated with each, survival results, and the recent decrease in operative mortality reported from several institutions. Some of the newer approaches to therapy are discussed--combinations of radiotherapy, operation, and palliative procedures. The importance of a diagnostic method that will detect the lesion at an earlier stage is stressed.

Pedigrees of southern surgical chairmen.

This review details the birth, medical education, surgical training, and previous academic appointments of the chairmen of departments of surgery in the medical schools in the geographic distribution of the Southern Medical Association.

Villous tumors of the duodenum.

Five cases of villous tumors of the duodenum are reported, all of which involve the ampulla of Vater. Three of the five lesions contained either infiltrating carcinoma or carcinoma in situ. Although preoperative endoscopic biopsy was performed on all tumors no malignancy was identified. Frozen sections done at the time of operation on the three patients with carcinoma also failed to identify malignancy. One patient underwent pancreaticoduodenectomy and four patients had local excision of the tumor. Three of the patients treated with local excision developed recurrence and two subsequently had pancreaticoduodenectomy. Because of the difficulty in making an accurate diagnosis and the chance of recurrence when local excision is employed, strong consideration should be given to pancreaticoduodenectomy as the initial form of treatment of these lesions.

Surgical management of the acutely obstructed colon. A review of 127 cases.

The surgical results in 127 cases of acute obstruction of the colon are presented. Carcinoma continues to account for the overwhelming number of cases, and there has been no appreciable change in the site of obstruction or age groups affected. In the current study, the overall mortality rate in patients with acute obstruction from all causes was 27 percent, which does not appear to be significantly different than it was 30 years ago. The overall mortality rate in patients with obstruction secondary to carcinoma was 23 percent. Under the specific circumstances of the cases reported herein, and on the basis of a limited experience, total colectomy and left colectomy as initial procedures in acute obstruction secondary to cancer had the same mortality rate as staged resection of the left colon. The only benefit found from either approach was an increase in the disease-free 5 year survival rate with staged resection. The overall survival rate was not enhanced by either approach.

Acute colonic diverticulitis.

Colonic diverticulosis is truly a disease of the 20th century. A direct correlation is thought to exist between the incidence of diverticular disease and the amount of dietary fiber. Acute colonic diverticulitis occurs in approximately 25 per cent of the patients with diverticula, and 20 per cent of the patients with diverticulitis will ultimately require surgical intervention. Because of the often virulent nature of the disease in younger patients and the prevalence in the geriatric population, an aggressive approach is advocated. Primary resection of the involved segment of colon is advocated in all cases requiring operation. A primary anastomosis can be constructed in stage I and some cases of stage II disease. This results in lower morbidity and mortality rates as well as fewer days of hospitalization and disability. Newer techniques such as diagnostic CT scanning, percutaneous drainage of diverticular abscess, and greater application of surgical stapling devices have done much to improve the ultimate outcome of colonic diverticulitis.

Gastric carcinoma in the young.

Thirty-eight cases of gastric carcinoma in patients 35-years-old and younger, occurring in the period 1948 to 1983, are reviewed. They comprised 2.2% of 1710 cases in all ages for the same 35 year period at the Charity Hospital. Women were afflicted as commonly as men. Blacks outnumbered whites 2.9:1.0. Obstruction, pain, and weight loss of relatively short duration were prominent symptoms. Tumors tended to be located distally in the stomach, and scirrhous in appearance. Histologically, diffuse type lesions were more common than intestinal or other type tumors. Radiographic evidence of disease was usually present in patients undergoing upper gastrointestinal series. Endoscopy with biopsy was a valuable diagnostic tool. Resectability in this group was not less than that achieved for all ages, however, only one patient has survived for five years. Advanced stage lesions predominated and were associated with poor survival. Earlier stage lesions in this age group appear to bear a more favorable prognosis.