Effects of prior aspirin and anti-ischemic therapy on outcome of patients with unstable angina. TIMI 7 Investigators. Thrombin Inhibition in Myocardial Ischemia.

Both aspirin and beta-adrenergic blocking drugs have been shown to reduce the risk of death or acute myocardial infarction (AMI) in patients with unstable angina, but their effect during chronic use on the presentation of acute coronary syndromes is less well defined. Calcium antagonists and oral nitrates are also widely prescribed for patients with coronary disease, but their effect on presentation of acute myocardial ischemia is unknown. We retrospectively examined the effects of prior aspirin and anti-ischemic medical therapy on clinical events in 410 patients hospitalized for unstable angina. Ischemic pain occurred at rest for a duration of 5 to 60 minutes. During hospitalization, 97% of patients received aspirin and all received the direct thrombin inhibitor bivalirudin for at least 72 hours. Despite being older and more likely to have risk factors for coronary disease and poor outcome, patients receiving aspirin before admission were less likely to present with non-Q-wave AMI (5% vs 14% in patients not on aspirin, p = 0.004). Prior beta blocker, calcium antagonist, or nitrate administration did not appear to modify presentation as unstable angina or non-Q-wave AMI. In a multivariate model, the combined incidence of death, AMI not present at enrollment, or recurrent angina was best predicted by age (adjusted odds ratio [95% confidence interval] 2.38 [1.14 to 3.98]) and presence of electrocardiographic changes with pain on presentation (adjusted odds ratio 2.83 [1.50 to 5.35]) but was not related to prior or in-hospital medical therapy. Thus, aspirin but not anti-ischemic therapy before hospitalization of patients with unstable angina was associated with a decreased incidence of non-Q-wave AMI on admission.

Reduced incidence and severity of accelerated graft atherosclerosis in cardiac transplant recipients treated with prophylactic antilymphocyte globulin.

Allograft coronary artery disease (ACAD) is the major factor limiting long-term survival of cardiac transplant recipients (CTRs). Although cyclosporine based triple drug immunosuppression has not decreased the occurrence of ACAD, some preliminary data suggests that prophylactic antilymphocyte preparations may reduce the incidence of this problem. All CTRs at Henry Ford Hospital have uniformly received prophylactic Minnesota Antilymphocyte Globulin (ALG), thereby providing a unique opportunity to investigate this hypothesis. One hundred three CTRs were followed for a median duration of 34 months with annual angiograms begun one year after transplant. Patients who died without an angiogram were considered to have ACAD based on autopsy results or if their death was clinically suspicious. Ninety-two patients underwent at least one angiogram. Fourteen patients had abnormal angiograms. Nine patients were identified as having ACAD by non-angiographic criteria. Five had autopsy proven disease, 3 died suspiciously, and 1 underwent successful re-transplantation for ACAD. By Kaplan-Meier analysis, the risk of developing ACAD was 12% in 1 year, 16% in 2 years, 22% in 3 years, 26% in 4 years, and 29% in 5 years. Risk of ACAD increased with older recipient's age, higher triglyceride levels, and diabetes, but was not affected by active CMV infection, number of acute rejection episodes, and HLA mismatching. These results suggest that prophylactic ALG reduces the occurrence of ACAD.

Effects of in utero and postnatal sodium saccharin exposure on the nutritional status of the young rat. I. Effects at 30 days post-birth.

The incidence of sodium saccharin (NaS)-associated bladder tumours in male rats increases when exposure to high doses begins in utero or at birth compared with treatment after weaning. The present experiment evaluated the effect of NaS exposure on selected physiological parameters in young second generation rats. 6-wk-old male and female Sprague-Dawley rats were placed on either a diet supplemented with 7.5% NaS or an untreated diet, and mated 4-6 wk later. Treatment was continued through lactation and the offspring were weaned on to the same diet. Body weights were significantly depressed in NaS-treated litters by 4 days after birth, and were 35% lower than controls by 30 days when the animals were killed. NaS treatment of the offspring was associated with an increase in faecal moisture content and caecal content weight, changes in several urinary analytes, a 50% increase in serum cholesterol a 10-fold increase in serum triglycerides and decreases in serum and hepatic vitamins. In addition, NaS-treated dams and pups were anaemic. Relatively few differences between males and females were noted, but significant inter-litter differences existed. The numerous physiological changes indicate that 7.5% dietary NaS exceeds the maximum tolerated dose for weanling rats.

Effects of in utero and postnatal sodium saccharin exposure on the nutritional status of the young rat. II. Dose response and reversibility.

A previous study in our laboratory demonstrated that 30-day-old Sprague-Dawley rats exposed to 7.5% sodium saccharin (NaS) since conception differ from untreated rats in several physiological parameters. In the present study, to determine the dose response of the changes associated with NaS treatment, animals were evaluated at 30 days post-birth, after treatment with dietary levels of 0, 1, 3 or 7.5% NaS since conception. Most physiological consequences of NaS treatment in the weanling rat, including anaemia and reductions in serum folate and vitamin A concentrations, were dose dependent. Serum vitamin E, cholesterol and triglyceride concentrations were decreased at the two lower doses of NaS but were significantly increased with 7.5% NaS. The no-effect level (NOEL) was similar for physiological effects and for bladder tumour production in two-generation studies (1% NaS in the diet). The reversibility of the effects of 7.5% NaS was examined in 90-day-old rats. The increases in lipids and vitamin E were reversible. Although values for haematological parameters and serum vitamin A remained significantly reduced at 90 days, changes were less severe than at 30 days. Histological examinations revealed that the effects of 7.5% dietary NaS on the bladder were negligible, indicating that the physiological changes observed in the young rat are probably not directly related to the production of bladder tumours.

Angioplasty of long or tandem coronary artery lesions using a new longer balloon dilatation catheter: a comparative study.

To determine whether or not a new 3 cm long angioplasty balloon was more effective in treatment of long (15-25 mm) or tandem (less than 25 mm overall length) coronary lesions, 44 consecutive patients with suitable lesions were alternately assigned to treatment with shorter, standard, 2 cm length, or long, 3 cm balloons. Primary success of PTCA was achieved in 95%. Those treated with long balloons required fewer inflations (3.3 +/- 1.5 vs. 5.7 +/- 2.1, P = .0001) and showed fewer moderate or severe intimal dissections of the lesions (4/22 vs. 12/22, p = .028). The use of 3 cm PTCA balloons in long or tandem lesions appears to be efficacious and less likely to cause dissections than shorter, 2 cm length devices.

The effect of dietary fat on tumor growth.

Experiments in animals have shown that high-fat diets can enhance tumor growth. Animals receiving high-fat diets routinely ingest up to 5 times the level of fat (by weight) found in standard chow diets. Rats given oil by gavage can triple caloric intake from fat compared to untreated controls. In laboratory animals, high-fat diets appear to play a role during the postinitiation phase of tumorigenesis. The type, level, and nature of the dietary fat may also affect the outcome of bioassays. Fat does not initiate the tumorigenic process. Additional factors must be considered when studying and interpreting the effects of dietary fat. Animal diets and dietary fats should be protected against oxidation. Antioxidants protect against oxidation but may also modify the tumorigenic process. Adequate levels of essential fatty acids must be provided. Dietary fat level can alter nutrient density and palatability; each of these factors can affect nutrient intake which can in turn influence metabolic processes.

Urinary excretion of dimethylnitrosamine: a quantitative relationship between dose and urinary excretion.

The urinary excretion of dimethylnitrosamine (DMN) was studied in male Sprague-Dawley rats. Animals were given DMN (3, 5, 10, 20, 30 and 50 mg/kg body weight, i.p.) or [3H]DMN (0.1, 1 and 3 mg; 8.7, 1.5 and 0.28 mCi/kg body weight, respectively, i.p.) diluted with sterile 0.9% NaCl. Urine was collected for 24 h after dosing. DMN was quantitated by gas chromatography using a Thermal Energy Analyzer as detector and [3H]DMN by liquid scintillation counting after purification by high pressure liquid chromatography. Multiple regression analysis programs were used to evaluate the fit of the data to a variety of models relating excretion to dose. All models which gave an acceptable fit including a term for dose squared. The models are discussed in terms of the relationship between urinary excretion and blood clearance of DMN.

In vivo metabolism and whole-blood clearance of n-nitrosomethylbenzylamine in the rat.

The pharmacokinetics and metabolism of N-nitrosomethyl-benzylamine, N-nitroso[methyl-14C]benzylamine, and N-nitrosomethyl[benzyl-7-14C]amine were studied in male Sprague-Dawley rats, and a major urinary metabolite was identified. N-Nitrosomethylbenzylamine (4.7 mg/kg body weight i.p.) was distributed throughout extracellular water and cleared from the whole blood by metabolism with a half-life of 66 min. Less than 1% of the administered dose of N-nitrosomethylbenzylamine (4.7 mg/kg i.p. or 3.3 mg/kg intragastric intubation) was excreted and expired as the parent compound. In the 24-hr period following injection of N-nitroso[methyl-14C1benzylamine (3.4 mg, 1 mCi/kg i.p.), 46% of the radioactivity administered was expired with a half-life of 2.1 hr. In contrast, 81% of the radioactivity from a dose of N-nitrosomethyl[benzyl-7-14C1amine (2.4 mg, 1 mCi/kg i.p.) was excreted in the urine with a half-life of 4.2 hr. Hippuric acid accounted for 80% of the radioactivity recovered in the urine.

Nitrosamine carcinogenicity: a quantitative relationship between molecular structure and organ selectivity for a series of acyclic N-nitroso compounds.

A mathematical model has been developed which describes the selectivity between liver and other target organs for a series of carcinogenic N-nitro-sodialkylamines. The relationship requires structural terms for the parent molecule as well as for the potential metabolites. This suggests that the nitrosamine metabolites are involved in tumor induction and that they participate directly in the mechanisms responsible for selecting the target organ.

Reaction of nitrosamines in the Udenfriend system: principal products and biological activity.

Reaction of diethylnitrosamine in the non-enzymatic, ascorbic acid-dependent, hydroxylating system of Udenfriend yielded N-nitroso-2-(ethylamino)-ethanol as the major product extracted into methylene chloride. The major product derived from nitrosopiperidine in the same system was N-nitroso-4-piperidone. These products, however, were mutagenic to Salmonella typhimurium TA 1535 only when activated by a rat liver microsomal preparation.