Influence of age on induction of mammary tumors by diethylstilbestrol in C3H/HeN mice with low murine mammary tumor virus titer.

C3H/HeN female mice with low murine mammary tumor virus titer (MTV-) were fed diets containing a targeted concentration of 640 ppb diethylstilbestrol [(DES) CAS: 56-53-1; 4,4'-(1,2-diethyl-1,2-ethenediyl)bis-phenol]. Mice were started on DES at 3, 5, 7, or 9 weeks of age. Some continued on the diet throughout the rest of their life-spans, whereas others were killed as soon as they had been fed DES for 2, 4, 6, 8, 10, or 12 weeks. Controls were also examined throughout the study. Among mice killed early, the only observation significantly influenced by age at the start of DES treatment was the presence or absence of corpora lutea (CL). DES did not prevent CL from appearing in mice started on DES at 7 or 9 weeks of age, but it did prevent their appearance in about 25% of the mice started at 5 weeks and in up to 75% of the mice started at 3 weeks of age. In the life-span-exposure groups, CL either disappeared or were never formed in 88% or more of the mice, regardless of age at the start of treatment. Neoplastic or presumptive preneoplastic lesions apparently influenced by DES in the life-span-treatment groups included ovarian tubular adenomas; granulosa cell tumors and luteomas; pituitary cystoid degeneration, hyperplasia, and adenomas; uterine adenocarcinomas and cervical adenosis; mesotheliomas; and mammary hyperplastic alveolar nodules (HANs) and adenocarcinomas. Luteoma and granulosa cell tumor incidences were reduced by DES, regardless of age at the start of treatment. Influence of age at the start of treatment was minimal or not apparent for mesotheliomas, uterine adenocarcinomas, or pituitary adenomas; however, pituitary cystoid degeneration and hyperplasia and cervical adenosis occurred in higher frequency and/or with shorter duration of DES exposure the earlier that treatment was started. A delay in the start of DES treatment was associated with a remarkable delay in HAN and mammary adenocarcinoma development. This was especially apparent in young mice (3-7 wk old) in which a 2-week delay in treatment resulted in a 20-week delay in HAN or tumor onset. Age at the start of treatment was a major factor in susceptibility of C3H/HeN-MTV- female mice to DES-induced mammary tumorigenesis.

Mammary tumorigenesis in C3H/HeN-MTV + mice treated with diethylstilboestrol for varying periods.

C3H/HeN-MTV+ female mice were fed diets containing 320 or 640 ppb diethylstilboestrol (DES). DES feeding was started at 3 wk of age and was either continued throughout life or discontinued after 4, 8 or 26 wk of administration. A control group consisted of mice fed the same diet without DES, for the duration of the experiment. Mice were killed when palpable body masses (presumed to be mammary adenocarcinomas) reached a diameter of 1 cm. Adenocarcinomas developed in 79% of control mice and 96% of the mice exposed to DES for 26 wk, irrespective of the dose. The frequency and rate of removal of tumour-bearing mice were not increased further with lifetime exposure at a given dose. The time at which the first tumour occurred was largely dependent on the duration of exposure, not dose. The rate of occurrence of subsequent tumours was dependent on dose and duration of exposure; the rate of removal of mice with mammary adenocarcinomas was significantly greater at 640 ppb than at 320 ppb DES. Tumour frequency was 83% in mice exposed to 320 ppb DES for 8 wk and in those exposed for 4 wk; however, tumours developed at a faster rate in mice exposed for 8 wk. Tumour frequency was 94-96% in mice exposed to 640 ppb DES for 4 wk and 8 wk, and tumours developed more rapidly in mice exposed for 8 wk than in those exposed for 4 wk. When data were plotted as log-dose v. log-t50 (time to a probability that half the mice would be removed with mammary tumours) linear extrapolation to the control log-t50 gave an estimate of the no-effect level of exposure to DES. This estimate was remarkably consistent for all data sets (40-93 ppb) and was independent of the duration of exposure.

Comparison of patient-controlled analgesia and epidural morphine for postcesarean pain and recovery.

A greater awareness of the advantages and limitations of new methods of administering postcesarean analgesia would help the obstetrician care for the recovering patient. Patient-controlled analgesia and epidural morphine are two new modalities for postoperative pain relief. The purpose of this prospective investigation was to compare their effectiveness, safety, side effects, patient satisfaction and cost. During an eight-month period, 161 women undergoing cesarean delivery were assigned to receive narcotics by either epidural morphine (76 patients) or patient-controlled analgesia (85 patients) using a combined continuous infusion and demand dosing of meperidine. The demographic characteristics of the two groups were similar. Mild or no pain was reported with similar frequencies in both groups. No reduced respiration or undesired sedation was seen in either group. The postoperative times before sitting at the bedside, ambulating, tolerating clear liquids and leaving the hospital were also comparable. No complications were encountered with patient-controlled analgesia, but pruritus and alarms from apnea monitors occurred commonly in the epidural morphine group. The costs to the patient were similar for the two groups. Patient-controlled analgesia using a combined continuous infusion and demand dosing is an acceptable alternative to epidural morphine after cesarean delivery.

Development and use of an automated clinical pharmacy services documentation system.

Clinical pharmacy practice has been shown to have a positive impact on patient care in hospitals, but is still the subject of much scrutiny in light of the current status of reimbursement for health care in the institutional environment. Although a number of systems have been utilized in an attempt to document workload and the impact of clinical pharmacy services, the ideal system has yet to be developed and methods for assessing the data generated are limited. This paper describes the development of an automated clinical pharmacy services documentation system which is interactive with database management, word processing, and statistics software. The present and future utilization of this system at the University of Nebraska Hospital and Clinics is discussed.

Dietary and age influence on the pharmacokinetic parameters of 2-acetylaminofluorene in BALB/c mice.

In a chronic study conducted in our laboratories, we found dietary effects on 2-acetylaminofluorene (2-AAF) toxicity. To determine if the absorption, distribution, metabolism, or elimination of 2-AAF was altered by the age of the animals, diet, or 2-AAF treatment, pharmacokinetic studies were conducted on young (11 weeks) and old (78 weeks) BALB/c mice that had been fed one of four diets containing 4 or 24% fat and 12 or 24% protein. Blood, urine, and feces samples were obtained over a 31-hr period after dosing with 500 ppm 2-[14C]AAF (10 microCi/mouse). Total radioactivity was determined after combusting each sample in an oxygen atmosphere and counting in a scintillation counter. The data from each individual mouse was simulated on an analog-digital hybrid computer utilizing a two-compartment model with metabolism. The pharmacokinetic parameters within groups were analyzed to make statistical comparisons of the effects of diet, dose, age, and interactions among the groups. The pharmacokinetic predictions of a shorter elimination half-life, smaller area-under-the-curve value, and therefore a decreased exposure to 2-AAF and metabolites due to an increased elimination rate of the parent compound through the urine were consistent with the decreased pathological effects found from the chronic study for the low protein/low fat diet mice.

Effect of a P & T committee newsletter on anti-infective prescribing habits.

P & T newsletters are commonly employed as a way in which to educate the medical staff. However, studies suggest that a newsletter is an ineffective method of education. This study describes the effects of a newsletter and direct in-service education on altering prescribing habits of physicians in a university-based teaching hospital. The newsletter and in-service recommended that physicians switch from a commonly used anti-infective to a more cost-effective alternative that had recently been added to the formulary. Prescribing patterns were altered and sustained for at least 3 months. The newsletter was at least as effective as direct in-service education.

Pathological changes in female C3H mice continuously fed diets containing diethylstilbestrol or 17beta--estradiol.

To study the long term effects of estrogen administration in mice, virgin female C3H/HeJ mice are being fed diets containing 0, 10, 100 or 500 ppb of diethylstilbestrol (DES) or 0, 100, 1000, or 5000 pph of 17beta-estradiol (E2) from 6 to 110 weeks of age. C3HeB/FeJ mice are being fed diets containing 08 10, 100, or 500 ppb DES FROM 6 TO 136 WEEKS OF AGE. Pathologic studies were conducted on 396 such mice sacrificed at 52 weeks and on over 500 others sacrificed at various intervals. After 52 weeks on 500 ppb DES or 5000 ppb E2, the cervix of both populations often showed stromal mucoid changes and adenosis characterized by focal replacement of squamous by columnar epithelium lining the cervical canal assoicated with glandular downgrowths into the subjacent stroma. The uterine horns showed hyperplastic glands, which often penetrated the muscularis, and focal endometrial and perivascular hyalin deposits. The ovaries showed atrophy with absence of corpora lutea. Ceroid deposits were increased in the ovaries and adrenals. Sternal bony trabeculae were increased. The incidence of uterine cervical adenosis and of mammary hyperplastic alveolar nodules and tumors (mainly type B, Dunn's classification), was higher in C3H/HeJ than in C3HeB/FeJ mice. Mice on lower doses of DES or E2 had less frequent and severe similar changes. Tumors observed to date only in estrogen-treated mice included 4 endometrial adenocarcinomas and an adenoacanthoma of a uterine horn, 14 cervical adenocarcinomas often appearing to arise from areas of adenosis, a vaginal squamous cell carcinoma, a cervical granular cell myoblastoma, 1 sternal and 3 cranial osteosarcomas, and a mesothelioma. The majority of the malignancies occurred in C3H/HeJ mice. These findings indicate that the mammary tumor virus factor facilitates DES-induced mammary tumorigenesis in C3H mice and may contribute to other DES-induced malignant and premalignant lesions.

Oil gavage test-compound administration effects in NTP carcinogenesis-toxicity testing.

Consulting toxicologists began in 1982 to question the use and potential involvement of oil gavage test-compound administration in unexpected NTP carcinogenesis responses. Investigations have focused on corn oil gavage alternatives, vehicle type and volume, alteration of MTD, teratogenic effects, disposition of test compounds, and target tissues. Micoencapsulation will require considerable development research to make it a suitable alternative. Vehicle type and volume appear to have different effects on the apparent MTD, teratogenicity and disposition of very similar compounds. Only two tissue effects have been observed in the NTP oil gavage bioassay data. First, there is a sporadic and weak association with exocrine pancreatic acinar cell proliferative lesions; these lesions are highly correlated with overweight male Fischer 344/N rats. Second, leukemia is reduced about 50 percent in the male Fischer 344/N rats; this is a strong association which results in an 8-10 percent increase in survival. The protective effect of corn oil gavage is remarkable and there is no significant enhancement of tumor development. Corn oil gavage under the conditions of the NTP carcinogenesis bioassay does contribute to overnutrition and undesirable increased body weight, especially in male Fischer 344/N rats. The NTP and NCTR research programs include research plans to address critical oil gavage, diet composition feeding regimen, exercise and hormonal status questions. Results of these studies will point the way to improving long-term carcinogenesis and toxicity testing.

Nonneoplastic changes induced in female C3H mice by chronic exposure to diethylstilbestrol or 17 beta-estradiol.

The long-term nonneoplastic effects of estrogenic diets were studied in female C3H/HeJ and C3HeB/FeJ mice. C3H/HeJ mice received diets containing 0, 10, 100, or 500 ppb diethylstilbestrol (DES) or 100, 1000, or 5000 ppb 17 beta-estradiol (E2) from 6 to 110 wk of age. C3HeB/FeJ females were fed diets containing nominal concentrations of 0, 10, 100, or 500 ppb DES from 6 to 136 wk of age. Responses of both strains to DES were qualitatively identical. Histological changes in the reproductive tract induced or increased by DES in both strains and by E2 in C3H/HeJ mice included stromal mucoid changes in the vagina and cervix, epithelial keratinization in the vagina, and glandular hyperplasia in the uterine horns. Increasing doses above 10 ppb DES or 100 ppb E2 increased the prevalence and, in some cases, severity of these responses. Dose-responses to DES for these endpoints were virtually indistinguishable in the two strains. At 10 ppb DES or 100 ppb E2 there were minimal or no observable effects. When the nonneoplastic dose-response data were compared with neoplastic dose-response data previously reported, no consistent relation between doses causing neoplastic and nonneoplastic responses was seen for the two estrogens.

Neoplastic and preneoplastic lesions induced in female C3H mice by diets containing diethylstilbestrol or 17 beta-estradiol.

To study the long term effects of estrogenic diets, 2160 virgin female C3H/Hel mice, having a high titer to the mammary tumor virus factor (MMTV), were fed diets containing 0, 10, 100, 500, or 1000 ppb diethylstilbestrol (DES) or 100, 1000, or 5000 ppb 17 beta-estradiol (E2) from 6 to 110 weeks of age; 1368 virgin female C3HeB/FeJ mice, having a low titer to the MMTV, were fed diets containing 0, 10, 1000, or 500 ppb DES from 6 to 136 weeks. In estrogen-treated mice, the incidence of cervical adenosis and of mammary hyperplastic alveolar nodules was increased and the time to development of mammary adenocarcinomas was shortened. These changes tended to increase with dose and time and appeared earlier in the C3H/HeJ mice. Other tumors observed included 32 cervical and 20 endometrial adenocarcinomas, 16 cervical granular cell myoblastomas, 12 peritoneal mesotheliomas involving the uterus, 2 cervical and 4 vaginal squamous cell carcinomas, 2 ovarian teratomas, 6 osteosarcomas, 25 pheochromocytomas and 3 thyroid carcinomas. Of these tumors, 1 cervical and 2 endometrial adenocarcinomas, and 4 pheochromocytomas occurred in C3HeB/FeJ control mice at 104-130 weeks; none occurred in C3H/HeJ controls. This study indicates that the MMTV facilitates the development of mammary lesions in C3H mice, that estrogens predispose C3H mice to endometrial and cervical adenocarcinomas, and that cervical adenosis may be a precursor of cervical adenocarcinoma in C3H mice and serve as an early indicator of the potential uterine carcinogenicity of a test compound. It supports the view that the C3H mouse may serve as an animal model for uterine adenocarcinomas and adenosis in women exposed to estrogens.