Carbenoxolone Disodium Treatment for Canine Pituitary-Dependent Hyperadrenocorticism

Pituitary-dependent hyperadrenocorticism (PDH) is mainly caused by pituitary corticotroph tumors in dogs. A characteristic feature of corticotroph tumors is their resistance to negative feedback by glucocorticoids. In some animal species, including dogs, the aberrant expression of 11β-hydroxysteroid dehydrogenase (11HSD), a cortisol metabolic enzyme, is observed in corticotroph tumors. We previously reported that carbenoxolone (CBX), an inhibitor of 11HSD, suppressed ACTH secretion from the pituitary gland, and decreased cortisol concentrations in healthy dogs. Therefore, the aim of this study was to investigate the therapeutic effects of CBX on dogs with PDH. Six dogs with PDH were treated with 60 to 80 mg/kg/day of CBX for 6 weeks, followed by trilostane, which is a commonly used agent for canine PDH. CBX treatment led to a gradual decrease in both basal and in corticotropic releasing hormone (CRH)-stimulated plasma ACTH concentrations and CRH-stimulated serum cortisol concentrations, without side effects. However, basal and stimulated ACTH and cortisol concentrations remained higher than those of healthy dogs, and clinical symptoms such as polydipsia and polyuria were not ameliorated. After a 2-week wash-out interval, trilostane was administered for 2 weeks. Although basal plasma ACTH concentrations were higher after trilostane treatment than CBX treatment, polydipsia and polyuria resolved in all six dogs. The reason for the lack of improvement in polydipsia and polyuria with CBX treatment is unclear. Other mechanisms, in addition to a partial decrease in ACTH secretion, are likely to be involved. In conclusion, this is the first study to report the in vivo effects of CBX in dogs with PDH. The findings suggest that CBX inhibits ACTH secretion from canine pituitary tumors, resulting in lower cortisol concentrations.     

Evaluation of adverse effects in tamoxifen exposed healthy female dogs

Background

Hypertension and proteinuria are medical complications associated with the multisystemic effects of long-term hypercortisolism in dogs with hyperadrenocorticism (HAC).

Methods

This study investigated the relationships among adrenocorticotropic hormone (ACTH)-stimulation test results, systemic blood pressure, and microalbuminuria in clinically-healthy dogs (n = 100), in dogs affected with naturally occurring pituitary-dependent (PDH; n = 40), or adrenal-dependent hyperadrenocorticism (ADH; n = 30).

Results

Mean systemic blood pressure was similar between clinically healthy dogs and dogs with HAC (p = 0.803). However the incidence of hypertension was highest in dogs with ADH (p = 0.017), followed by dogs with PDH, with the lowest levels in clinically healthy dogs (p = 0.019). Presence of microalbuminuria and albuminuria in clinically healthy dogs and dogs affected with HAC was significantly different (p < 0.001); incidences of albuminuria followed the same pattern of hypertension; highest incidence in dogs with ADH, and lowest level in clinically healthy dogs; but microalbuminuria showed a different pattern: clinically healthy dogs had highest incidences and dogs with ADH had lowest incidence. The presence of albuminuria was not associated with blood pressure values, regardless of whether dogs were clinically healthy or affected with ADH or PDH (p = 0.306).

Conclusions

Higher incidence of hypertension and albuminuria, not microalbuminuria was seen in dogs affected with HAC compared to clinically healthy dogs; incidence of hypertension and albuminuria was significantly higher in dogs affected with ADH compared to PDH. However, presence of albuminuria was not correlated with systemic blood pressure.     

Sulpiride improves inadequate lactation.

Twenty-eight newly delivered mothers with inadequate lactation volunteered for a placebo-controlled double-blind trial of sulpiride 50 mg thrice daily for four weeks. Treatment was allocated at random, and serum prolactin concentrations and breast-milk yields were measured before and serially during the trial. Of the 26 women who completed the trial, 14 had taken sulpiride and 12 the placebo. In the sulpiride-treatment group the mean maternal serum prolactin concentration rose from 49.0 +/- SE 3.6 micrograms/l to a maximum of 402.1 +/0 43.2 micrograms/l at two weeks; in the placebo-treated group, however, the concentration fell during the trial (from 84.7 +/- 24.0 micrograms/l to 47.8 +/- 8.6 micrograms/l). Mean breast-milk yields also increased in the sulpiride-treatment group (by an average of 212-265 ml) and fell in the women given placebo. Of the 14 infants in the sulpiride-treatment group, four did not need supplementary feeds during the trial; in the control group, however, all infants continued to require such feeds. Infants in the sulpiride-treatment group gained significantly more weight than did the controls (p less than 0.05). Three women taking sulpiride complained of mild side effects, but none occurred in the infants. These findings suggest that sulpiride is an effective treatment for inadequate lactation in the puerperium.     

Effects of aglépristone, a progesterone receptor antagonist, administered during the early luteal phase in non-pregnant bitches

Aglépristone, a progesterone receptor antagonist, was administered to six non-pregnant bitches in the early luteal phase in order to determine its effects on the duration of the luteal phase, the interestrous interval, and plasma concentrations of progesterone and prolactin. Aglépristone was administered subcutaneously once daily on two consecutive days in a dose of 10 mg/kg body weight, beginning 12 +/- 1 days after ovulation. Blood samples were collected before, during, and after administration of aglépristone for determination of plasma progesterone and prolactin concentrations. The differences in mean plasma concentration of progesterone and of prolactin before, during, and after treatment were not significant. Also, the duration of the luteal phase in the six treated bitches (72 +/- 6 days) did not differ significantly from that in untreated control dogs (74 +/- 4 days ). However, the intervals during which plasma progesterone concentration exceeded 64 and 32 nmol/l were significantly shorter in the six treated bitches than in untreated control dogs. The interestrous interval was significantly shorter in beagle bitches treated with aglépristone (158 +/- 16 days) than in the same group prior to treatment (200 +/- 5 days ). It is concluded that administration of aglépristone during the early luteal phase in the non-pregnant bitch affects progesterone secretion, but not sufficiently to shorten the luteal phase. The shortening of the interestrous interval suggests that aglépristone administered in the early luteal phase influences the hypothalamic-pituitary-ovarian axis.     

The importance of prolactin for initiation of lactation in the pregnant ewe

A single injection of ergocryptine (0.5 mg/kg liveweight) given to ewes 0.5-20 days prepartum or two injections (0.5 mg/kg liveweight per injection) given c. 30 and 10 days prepartum reduced concentrations of plasma prolactin to negligible (less than 5 ng/ml) values for 4 weeks after parturition, but did not affect concentrations of growth hormone and placental lactogen. Milking of treated ewes had no effect on concentrations of plasma prolactin during the first 4 weeks of lactation, but concentrations of growth hormone were increased during the 10-20 min period after milking. The half-life of prolactin in plasma was estimated as 21 min. In spite of the dramatic effect of ergocryptine on plasma prolactin all treated ewes secreted copious quantities of milk of normal composition. Mean daily yields of ewes treated with ergocryptine were not significantly different (P greater than 0.05) from those of untreated control ewes, but the mean +/- s.e.m. of total milk production over the first 3 weeks of lactation for ergocryptine-treated ewes was significantly lower (P less than 0.05) than that of control ewes (9.5 +/- 1.11 v. 14.1 +/- 1.20 kg milk). The results suggest that prolactin is not an essential component of the lactogenic and galactopoietic complexes of hormones in the ewe.     

Effects of gonadectomy on prolactin and LH secretion and the pituitary-thyroid axis in male dogs

The effects of gonadectomy on the secretion of prolactin, LH, TSH, and thyroxine were investigated. Blood serum hormone concentrations were analysed before and at 20, 120, and 180 min after a single iv TRH injection in each of eight healthy intact and castrated male beagle dogs before (control) and after 4-week treatment with the dopamine-2 receptor agonist cabergoline. Under control conditions the mean prolactin, TSH, and thyroxine concentrations were similar in intact and gonadectomised dogs, and administration of TRH provoked a significant (p < 0.01) increase in concentrations of the three hormones. The overall inhibitory effect of cabergoline treatment on prolactin secretion was more pronounced in the castrated dogs compared with the intact group. Cabergoline significantly suppressed the TRH-induced prolactin increase in each group (p < 0.01). Corresponding TRH-stimulated TSH concentrations were not affected by cabergoline. In the gonadectomised dogs, thyroxine concentrations before and at 120 and 180 min after TRH injection were significantly lower than under control conditions. LH concentrations were always higher (p < 0.01) in gonadectomised dogs compared with the intact dogs, but appeared to be affected neither by TRH nor by cabergoline administration. It can thus be concluded from the results, that gonadectomy does not result in hyperprolactinaemia in male dogs, while LH concentrations are significantly increased due to missing androgen feedback. Thyroid function remains unaffected by gonadectomy. Testicular steroids appear to interact with central dopaminergic and probably other neuroendocrine mechanisms regulating the secretion of prolactin, TSH, and thyroxine. Thus, long-term dopamine-2 receptor agonistic treatment may lead to a hypothyroid condition in castrated male dogs.     

Lipid peroxides and atherosclerosis.

Plasma lipid peroxide concentrations were measured in 100 patients with occlusive arterial disease proved angiographically (50 patients with ischaemic heart disease, 50 with peripheral arterial disease) and compared with values in 75 control patients with no clinical evidence of atherosclerosis. Lipid peroxide concentrations were significantly higher in patients both with ischaemic heart disease (median 4.37 mumol/l (interquartile range 3.85-5.75 mumol/l); p less than 0.001) and with peripheral arterial disease (median 4.37 mumol/l (3.88-5.21 mumol/l); p less than 0.001) than in controls (median 3.65 mumol/l (interquartile range 3.29-3.89 mumol/l). Overall there was a significant but weak correlation between plasma lipid peroxide and plasma triglyceride concentrations (rs = 0.25; p less than 0.001) but not between plasma lipid peroxide and plasma total cholesterol concentrations. Furthermore, hypertension, obesity, diabetes, smoking, positive family history, and intake of beta blockers and thiazide diuretics were not associated with significant differences in lipid peroxide values. This study provides clinical support to experimental data indicating that peroxidised lipids may be important in atherogenesis and its complications and also suggests that peroxidised lipids may provide an index of the severity of atherosclerosis.     

Chronic exposure of coho salmon to sublethal concentrations of copper--II. Distribution of copper between high- and low-molecular-weight proteins in liver cytosol and the possible role of metallothionein in detoxification

1. Liver cytosol samples from juvenile coho salmon exposed over a 14-week period to 70 micrograms/l (1/4 LC50) or 140 micrograms/l (1/2 LC50), were separated into high-molecular-weight and low-molecular-weight fractions by column chromatography on Sephadex G-75, and compared to similar samples obtained from control fish. 2. The levels of copper in the low-molecular-weight function of fish exposed to 70 micrograms/l were not significantly increased over control values for the first 6 weeks but then increased rapidly, while those of fish exposed to 140 micrograms/l increased substantially in the first 2-4 weeks of exposure, then levelled off. 3. In the exposed fish the levels of copper in the high-molecular-weight fraction were not significantly elevated above control levels over the first 8-10 weeks but then increased significantly. 4. The low-molecular-weight fractions of exposed fish were shown to contain increasing levels of metallothionein. The metallothionein was isolated on DEAE-cellulose and characterized by amino acid analyses.     

Recurrent breast cancer treated with the antioestrogen tamoxifen: correlation between hormonal changes and clinical course.

Forty-five post-menopausal women with recurrent breast cancer were treated with the antioestrogen, tamoxifen, 20 mg twice daily. Clinical assessment after 12 weeks indicated that 18 (40%) showed some remission. Gonadotrophins were suppressed within two weeks to relatively constant concentrations within the post-menopausal range, responses to luteinising hormone-releasing hormone (LH-RH) did not change, and androgen concentrations remained within the normal range in all patients. Oestradiol concentrations rose steadily only in women in whom treatment failed. Serum prolactin concentrations were raised in 18 out of the 44 (41%) patients in whom they were measured; 13 of these did not respond to treatment. Treatment did not change the average prolactin concentration when this was within the normal range, but it significantly reduced prolactin concentrations in hyperprolactinaemic patients--within two weeks (P less than 0-01) in those who responded well and by six weeks (P less than 0-05) in those who showed no remission. Among patients with normal prolactin values the release of prolactin after thyrotrophin-releasing hormone was significantly greater in those with no remission than in those who responded to tamoxifen. Responses in those with hyperprolactinaemia were reduced to about half the control values, and again this change occurred faster in those who were successfully treated. Patients therefore seem to have a better chance of responding to anti-oestrogen treatment if prolactin secretion is low.     

Role of steroid hormones and prolactin in canine mammary cancer

In several animal studies, prolactin has been found to be essential for mammary epithelial development, and its administration has been consistently shown to increase the rate of mammary tumours. High levels of steroid hormones have also been suggested to enhance mammary cancer development. The present study investigates the levels of the following hormones in serum and in tissue homogenates in dogs bearing canine mammary tumours: prolactin (PRL), progesterone (P4), dehydroepiandrosterone (DHEA), androstenedione (A4), testosterone (T), 17beta-estradiol (17beta-E2) and estrone sulfate (S04E1). Eighty mammary tumours (40 dysplasias and benign and 40 malignant tumours) from 32 female dogs, and 10 normal mammary glands from eight female dogs without history of mammary tumours, were analysed. Prolactin and steroid hormones in serum and tissue homogenates, were analysed by enzyme immunoassays (EIA) techniques, previously validated for this animal species. Levels of prolactin in tissue homogenates were significantly different between malignant and benign mammary tumours (p<0.01). Serum prolactin concentrations were lower in the control group as compared with the group of dogs with benign tumours and in dogs with malignant tumours (p=0.01). Serum prolactin levels in dogs with benign lesions were not significantly different than those obtained from dogs with malignant tumours. Levels of steroid hormones were significantly higher in malignant tumours compared with the benign tumours and normal mammary glands (p<0.01) both in serum and homogenate determinations. Our results suggest that the canine neoplastic mammary gland could be a source of prolactin. Our hypothesis is that both prolactin and steroid hormones are involved in the growth of canine mammary cancer, and that they might have an autocrine/paracrine role in the maintenance of this disease.     

Temporal changes in prolactin and corticosterone response during chronic treatment with d-fenfluramine

In order to elucidate the mechanism of development of tolerance to the anorectic effect during chronic treatment with d-fenfluramine (d-F), we examined the temporal changes induced by d-F in food intake and prolactin (PRL) and corticosterone secretion. Male Sprague-Dawley rats were treated for 14 days with d-F (2.5 mg/kg i.p.) or saline twice daily and were given free access to food and water. Groups of 8 rats were sacrificed 30 min after d-F or saline injection at days 1, 4 and 14 for measurements of serum PRL and corticosterone. Food intake and weight gain were reduced significantly by d-F during the first 2-3 days of treatment but not thereafter. Compared with saline, d-F initially increased PRL (57 +/- 9 vs. 7 +/- 0.7 ng/ml) and corticosterone (42 +/- 2 vs. 14 +/- 3 micrograms/dl) serum concentrations. At 4 days, PRL was still significantly increased (43 +/- 5 vs. 10 +/- 4 ng/ml) but corticosterone returned to basal levels. At 14 days, PRL and corticosterone concentrations in the d-F group were not different from corresponding values in the saline group. To verify whether the loss of corticosterone and PRL responses to d-F was not due to a depletion of hormone stores, direct stimulation of corticosterone with corticotrophin and of PRL with metoclopramide were made at days 4 and 14, respectively. Corticotrophin (0.25 mg/kg i.p.) increased corticosterone concentrations similarly in d-F-treated (45 +/- 8 micrograms/dl) and in saline-treated rats (51 +/- 7 micrograms/dl).(ABSTRACT TRUNCATED AT 250 WORDS)     

Adrenal cortical response in clinically normal dogs before and after adaptation to a housing environment

58 dogs (29 males and 29 females) selected as healthy on clinical and biochemical evaluations were subjected to an ACTH adrenal function test 2 days after their admission to a veterinary hospital (t + 0). Basal female serum cortisol concentrations were significantly higher than concentrations in males (77 nmol/l versus 43 nmol/l; P less than 0.01). Concentrations post stimulation were not statistically different (P greater than 0.05) between males and females: 306 (+/- 69) nmol/l versus 291 (+/- 73) nmol/l, respectively. Twelve dogs (6 males and 6 females), randomly selected from the 58, were subjected to the same test 5 weeks later (t + 5) and 12 weeks later (t + 12). Basal cortisol concentrations were lower at t + 5 or at t + 12 than at t + 0. Post stimulation mean cortisol concentrations were lower in males than in females at t + 5 (162 versus 232 nmol/l; P less than 0.05) but not at t + 0 (262 versus 320 nmol/l; P greater than 0.05) and t + 12 (188 versus 233 nmol/l; P greater than 0.05). These findings are indicating an increased susceptibility of bitches to environmental stress.     

Relationship between myocardial amiodarone concentration and antiarrhythmic effect in dogs with myocardial infarction and electrically induced ventricular arrhythmias

The relationship between the antiarrhythmic effect of amiodarone and its myocardial concentration was studied in dogs with 1-week-old myocardial infarction and reproducibly inducible sustained ventricular tachycardia or ventricular fibrillation. Three groups of animals (n = 10/group) received amiodarone, 40 mg.kg-1.day-1 (low-dose amiodarone), amiodarone 60 mg.kg-1.day-1 (high-dose amiodarone), or no amiodarone (control group). After 1 week of treatment, programmed electrical stimulation was repeated, and plasma and myocardial amiodarone and desethylamiodarone concentrations were measured. In the control group, sustained ventricular tachycardia or ventricular fibrillation was induced in six dogs (p = NS) when compared with baseline data. In the low-dose amiodarone group, sustained ventricular tachycardia or ventricular fibrillation was induced only in two dogs after 1 week of treatment (p less than 0.01 vs. baseline data). Sustained ventricular tachycardia or ventricular fibrillation was induced in seven dogs after treatment with high-dose amiodarone (p = NS vs. baseline data). Plasma amiodarone concentration in the low-dose amiodarone group (2.54 +/- 1.95 micrograms/mL) was significantly less (p less than 0.01) than that in the high-dose amiodarone group (4.64 +/- 1.66 micrograms/mL). Similarly, the plasma desethylamiodarone in the low-dose amiodarone group (0.32 +/- 0.16 microgram/mL) was significantly less (p less than 0.001) than that in the high-amiodarone dose group (0.56 +/- 0.23 microgram/mL). The myocardial amiodarone concentration in the low-dose amiodarone group (49.7 +/- 23.1 micrograms/g) was significantly lower (p less than 0.001) than that in the high-dose group (98.4 +/- 32.1 micrograms/g).(ABSTRACT TRUNCATED AT 250 WORDS)     

Human urinary epidermal growth factor: effects of age, sex and pregnancy

Urinary concentrations of immunoreactive human epidermal growth factor (hEGF) were determined by specific homologous radioimmunoassay in 169 healthy men (aged 20-69 years), 275 healthy women (20-8 years). healthy women (20-68 years) and 413 pregnant women (20-39 years). Relative hEGF concentrations in urine (micrograms/g creatinine) decreased significantly in both sexes between 24 and 64 years of age. The relative concentrations of hEGF in urine were significantly higher in women than in men at ages 20-69 years. The mean values of relative urinary hEGF concentrations in pregnant women in their twenties and thirties (30.0 +/- 0.7 micrograms/g creatinine and 29.6 +/- 1.2 micrograms/g creatinine) were significantly higher than those in age-matched nonpregnant women (27.3 +/- 1.8 micrograms/g creatinine and 22.8 +/- 0.7 micrograms/g creatinine). Among the trimesters, it was highest in the 2nd trimester of women in the twenties and thirties (33.4 +/- 1.3 micrograms/g creatinine and 31.7 +/- 1.9 micrograms/g creatinine). The significance of the increased urinary excretion of hEGF (micrograms/g creatinine) in pregnancy is not known. Further studies are required to find a source of hEGF in urine and a possible relation between increased hEGF excretion and fetoplacental growth and development.     

Effect of suppressing prolactin in the mouse on liveweight, food intake and ovulation rate

The involvement, if any, of prolactin in the relationship between appetite and ovulation rate was studied in mice. Injections of 0, 50, 100 or 150 micrograms of bromocriptine were given twice-daily to 46-day-old virgin mice for a minimum of 15 days. Between days 5 and 12 of treatment, mice receiving either 50, 100 or 150 micrograms of bromocriptine consumed 3.1, 4.3 and 6.2 g more food, respectively, than did mice in the control group. Liveweights and liveweight gain, however, were unaffected by bromocriptine injections. From day 0 to 12 of treatment mice grew 0.16, 0.15, 0.21 and 0.16 g/day in the 0, 50, 100 and 150 micrograms bromocriptine groups, respectively, (P greater than 0.05). Plasma prolactin concentrations were suppressed, but ovulation rates were similar in the 50, 100 and 150 micrograms bromocriptine groups compared with the control (median prolactin concentrations and mean ovulation rates were 32.9, 32.5 and 31.6 ng/ml and 14.4, 15.1 and 15.7 ova, respectively, compared with 217.2 ng/ml and 14.9 ova in the control). The results do not support the hypothesis that prolactin directly mediates a relationship between appetite and ovulation rate in the post-pubertal mouse.     

Correlation between manifestations of digoxin toxicity and serum digoxin,calcium, potassium,and magnesium concentrations and arterial pH.

In 18 patients with gastrointestinal manifestations of digoxin toxicity the mean serum digoxin concentration (+/- SEM) was 3.16 micrograms/l (+/- 0.25), the calcium to potassium ratio 0.31 (+/- 0.01), and the mean arterial pH 7.406 (+/- 0.017). In contrast 19 patients with digoxin induced automaticity had a mean serum digoxin concentration of 1.24 micrograms/l (+/- 0.15; p less than 0.001), a calcium to potassium ratio of 0.38 (+/- 0.01; p less than 0.01), and an arterial pH of 7.498 (+/- 0.008; p less than 0.001). Eight out of 13 patients with digoxin induced cardiotoxicity had serum concentrations of the drug within the therapeutic range (0.8-2.0 micrograms/l). The calcium to potassium ratio, however, was lower than in the patients with automaticity (0.31 +/- 0.02; p less than 0.01) and the arterial pH was 7.370 (+/- 0.033; p less than 0.05). Serum magnesium concentrations were similar in all groups. In this study patients with digoxin induced gastrointestinal symptoms had high serum concentrations of the drug, whereas those with drug induced automaticity had therapeutic concentrations. This second group, however, was identified by their higher calcium to potassium ratios and higher pH values.     

The regulation of ovine placental lactogen the role of the fetal hypothalamic-pituitary axis

The possible r?le of the fetal hypothalamic-pituitary axis in regulating the secretion of ovine placental lactogen (oPL) was investigated in chronically-catheterised ewes and fetuses in late pregnancy. Intravascular administration of agents to fetuses that significantly increased fetal prolactin concentrations (chlorpromazine 6.25 mg;thyrotrophin releasing hormone, 10 micrograms), significantly reduced fetal prolactin concentrations (bromocriptine, 0.033 mg/h), or significantly reduced fetal growth hormone (GH) concentrations (somatostatin, 2.5 micrograms/min), had no effect on maternal or fetal oPL concentrations. Mean fetal levels of prolactin or GH in late gestation could not be correlated with oPL concentrations, although fetal hypophysectomy prevented the normal prepartum fall in oPL concentrations.     

Age-related differences in the pituitary prolactin response to thyrotropin-releasing hormone

We have previously reported that human subjects undergoing surgery for inguinal hernias exhibit an age-related attenuation in the plasma prolactin response, with no differences during resting conditions. We suggested that these differences were due to age-related neuroendocrine changes, but that peripheral factors may play a role as well. In the present study, we have assessed the pituitary response to 500 micrograms of thyrotropin-releasing hormone (TRH) in the very same subjects previously studied during surgery. Blood samples were drawn immediately prior to, as well as 10, 20, 40 and 60 minutes following the intravenous administration of TRH. There was a clear-cut age-related attenuation in the pituitary prolactin response with no difference in the thyrotropin (TSH) response. Maximum prolactin response in the young subjects was 31.7 micrograms/l and 19.2 micrograms/l in old subjects (F(4) = 3.5, p less than .01, two-way ANOVA). These results indicate that the age-related differences in the prolactin response to stress are mainly due to pituitary changes. However, prolactin-secreting cells are under the control of the hypothalamus. Therefore, the possibility must be considered that aging or other concurrent factors could be exerting their influence via the hypothalamus and not necessarily directly at the pituitary level.     

Hormonal consequences of subcutaneous 6-methoxy-2-benzoxazolinone pellets or injections in prepubertal male and female rats

Prepubertal 27-day-old female rats maintained in a 14L:10D cycle (lights on 06:00 h) were injected s.c. at 13:00 h with saline or 2, 20 or 200 micrograms 6-methoxy-2-benzoxazolinone (6-MBOA) and killed 25-27 h later. No significant differences in body, pituitary or ovarian weight were noted. Differences in uterine weight (mg/100 g body weight) and in circulating free thyroxine index fit the pattern of a reduction after the lower doses with reversal of this effect after the highest dose. A dose-related rise in plasma prolactin concentration was accompanied by a significant increase in pituitary prolactin at the lowest (2 micrograms) dose. When 27-day-old prepubertal male and female rats maintained in a 14L:10D cycle were implanted with a beeswax pellet or a wax pellet that contained 100 micrograms or 1 mg 6-MBOA and killed 3 days later between 14:00 and 16:00 h, body and absolute ventral prostate weights (but not weights of other accessory organs, testes or relative ventral prostate weights) in males were lower. Pituitary (but not plasma) prolactin concentrations were higher after the lower dose compared to the controls; pituitary and plasma values of LH and FSH were unchanged. In females, reproductive variables were unchanged except for a reduction of pituitary prolactin after the 1 mg dose. Triiodothyronine and its free index were elevated after the higher dose in males and the lower dose in females. The free thyroxine index appeared raised after the larger dose only in males.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunoreactive trypsins in sera from dogs before and after induction of experimental pancreatitis

Radioimmunoassays for anionic and cationic dog trypsins are described. Characterization of the immunoreactivities in sera from fasting dogs demonstrated the presence of the two proenzymes only. Fasting sera from 10 dogs contained anionic and cationic trypsinogen in concentrations between 17-110 micrograms/l and 7-19 micrograms/l, respectively. Induction of experimental pancreatitis in dogs was accompanied by a large increase of immunoreactive anionic and cationic trypsins in the circulation. During the progress of the pancreatitis, immunoreactive trypsin with larger molecular weight than trypsinogen appeared. This high molecular weight immunoreactive trypsin was not seen in serum after intravenous injection of pancreatic juice in dogs. The high molecular weight immunoreactive trypsin probably consists of trypsin in complex with protease inhibitors. In vitro studies showed that the immunoreactivity of trypsin decreased considerably after binding to alpha 1-antitrypsin or alpha-macroglobulins.