Oral bioavailability of P‐glycoprotein substrate drugs do not differ between ABCB1‐1Δ and ABCB1 wild type dogs

Mealey, K.L., Waiting, D., Raunig, D.L., Schmidt, K.R., Nelson, F.R. Oral bioavailability of P‐glycoprotein substrate drugs do not differ between ABCB1‐1Δ and ABCB1 wild type dogs. J. vet. Pharmacol. Therap. 33 , 453–460. Previous studies have indicated that intestinal P‐glycoprotein (P‐gp) limits the oral bioavailability of substrate drugs and alters systemic pharmacokinetics. In this study, dogs lacking functional P‐gp were used to determine the contribution of P‐gp to the oral bioavailability and systemic pharmacokinetics of several P‐gp substrate drugs. The P‐gp substrates quinidine, loperamide, nelfinavir, cyclosporin and the control (non P‐gp substrate) drug diazepam were individually administered intravenously and per os to ABCB1‐1Δ dogs, which have a P‐gp null phenotype and ABCB1 wildtype dogs. ABCB1‐1Δ dogs have been shown to have greater brain penetration of P‐gp substrates, but limited information is available regarding oral bioavailability of P‐gp substrate drugs in this animal model. Plasma drug concentration vs. time curves were generated and pharmacokinetic parameters were calculated for each drug. There were no differences in oral bioavailability between ABCB1‐1Δ dogs and ABCB1 wildtype dogs for any of the drugs studied, suggesting that intestinal P‐gp does not significantly affect intestinal absorption of these particular substrate drugs in ABCB1‐1Δ dogs. However, small sample sizes and individual variability in CYP enzyme activity may have affected the power of the study to detect the impact of P‐gp on oral bioavailability.     

Effects of dermal dexamethasone application on ACTH and both basal and ACTH-stimulated cortisol concentration in normal horses

There are no data available regarding the systemic (adverse) effects which might be induced by topical/dermal glucocorticoids (GCs) application in the horse. Besides their widespread use for the treatment of a variety of peripheral inflammatory disorders such as atopic dermatitis, eczemas or arthritis in the horse, their surreptitious application has become a concern in doping cases in competition/performance horses. Assessing both basal and ACTH‐stimulated plasma cortisol as well as basal ACTH concentrations following application of dexamethsone‐containing dermal ointment is necessary to determine influences on hypothalamus‐pituitary‐adrenal (HPA) axis. Ten clinically healthy adult standardbred horses (6 mares, 4 geldings) were rubbed twice daily each with 50 g dexamethasone‐containing ointment on a defined skin area (30 × 50 cm) for 10 days. RIA and chemiluminescent enzyme immuno‐metric assay were used to determine resting and ACTH‐stimulated plasma cortisol and basal ACTH concentrations, respectively. HPA feedback sensitivity and adrenal function were measured by a standard ACTH stimulation test. Dermal dexamethasone suppressed significantly the resting plasma cortisol level (to 75–98%) below baseline (P < 0.001) within the first 2 days and decreased further until day 10. ACTH stimulation test showed a markedly reduced rise in plasma cortisol concentrations (P < 0.001 vs. baseline). Plasma ACTH level decreased also during topical dexamethasone application. The number of total lymphocytes and eosinophil granulocytes was reduced, whereas the number of neutrophils increased. No significant change of serum biochemical parameters was noted. Dermal dexamethasone application has the potential to cause an almost complete and transient HPA axis suppression and altered leukocyte distribution in normal horses. The effects on HPA axis function should be considered in relation to the inability of animals to resist stress situations. The data further implicate that percutaneously absorbed dexamethasone (GCs) may cause systemic effects relevant to ‘doping’.     

Frequency of the mutant MDR1 allele associated with multidrug sensitivity in a sample of collies from France

A study was performed to determine the frequency of the mutant MDR1 allele associated with ivermectin sensitivity in a sample of collies living in France. Buccal swab samples were collected from approximately 83 collies for determination of MDR1 genotype. DNA was extracted and the polymerase chain reaction was performed to amplify a 148 bp (wildtype MDR1 genotype) or 144 bp (mutant MDR1 genotype) amplicon containing the MDR1 mutation. Sequence analysis was performed to determine the genotype of each dog. Adequate quantities of DNA for unequivocal genotyping were obtained from only 25 of 83 swabs. Twenty percent (5/25) of the collies studied were homozygous for the normal allele (normal), 32% (8/25) were heterozygous (carrier), and 48% (12/25) were homozygous for the mutant allele (affected). The results of this study indicate that a high percentage of collies presenting to veterinarians in France harbor the MDR1 mutation, thus impacting some therapeutic decisions.     

Effects of a program of human interaction and alterations in diet composition on activity of the hypothalamic-pituitary-adrenal axis in dogs housed in a public animal shelter

OBJECTIVE: To determine whether a program of human interaction or alterations in diet composition would alter activity of the hypothalamic-pituitary-adrenal (HPA) axis in dogs housed in an animal shelter. DESIGN: Prospective study. ANIMALS: 40 dogs. PROCEDURE: Dogs were (n = 20) or were not (20) enrolled in a program of regular supplemental human interaction (20 min/d, 5 d/wk, for 8 weeks) involving stroking, massaging, and behavioral training. In addition, half the dogs in each group were fed a typical maintenance-type diet, and the other half were fed a premium diet. Plasma cortisol and ACTH concentrations were measured during weeks 0, 2, 4, and 8 and before and after exposure to a battery of novel situations during weeks 0 and 8. RESULTS: Plasma cortisol concentration was significantly decreased by week 2, but plasma ACTH concentration was not significantly decreased until week 8 and then only in dogs fed the premium diet. Following exposure to novel situations, plasma cortisol and ACTH concentrations were significantly increased. However, during week 8, dogs enrolled in the program of human interaction had significantly lower increases in cortisol concentration than did dogs not enrolled in the program. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that both a program of human interaction and alterations in diet composition have moderating effects on activity of the HPA axis in dogs housed in an animal shelter and that activity of the HPA axis may be increased for a longer period during shelter housing than measurement of plasma cortisol concentration alone would suggest.     

Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Hospitalized Neonatal Foals

Background: Transient hypothalamic-pituitary-adrenal (HPA) axis dysfunction occurs frequently in critically ill humans and impacts survival. The prevalence and impact of HPA axis dysfunction in critically ill neonatal foals are not well characterized.
Hypotheses: (1) HPA axis dysfunction occurs in hospitalized neonatal foals, and is characterized by inappropriately low basal serum cortisol concentration or inadequate cortisol response to exogenous adrenocorticotropic hormone (ACTH); (2) hospitalized foals with HPA axis dysfunction have more severe disease and are less likely to survive than hospitalized foals with normal HPA axis function.
Animals: Seventy-two hospitalized foals and 23 healthy age-matched foals.
Methods: Basal ACTH and cortisol concentrations were measured and a paired low-dose (10 μg)/high-dose (100 μg) cosyntropin stimulation test was performed at admission in hospitalized foals. HPA axis dysfunction was defined as (1) an inappropriately low basal cortisol concentration or (2) an inadequate increase in cortisol concentration (delta cortisol) after administration of cosyntropin, with cut-off values for appropriate basal and delta cortisol concentrations determined from results obtained in healthy age-matched foals.
Results: Forty-six percent of hospitalized foals had an inappropriately low basal cortisol concentration and 52% had an inadequate delta cortisol concentration after administration of the 100 μg dose of cosyntropin. An inadequate delta cortisol response to the high (100 μg) dose of cosyntropin was significantly correlated with shock and multiple organ dysfunction syndrome in hospitalized foals, and with decreased survival in a subgroup of septic foals.
Conclusions and Clinical Importance: HPA axis dysfunction occurs frequently in hospitalized neonatal foals, and negatively impacts disease severity and survival.     

Loperamide‐induced expression of immune and inflammatory genes in Collies associated with ivermectin sensitivity

This study evaluated the impact of the ABCB1‐1Δ mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given the unrelated ABCB1 substrate loperamide, to identify potential biomarkers predictive of drug safety. Thirty‐two healthy intact Collies consisting of dogs with either a wild‐type, heterozygous mutant, or homozygous mutant genotype were used. Whole blood samples were collected from Collies at 0 or 5 h following administration of loperamide at a dose of 0.10 mg/kg. Whole‐genome gene expression microarray was conducted to examine for changes in gene expression. Microarray analysis identified loperamide‐induced changes in gene expression which were specifically associated with ivermectin‐sensitive phenotypes in Collies possessing the ABCB1‐1Δ mutation. Gene pathway analysis further demonstrated that the altered genes are involved in immunological disease, cell death and survival, and cellular development. Thirteen genes, including CCL8 and IL‐8, were identified. Collie dogs harboring ABCB1‐1Δ mutation which also exhibited toxicity toward ivermectin demonstrated systematic responses following loperamide treatment exhibited by altered expression of genes involved in immune and inflammatory signaling pathways. Genes such as CCL8 and IL‐8 are potential biomarkers in whole blood that may predict the safety of loperamide in dogs with ABCB1‐1? mutation associated with ivermectin sensitivity.     

Effects of single intravenously administered doses of dexamethasone on response to the adrenocorticotropic hormone stimulation test in dogs

The effects of single IV administered doses of dexamethasone on response to the adrenocorticotropic hormone (ACTH) stimulation test (baseline plasma ACTH, pre-ACTH cortisol, and post-ACTH cortisol concentrations) performed 1, 2, and 3 days (experiment 1) or 3, 7, 10, and 14 days (experiment 2) after dexamethasone treatment were evaluated in healthy Beagles. In experiment 1, ACTH stimulation tests were carried out after administration of 0, 0.01, 0.1, 1, and 5 mg of dexamethasone/kg of body weight. Dosages greater than or equal to 0.1 mg of dexamethasone/kg decreased pre-ACTH plasma cortisol concentration on subsequent days, whereas dosages greater than or equal to 1 mg/kg also decreased plasma ACTH concentration. Treatment with 1 or 5 mg of dexamethasone/kg suppressed (P less than 0.05) post-ACTH plasma cortisol concentration (on day 3 after 1 mg of dexamethasone/kg; on days 1, 2, and 3 after 5 mg of dexamethasone/kg). In experiment 2, IV administration of 1 mg of dexamethasone/kg was associated only with low (P less than 0.05) post-ACTH plasma cortisol concentration in dogs on day 3. In experiment 2, pre-ACTH plasma cortisol and ACTH concentrations in dogs on days 3, 7, 10, and 14 and post-ACTH plasma cortisol concentration on days 7, 10, and 14 were not affected by dexamethasone administration. The results suggest that, in dogs, a single IV administered dosage of greater than or equal to 0.1 mg of dexamethasone/kg can alter the results of the ACTH stimulation test for at least 3 days. The suppressive effect of dexamethasone is dose dependent and is not apparent 7 days after treatment with 1 mg of dexamethasone/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypothalamo‐pituitary‐adrenocortical axis in stress‐susceptible and stress‐resistant pigs: endocrine responses to corticotrophin‐releasing factor and vasopressin*

Swiss Landrace pigs selected into genetically well‐characterized low and high tissue fat lines (f and F respectively) react differently to exogenous and endogenous stressors. Response of the hypothalamo‐pituitary‐adrenocortical (HPA) axis to i.v. administered ovine corticotrophin‐releasing factor (oCRF) and lysine vasopressin (LVP) in young females, intact and pretreated with dexamethasone or metyrapone, leads to the conclusion that different stress susceptibility of the two lines correlates with the sensitivity of pituitary corticotrophs to oCRF stimulation. Total amount of ACTH released after stimulation with submaximal oCRF doses was roughly equal in both lines, and cortisol level is even lower in the f‐line, most likely due to the considerably enhanced metabolic clearance rate of cortisol (lower half‐life of plasma cortisol compared with F‐line). LVP‐stimulated ACTH release is comparable with that of oCRF is stronger in the f‐line. Combined effect of oCRF and LVP is rather additive than synergistic but the half‐life ratio cortisol/ACTH after this stimulation is about four times higher than for stimulation by LVP and oCRF separately. In cases of externally stimulated HPA axis, cortisol plasma concentration tightly cross‐correlates with that of ACTH.     

Frequency of the mutant MDR1 allele associated with multidrug sensitivity in a sample of herding breed dogs living in Australia

A study was performed to determine the frequency of the mutant MDR1 allele associated with ivermectin sensitivity in a sample of Collies and other herding breeds living in Australia. Buccal swab samples were collected from 33 Collies, 17 Australian Shepherds, 7 Border Collies and 7 Shelties for determination of MDR1 genotype. DNA was extracted and the polymerase chain reaction was performed to amplify a 148 base pair (wildtype MDR1 genotype or 144 base pair (mutant MDR1 genotype) amplicon containing the MDR1 mutation. Sequence analysis was performed to determine the genotype of each dog. Adequate quantities of DNA for unequivocal genotyping were obtained from 61 of 64 samples. The previously described MDR1 mutation was identified in Collies, Australian Shepherds and Shelties living in Australia, but not in Border Collies (although sample numbers were low). Twelve percent (4/33) of the Collies studied were homozygous for the normal allele (normal), 64% (21/33) were heterozygous (carrier) and 24% (8/33) were homozygous for the mutant allele (affected). Results of this study indicate that a high percentage of herding breeds presenting to veterinarians in Australia harbor the MDR1 mutation, thus impacting some therapeutic decisions.     

Evaluation of plasma aldosterone concentrations before and after ACTH administration in clinically normal dogs and in dogs with various diseases

Plasma aldosterone concentrations were measured in response to adrenocorticotropic hormone (ACTH) gel administration in clinically normal dogs, in dogs with hypoadrenocorticism, and in dogs (with electrolyte abnormalities) that did not have hypoadrenocorticism. Baseline plasma aldosterone concentrations were determined from specimens obtained every 10 minutes for 3 hours from 2 dogs and every 30 minutes for 7.5 hours from 2 other dogs. During the evaluation period, plasma aldosterone concentrations varied by at least 50% in each dog. A randomized crossover design was used to compare changes in plasma aldosterone concentrations after administration of ACTH gel and physiologic NaCl solution. Dogs had significantly (P = 0.002) higher plasma aldosterone concentrations after administration of ACTH gel than after administration of NaCl solution. Plasma cortisol concentrations increased as expected after ACTH gel administration. Analysis of cortisol and aldosterone concentrations in the same specimens obtained at 7 sample collection times did not reveal significant linear correlation, and scatterplots did not indicate a nonlinear association. In addition, plasma aldosterone concentrations were determined in response to ACTH administration alone and to ACTH combined with a high dose of dexamethasone (0.1 mg/kg, IV). The plasma aldosterone response to ACTH alone was not significantly different from the response to ACTH combined with dexamethasone. For both tests, plasma aldosterone concentrations at 60 and 120 minutes after ACTH administration were significantly (P less than 0.0005 and P = 0.0001, respectively, increased, compared with base-line values. Six dogs with adrenocortical hypofunction, as determined by plasma cortisol concentrations before and after ACTH administration, had plasma aldosterone concentrations that were diminished or did not increase after ACTH administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of serum 17-hydroxyprogesterone concentration after administration of ACTH in dogs with hyperadrenocorticism

OBJECTIVE: To evaluate serum 17-hydroxyprogesterone (17-OHP) concentration measurement after administration of ACTH for use in the diagnosis of hyperadrenocorticism in dogs. DESIGN: Prospective study. ANIMALS: 110 dogs. PROCEDURE: Serum 17-OHP concentrations were measured before and after ACTH stimulation in 53 healthy dogs to establish reference values for this study. Affected dogs had pituitary-dependent (n = 40) or adrenal tumor-associated (12) hyperadrenocorticism or potentially had atypical hyperadrenocorticism (5; diagnosis confirmed in 1 dog). In affected dogs, frequency interval and borderline and abnormal serum 17-OHP concentrations after ACTH stimulation were determined. Serum cortisol concentrations were assessed via low-dose dexamethasone suppression and ACTH stimulation tests. RESULTS: In healthy dogs, serum 17-OHP concentration frequency intervals were grouped by sex and reproductive status (defined as < 95th percentile). Frequency intervals of serum 17-OHP concentrations after ACTH stimulation were < 77, < 2.0, < 3.2, and < 3.4 ng/mL (< 23.3, < 6.1, < 9.7, and < 10.3 nmol/L) for sexually intact and neutered females and sexually intact and neutered males, respectively. In 53 dogs with confirmed hyperadrenocorticism, serum cortisol concentrations after ACTH stimulation and 8 hours after administration of dexamethasone and serum 17-OHP concentrations after ACTH stimulation were considered borderline or abnormal in 79%, 93%, and 69% of dogs, respectively. Two of 5 dogs considered to have atypical hyperadrenocorticism had abnormal serum 17-OHP concentrations after ACTH stimulation. CONCLUSIONS AND CLINICAL RELEVANCE: Serum 17-OHP concentration measurement after ACTH stimulation may be useful in the diagnosis of hyperadrenocorticism in dogs when other test results are equivocal.     

Duration of pituitary and adrenocortical suppression after long-term administration of anti-inflammatory doses of prednisone in dogs.

Duration and magnitude of hypothalamic-pituitary-adrenal axis suppression caused by daily oral administration of a glucocorticoid was investigated, using an anti-inflammatory dose of prednisone. Twelve healthy adult male dogs were given prednisone orally for 35 days (0.55 mg/kg of body weight, q 12 h), and a control group of 6 dogs was given gelatin capsule vehicle. Plasma cortisol (baseline and 2-hour post-ACTH administration) and plasma ACTH and cortisol (baseline and 30-minutes post corticotropin-releasing hormone [CRH] administration) concentrations were monitored biweekly during and after the 35-day treatment period. Baseline plasma ACTH and cortisol and post-ACTH plasma cortisol concentrations were significantly (P less than 0.05) reduced in treated vs control dogs after 14 days of oral prednisone administration. By day 28, baseline ACTH and cortisol concentrations remained significantly (P less than 0.05) reduced and reserve function was markedly (P less than 0.0001) reduced as evidenced by mean post-CRH ACTH, post-CRH cortisol, and post-ACTH cortisol concentrations in treated vs control dogs. Two weeks after termination of daily prednisone administration, significant difference between group means was not evident in baseline ACTH or cortisol values, post-CRH ACTH or cortisol values, or post-ACTH cortisol values, compared with values in controls. Results indicate complete hypothalamic-pituitary-adrenal axis recovery 2 weeks after oral administration of an anti-inflammatory regimen of prednisone given daily for 5 weeks.     

The effects of mutated skeletal ryanodine receptors on hypothalamic-pituitary-adrenal axis function in boars

The objectives of the current experiment were to determine whether boars heterozygous for the mutation in skeletal ryanodine receptors (sRyR), known to cause porcine stress syndrome, differed from wild-type boars in hypothalamic-pituitary-adrenal axis (HPA) function. We have examined basal plasma ACTH, cortisol, and corticosteroid-binding globulin (CBG) concentrations; plasma ACTH and cortisol responses to a nose-snare stressor and at slaughter; dexamethasone suppression of plasma ACTH and cortisol concentrations; and glucocorticoid receptor (GR) density in the pituitary gland, hippocampus, hypothalamus, and frontal cortex. We have also examined carcass yields, composition, and meat quality to determine whether differences in HPA activity were accompanied by an increased incidence of meat quality characteristics associated with pale, soft, exudative (PSE) meat. Thirty boars either heterozygous or wild-type (n = 15 per genotype) for mutated sRyR were tested for HPA function at 7 mo of age. Heterozygous boars had lower basal plasma ACTH (P < .05) and cortisol (P < .04) concentrations. Integrated basal plasma ACTH and cortisol levels were also lower (P < .05 and P < .005, respectively). Genotype had no significant effect on basal CBG, stressor-induced (nose snare or slaughter) or dexamethasone suppression of plasma ACTH or cortisol concentrations. No differences in immunoreactive GR levels were found in the pituitary gland or any brain region examined. We did find a significant, negative correlation (r = -.62, P < .02) between peak (0800) basal plasma ACTH concentrations and hippocampal GR levels. The alterations in basal HPA function in heterozygous boars were accompanied by lighter body weights (P < .03), decreased carcass fat depth (P < .04), and increased carcass lean yields (P < .02). There was a higher incidence of meat quality characteristics associated with PSE meat in heterozygous boars indicated by higher carcass temperatures (P < .04) and meat brightness (P < .0001) with lower carcass pH at slaughter (P < .03) and after chilling (P < .003). In conclusion, we have found differences in basal and not stressor-induced HPA function between boars heterozygous and wild-type for mutated sRyR. This altered basal HPA activity was accompanied by an increased incidence of meat quality aspects associated with PSE meat in heterozygous boars.     

Non-dexamethasone-suppressible, pituitary-dependent hyperadrenocorticism in a dog

A 5-year-old female dog with hyperadrenocorticism was determined to have pituitary-dependent hyperadrenocorticism even though plasma cortisol concentrations were not suppressed after high-dosage dexamethasone administration. The diagnosis was based on a supranormal response of plasma cortisol to ACTH administration and a lack of suppression of plasma cortisol concentration after administration of 0.1 mg of dexamethasone/kg. Although a higher dosage of dexamethasone (1 mg/kg) did not cause suppression of plasma cortisol, plasma ACTH concentrations in the dog were increased above those in clinically normal dogs, supporting a diagnosis of pituitary-dependent hyperadrenocorticism. During treatment with mitotane, the dog became unconscious and died. Necropsy revealed a pituitary tumor that had compressed and displaced the hypothalamus. Although high-dosage dexamethasone suppression tests often are useful in the differential diagnosis of hyperadrenocorticism, a lack of suppression of plasma cortisol does not necessarily exclude pituitary-dependent hyperadrenocorticism.     

Hypothalamic-Pituitary-Adrenal Axis Assessment in Healthy Term Neonatal Foals Utilizing a Paired Low Dose/High Dose ACTH Stimulation Test

Background: Hypothalamic-pituitary-adrenal (HPA) axis function is dynamic in the neonatal foal. The paired low dose/high dose cosyntropin (ACTH) stimulation test allows comprehensive HPA axis assessment, but has not been evaluated in neonatal foals.
Hypothesis: Foal age will significantly affect cortisol responses to a paired 10 and 100 μg dose cosyntropin stimulation test in healthy neonatal foals.
Animals: Twenty healthy neonatal foals.
Methods: HPA axis function was assessed in 12 foals at birth and at 12–24, 36–48 hours, and 5–7 days of age. At each age, basal cortisol and ACTH concentrations were measured and cortisol responses to 10 and 100 μg cosyntropin were assessed with a paired ACTH stimulation test protocol. Eight additional 36–48-hour-old foals received saline instead of 10 μg cosyntropin in the same-paired ACTH stimulation test design.
Results: At birth, foals had significantly higher basal cortisol and ACTH concentrations and higher basal ACTH : cortisol ratios compared with foals in all other age groups. A significant cortisol response to both the 10 and 100 μg doses of cosyntropin was observed in all foals. The magnitude of the cortisol response to both doses of cosyntropin was significantly different across age groups, with the most marked responses in younger foals. There was no effect of the paired ACTH stimulation test design itself on cortisol responses.
Conclusions and Clinical Importance: A paired 10 and 100 μg cosyntropin stimulation test can be used to evaluate HPA axis function in neonatal foals. Consideration of foal age is important in interpretation of HPA axis assessment.     

Secretion of sex hormones in dogs with adrenal dysfunction

OBJECTIVE: To evaluate adrenal sex hormone concentrations in response to ACTH stimulation in healthy dogs, dogs with adrenal tumors, and dogs with pituitary-dependent hyperadrenocorticism (PDH). DESIGN: Prospective study. ANIMALS: 11 healthy control dogs, 9 dogs with adrenal-dependent hyperadrenocorticism (adenocarcinoma [ACA] or other tumor); 11 dogs with PDH, and 6 dogs with noncortisol-secreting adrenal tumors (ATs). PROCEDURE: Hyperadrenocorticism was diagnosed on the basis of clinical signs; physical examination findings; and results of ACTH stimulation test, low-dose dexamethasone suppression test, or both. Dogs with noncortisol-secreting ATs did not have hyperadrenocorticism but had ultrasonographic evidence of an AT. Concentrations of cortisol, androstenedione, estradiol, progesterone, testosterone, and 17-hydroxyprogesterone were measured before and 1 hour after i.m. administration of 0.25 mg of synthetic ACTH. RESULTS: All dogs with ACA, 10 dogs with PDH, and 4 dogs with ATs had 1 or more sex hormone concentrations greater than the reference range after ACTH stimulation. The absolute difference for progesterone, 17-hydroxyprogesterone, and testosterone concentrations (value obtained after ACTH administration minus value obtained before ACTH administration) was significantly greater for dogs with ACA, compared with the other 3 groups. The absolute difference for androstenedione was significantly greater for dogs with ACA, compared with dogs with AT and healthy control dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs with ACA secrete increased concentrations of adrenal sex hormones, compared with dogs with PDH, noncortisol-secreting ATs, and healthy dogs. Dogs with noncortisol-secreting ATs also have increased concentrations of sex hormones. There is great interdog variability in sex hormone concentrations in dogs with ACA after stimulation with ACTH.     

Effects of single intravenous doses of dexamethasone on baseline plasma cortisol concentrations and responses to synthetic ACTH in healthy dogs

The duration of adrenocortical suppression resulting from a single IV dose of dexamethasone or dexamethasone sodium phosphate was determined in dogs. At 0800 hours, 5 groups of dogs (n = 4/group) were treated with 0.01 or 0.1 mg of either agent/kg of body weight or saline solution (controls). Plasma cortisol concentrations were significantly (P less than 0.01) depressed in dogs given either dose of dexamethasone or dexamethasone sodium phosphate by posttreatment hour (PTH) 2 and concentrations remained suppressed for at least 16 hours. However, by PTH 24, plasma cortisol concentrations in all dogs, except those given 0.1 mg of dexamethasone/kg, returned to control values. Adrenocortical suppression was evident in dogs given 0.1 mg of dexamethasone/kg for up to 32 hours. The effect of dexamethasone pretreatment on the adrenocortical response to ACTH was studied in the same dogs 2 weeks later. Two groups of dogs (n = 10/group) were tested with 1 microgram of synthetic ACTH/kg given at 1000 hours or 1400 hours. One week later, half of the dogs in each group were given 0.01 mg of dexamethasone/kg at 0600 hours, whereas the remaining dogs were given 0.1 mg of dexamethasone/kg. The ACTH response test was then repeated so that the interval between dexamethasone treatment and ACTH injection was 4 hours (ACTH given at 1000 hours) or 8 hours (ACTH given at 1400 hours). Base-line plasma cortisol concentrations were reduced in all dogs given dexamethasone 4 or 8 hours previously.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum 17-alpha-hydroxyprogesterone and corticosterone concentrations in dogs with nonadrenal neoplasia and dogs with suspected hyperadrenocorticism

OBJECTIVE: To assess serum 17-alpha-hydroxyprogesterone (17OHP) and corticosterone concentrations in dogs with nonadrenal neoplasia and dogs being screened for hyperadrenocorticism. DESIGN: Prospective study. ANIMALS: 16 clinically normal dogs, 35 dogs with nonadrenal neoplasia, and 127 dogs with suspected hyperadrenocorticism. PROCEDURE: ACTH stimulation tests were performed in all dogs. Baseline serum cortisol and corticosterone concentrations were measured in the healthy dogs; baseline serum cortisol concentration and ACTH-stimulated cortisol, corticosterone, and 17OHP concentrations were measured in all dogs. Endogenous plasma ACTH concentration was also measured before administration of ACTH in dogs with neoplasia. RESULTS: In 35 dogs with neoplasia, 31.4% had high serum 17OHP concentration and 22.9% had high serum corticosterone concentration. Of the 127 dogs with suspected hyperadrenocorticism, 59 (46.5%) had high ACTH-stimulated cortisol concentrations; of those, 42 of 59 (71.2%) and 32 of 53 (60.4%) had high serum 17OHP and corticosterone concentrations, respectively. Of dogs with serum cortisol concentration within reference range after ACTH administration, 9 of 68 (13.2%) and 7 of 67 (10.4%) had high serum 17OHP and corticosterone concentrations, respectively. In the dogs with neoplasia and dogs suspected of having hyperadrenocorticism, post-ACTH serum hormone concentrations were significantly correlated. CONCLUSIONS AND CLINICAL RELEVANCE: Serum concentrations of 17OHP or corticosterone after administration of ACTH may be high in dogs with nonadrenal neoplasia and no evidence of hyperadrenocorticism. Changes in serum 17OHP or corticosterone concentrations after administration of ACTH are proportionate with changes in cortisol concentration.     

Adrenal response to adrenocorticotropic hormone in dogs before and after surgical attenuation of a single congenital portosystemic shunt

BACKGROUND: Dogs with single congenital portosystemic shunts (CPSS) often develop postoperative hypoglycemia and prolonged anesthetic recovery. These abnormalities could be attributable to inadequate adrenal response. However, adequacy of adrenal response after CPSS surgery is unexplored. HYPOTHESIS: Dogs with CPSS have inadequate postoperative adrenal response. ANIMALS: Eight nonoperated, 8 ovariohysterectomy (OHE), and 16 CPSS dogs. METHODS: Consecutive day ACTH stimulation tests were performed on nonoperated healthy dogs, healthy dogs before and after OHE, and CPSS dogs before and after surgery. Adequate response was defined as >50% or >30 ng/mL increase in cortisol after ACTH administration. Blood glucose (BG) was monitored before and after surgery. Prolonged anesthetic recovery and refractory hypoglycemia episodes were recorded. RESULTS: Results of consecutive day ACTH stimulation tests did not vary in normal dogs. Results of preoperative ACTH stimulation tests of CPSS and OHE dogs were not significantly different. Dogs with CPSS had higher postoperative baseline cortisol concentrations (median, 329 ng/mL) than OHE dogs (median, 153 ng/mL). Postoperative cortisol increase after ACTH in CPSS was < or =50% in 10/16 and < or =30 ng/mL in 6/16. After surgery, BG was < or =60 mg/dL in 7/16 CPSS dogs. Cortisol concentrations were not correlated with BG. Two CPSS dogs had refractory hypoglycemia and 4 had delayed recovery; all improved with dexamethasone administration (0.1-0.2 mg/kg/IV). CONCLUSIONS AND CLINICAL IMPORTANCE: Contrary to previous reports, baseline cortisol concentrations in CPSS and healthy dogs are similar. Many CPSS dogs have postoperative hypercortisolemia. Response to ACTH does not correlate with postoperative hypoglycemia or prolonged anesthetic recovery.