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Reto Neiger - One of the best experts on this subject based on the ideXlab platform.
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effect of Trilostane on hormone and serum electrolyte concentrations in dogs with pituitary dependent hyperadrenocorticism
Journal of Veterinary Internal Medicine, 2014Co-Authors: C Griebsch, C Lehnert, G J Williams, Klaus Failing, Reto NeigerAbstract:Background The effects of Trilostane on key hormones and electrolytes over 24 hours in dogs with pituitary-dependent hyperadrenocorticism (PDH) are unknown. Objectives To determine the plasma concentration of cortisol, endogenous adrenocorticotropic hormone (ACTH), aldosterone, sodium, potassium, and ionized calcium concentrations, and plasma renin activity over a 24-hour period after administration of Trilostane to dogs with well-controlled PDH. Animals Nine dogs (mean age 9.3 ± 0.67 years, mean weight 31.9 ± 6.4 kg) with confirmed PDH. Methods Prospective study. Thirty days after the first administration of Trilostane, blood samples were taken at −30, 0 (baseline), 15, 30, 60, and 90 minutes, and 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours after administration of Trilostane and plasma concentration of cortisol, endogenous ACTH, aldosterone, sodium, potassium, ionized calcium, and renin activity were determined. Results Cortisol concentrations decreased significantly (P < .001) 2–4 hours after Trilostane administration. From baseline, there was a significant (P < .001) increase in endogenous ACTH concentrations between hours 3–12, a significant increase (P < .001) in aldosterone concentration between hours 16–20, and a significant (P < .001) increase in renin activity between hours 6–20. Potassium concentration decreased significantly (P < .05) between hours 0.5–2. Conclusion and Clinical Importance Treatment with Trilostane did not cause clinically relevant alterations in plasma aldosterone and potassium concentration. Results suggest that in dogs with PDH, the optimal time point for an ACTH-stimulation test to be performed is 2–4 hours after Trilostane dosing. Future studies are necessary to establish interpretation criteria for a 2- to 4-hour postpill ACTH-stimulation test.
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a comparison of once and twice daily administration of Trilostane to dogs with hyperadrenocorticism
Tierärztliche Praxis Ausgabe K: Kleintiere Heimtiere, 2012Co-Authors: Monica Augusto, Reto Neiger, A Burden, Ian RamseyAbstract:Objective: This retrospective study describes the use of Trilostane given once versus twice daily in dogs with hyperadrenocorticism (SID vs. BID-group) in separate clinical trials. Material and methods: The groups were compared over a six month period using laboratory findings, dose required to suppress post-ACTH cortisol, and clinical scores from owner and clinician questionnaires. Results: Ninety-three dogs enrolled the trials but for analysis of the final visit results only 56 dogs filled the inclusion criteria: 30 dogs in the SID-group and 26 dogs in the BID-group. Both treatment groups showed an improvement in clinical scores with time and no significant difference between them. In the BID-group post-ACTH cortisol concentrations went below 250 nmol/l sooner and in a higher proportion of dogs than in the SID-group. Twice-daily administration of Trilostane also achieved a faster and more effective control for comparable daily doses. A higher individual tolerability (based on clinical scores) was found in the SID-group but there were no supporting laboratory findings. No dogs developed serious side-effects. Conclusion: This study reveals only small practical differences between once and twice daily Trilostane administrations in treating hyperadrenocorticism. And the overall benefits of twice daily dosing have to be considered against the effect on the owners and their compliance with treatment.
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efficacy of Trilostane for the treatment of equine cushing s syndrome
Equine Veterinary Journal, 2010Co-Authors: C M Mcgowan, Reto NeigerAbstract:Trilostane, a competitive 3-beta hydroxysteroid dehydrogenase inhibitor, has been used successfully to control clinical signs and cortisol excess in canine pituitary dependent hyperadrenocorticism. Trilostane was evaluated for its efficacy in resolving clinical and clinicopathological abnormalities of equine Cushing's syndrome (ECS) and to assess its safety. Twenty horses (mean age 21 years) diagnosed with ECS were followed for 1 or 2 years. Affected horses received 0.4-1 mg/kg (mean 0.5 mg/kg) Trilostane once daily. Clinical signs assessed over 1 or 2 years, showed a reduction in lethargy in all horses post treatment. Polyuria and/or polydipsia, present in 11 horses, was reduced in all after treatment. Recurrent or chronic laminitis, present in 16 horses, improved in 13/16 (81%) of cases. There were no side effects reported. Combined dexamethasone suppression and thyrotropin releasing hormone (TRH) stimulation tests were significantly different before and 30 days following therapy. There was a significant reduction (P = 0.01) of cortisol following TRH administration before (160 +/- 53.0 nmol/l) and after (130 +/- 46.1 nmol/l) Trilostane. Trilostane caused improvement in clinical signs in horses, without side effects, and a corresponding decrease in cortisol response to TRH administration. Trilostane may be a useful therapy for the treatment of ECS. Further work comparing the effects of Trilostane and pergolide is warranted.
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serum insulin concentrations in horses with equine cushing s syndrome response to a cortisol inhibitor and prognostic value
Equine Veterinary Journal, 2010Co-Authors: C M Mcgowan, R Frost, D U Pfeiffer, Reto NeigerAbstract:Reasons for performing study: Serum insulin concentration and its use as a prognostic indicator in horses with equine Cushing's syndrome (ECS) have been poorly documented. Objectives: To examine daily insulin variations in horses with ECS and the effect of treatment using Trilostane, a competitive inhibitor of 3beta-hydroxysteroid dehydrogenase. Further, we aimed to examine the relationship between baseline serum insulin concentration and survival in horses with ECS. Methods: Basal serum insulin concentrations were measured in 20 confirmed ECS cases by taking blood at regular 4 h intervals for 24 h (1200, 1600, 2000, 2400, 0400 and 0800 h) before treatment (Day 0) and 10 days, and 30 days and 1-2 years after the onset of Trilostane therapy. The temporal pattern of insulin was analysed using a linear mixed model approach, and the prognostic value of measurements on Day 0 assessed using receiver-operating characteristic analysis. Results: Horses with ECS showed a diurnal pattern of serum insulin concentration, highest value at 1200 h, and this pattern was not altered by treatment with Trilostane. Furthermore, despite a mild increase of serum insulin concentrations after 10 days of Trilostane therapy, insulin concentration was unaffected in the long term. Low serum insulin concentrations at the beginning of the trial were significantly associated with improved survival to 1-2 years. The 1200 h sampling before treatment had the highest prognostic value for prediction of survival with a sensitivity and specificity of at least 90% for serum insulin at 188 muu/ml to predict survival and nonsurvival, respectively. Conclusions and potential relevance: Insulin is a useful prognostic indicator for ECS, but potentially large variations can occur throughout a 24 h period, indicating a single sample may not be representative. Serum insulin concentration did not increase over 1-2 years in horses receiving Trilostane therapy.
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The effect of Trilostane treatment on circulating thyroid hormone concentrations in dogs with pituitary-dependent hyperadrenocorticism
Journal of Small Animal Practice, 2008Co-Authors: S. J. Kenefick, Reto NeigerAbstract:OBJECTIVE: To assess thyroid hormone levels in hyperadrenocorticoid dogs before and after therapy with Trilostane, a reversible inhibitor of steroidogenesis.\n\nMETHODS: Serum total thyroxine, free thyroxine and endogenous canine thyroid-stimulating hormone concentrations were measured in 20 dogs with spontaneously occurring hyperadrenocorticism before and six months after successful treatment with Trilostane.\n\nRESULTS: Fourteen dogs demonstrated an increase in thyroxine following Trilostane treatment; however, this was not significant (P=0.108). Fourteen dogs demonstrated an increase in canine thyroid-stimulating hormone concentrations with Trilostane therapy (P=0.006). Of the 14 dogs that demonstrated an increase in thyroxine concentrations following therapy, 10 also showed an increase in canine thyroid-stimulating hormone concentrations. Before treatment, free thyroxine values were within, above and below the reference range in 10, six and two dogs, respectively. Sixteen of 18 dogs had free thyroxine values within the reference range after treatment, with 11 dogs showing a decrease in free thyroxine levels following therapy (P=0.029).\n\nCLINICAL SIGNIFICANCE: While treatment with Trilostane did not induce a significant change of thyroxine concentrations, there was a significant increase in canine thyroid-stimulating hormone concentrations following treatment, a finding that supports thyroid-stimulating hormone suppression as one of the factors that contributes to the effects of glucocorticoids on the hypothalamic-pituitary-thyroid axis. The significant elevation in free thyroxine values following treatment with Trilostane was unexpected and did not support the findings of previous studies in this area.
Tangui Maurice - One of the best experts on this subject based on the ideXlab platform.
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the antidepressant like effects of the 3β hydroxysteroid dehydrogenase inhibitor Trilostane in mice is related to changes in neuroactive steroid and monoamine levels
Neuropharmacology, 2012Co-Authors: Julie Espallergues, Jamal Temsamani, Claude Laruelle, Tangui Maurice, Takayoshi Mamiya, Monique Vallee, Takenao Koseki, Toshitaka NabeshimaAbstract:In the present study, we analyzed the effects of a systemic treatment with the competitive 3β-hydroxysteroid dehydrogenase (3β-HSD) inhibitor Trilostane on: (i) neurosteroid and monoamine levels in the brain, and (ii) the antidepressant activity of steroids and antidepressants in the forced swimming test (FST). 3β-HSD converts pregnenolone (PREG) into progesterone (PROG) or dehydroepiandrosterone (DHEA) into androstenedione. These neuroactive steroids are known to regulate neurotransmitters effects in the brain, particularly glutamate, γ-aminobutyric acid (GABA) and serotonin (5-HT), with consequences on mood and depression. We previously reported that Trilostane showed antidepressant-like properties in the FST and concomitantly regulated plasma adrenocorticotropin (ACTH) and corticosterone levels, markers of the stress-induced hypothalamus-pituitary-adrenal (HPA) axis activation. We here observed that adrenalectomy/castration blocked the Trilostane effect, outlining the importance of peripheral steroid levels. Trilostane (25 mg/kg) decreased hippocampus PROG contents and paradoxically increased circulating PROG levels. It also increased PREG levels in the hippocampus and frontal cortex. In the FST, a co-treatment with Trilostane facilitated DHEAS (5-20 mg/kg) antidepressant activity, but showed only an additive, not facilitative, effect with PREGS (10-40 mg/kg), PROG (10-40 mg/kg) or allopregnanolone (ALLO, 1-8 mg/kg). Trilostane (25 mg/kg) treatment significantly increased 5-HT and (-)-norepinephrine (NE) turnovers in the hippocampus, an effect likely related to its antidepressant action. In co-administration studies, Trilostane further decreased immobility following fluoxetine (30-60 mg/kg), sertraline (20-40 mg/kg) and imipramine (20-40 mg/kg), but not desipramine (20-40 mg/kg), treatments. A significant additive effect was observed for the selective 5-HT reuptake inhibitors (SSRI) at their highest dose. This study confirmed that a systemic administration of Trilostane directly affected peripheral and brain levels in neuroactive steroids and monoamine turnover, resulting in antidepressant activity. The drug could be proposed as a co-treatment with SSRI. This article is part of a Special Issue entitled 'Anxiety and Depression'.
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the antidepressant like effect of the 3β hydroxysteroid dehydrogenase inhibitor Trilostane involves a regulation of β type estrogen receptors
Psychopharmacology, 2011Co-Authors: Julie Espallergues, Jamal Temsamani, Claude Laruelle, Alexandre Urani, Tangui MauriceAbstract:Trilostane is a competitive inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD), which notably converts pregnenolone into progesterone or dehydroepiandrosterone into androstenedione. Trilostane shows antidepressant-like properties in the forced swimming test (FST). The compound, however, induced only moderate effects on neuroactive steroid levels that could be related to its behavioral efficacy. We compared the behavioral effect of Trilostane with the other 3β-HSD inhibitor, cyanoketone, and analyzed the putative involvement of the β-type estrogen receptor (ERβ) in its antidepressant effect. Trilostane reduced immobility in the FST significantly at 12.5 and 25 mg/kg subcutaneously (s.c.), whereas cyanoketone (0–100 mg/kg s.c.) was ineffective. The negative ER modulator fulvestrant (ICI 182780) dose-dependently blocked the effect of Trilostane (25 mg/kg). Trilostane increased circulating estradiol levels in the 12.5–50 mg/kg dose-range, and this effect was unaffected by stress and not shared by cyanoketone (25 mg/kg). The Trilostane (25 mg/kg) treatment increased the ERβ mRNA expression in adrenals (+100%) and centrally, in the hippocampus (+330%). Stress and cyanoketone failed to affect ERβ mRNA levels in periphery or in the brain. These data demonstrate that the antidepressant-like potential of Trilostane is not due to its 3β-HSD inhibiting activity, since it is not shared by cyanoketone, but rather to its estrogenic activity. The compound, which releases estradiol and up-regulates ERβ receptors, could be used as a therapeutic tool to allow an estrogenic facilitation of antidepressant efficacy.
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the 3β hydroxysteroid dehydrogenase inhibitor Trilostane shows antidepressant properties in mice
Psychoneuroendocrinology, 2009Co-Authors: Julie Espallergues, Jamal Temsamani, Claude Laruelle, Tangui Maurice, Laurent GivaloisAbstract:Changes in neuro(active)steroid levels are involved in depressive states and mood disorders. For instance, dehydroepiandrosterone or pregnenolone sulfate showed anti-stress and antidepressant activity in rodents and regulation of allopregnanolone levels appeared to be one of the consequence of an effective antidepressant therapy in patients. 4alpha,5-Epoxy-17beta-hydroxy-3-oxo-5alpha-androstane-2alpha-carbonitrile (Trilostane) inhibits the activity of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) that, in particular, converts pregnenolone into progesterone. We examined whether systemic administration of Trilostane affects the response to stress and depression. An acute treatment with Trilostane (6.3-50mg/kg SC injected twice -16 and -2h before the measure) increased 3beta-HSD mRNA levels in the hippocampus and adrenals, but had little effect on protein levels. The Trilostane treatment failed to affect open-field, locomotor or exploratory behaviors, but significantly reduced the immobility duration in the forced swimming test, measuring antidepressant-like activity, and increased the time spent in open arm in the elevated plus-maze, measuring anxiety response. The antidepressant-like effect of Trilostane was effective after a repeated treatment (2.5-20mg/kgSC twice-a-day during 7 days) or in mice submitted to a restraint stress during 21 days and showing several behavioral and physiological parameters of depression (decreased body weight, increased adrenal glands weight and anhaedonia). Trilostane also reduced stress-induced increase in plasma corticosterone and ACTH levels, showing direct effect on HPA axis activity. These observations suggest that the 3beta-HSD inhibitor Trilostane present antidepressant-like activity, putatively by regulating brain and peripheral levels of neuroactive steroids.
Felicitas S. Boretti - One of the best experts on this subject based on the ideXlab platform.
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comparison of two prepill cortisol concentrations in dogs with hypercortisolism treated with Trilostane
BMC Veterinary Research, 2018Co-Authors: Felicitas S. Boretti, Claudia E. Reusch, Barbara Riond, Caterina Musella, Wanda Arabella Burkhardt, Claudia Kuemmerlefraune, Nadja S SieberruckstuhlAbstract:The ideal method for monitoring Trilostane therapy in dogs with hypercortisolism is still open to debate. Recently, determination of the pre-Trilostane (prepill) cortisol concentration has been proposed to be more repeatable than either post-Trilostane or post-ACTH cortisol. The aim of this study was to compare two prepill cortisol concentrations in dogs with hypercortisolism during Trilostane therapy. Sixteen client-owned dogs with naturally occurring hypercortisolism were prospectively included and cortisol concentrations were measured twice, 1 h apart, before the morning Trilostane dose (prepill 1 and 2 cortisol). A total of 47 prepill cortisol measurement pairs were included. Compared to prepill 1, prepill 2 cortisol was higher in 15, equal in 8 and lower in 24 pairs. Group agreement between prepill 1 and 2 cortisol was 70% (moderate agreement - weighted kappa 0.55). In 30% of the pairs, group assignment was discrepant, implying a different therapeutic decision. In some dogs certain circumstances (e.g. excessive barking, difficulties during blood collection, excitement at arrival) were identified as potential factors explaining the discrepancy between prepill 1 and 2 cortisol measurements. In a substantial number of dogs treated with Trilostane, the two prepill cortisol concentrations differed. Part of this difference might be ascribable to stressful events during test performance. When using prepill cortisol measurements to monitor Trilostane therapy, recording of any incident during handling that might affect cortisol release might be helpful to make a reliable decision about a Trilostane dose adaptation.
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effects of Trilostane on urinary catecholamines and their metabolites in dogs with hypercortisolism
BMC Veterinary Research, 2017Co-Authors: Nadja S Sieberruckstuhl, Claudia E. Reusch, Elena Salesov, S. Quante, Barbara Riond, Katharina Rentsch, Regina Hofmannlehmann, Felicitas S. BorettiAbstract:Glucocorticoids influence the synthesis and metabolism of catecholamines (epinephrine and norepinephrine) and metanephrines (metanephrine and normetanephrine). The aim of this study was to measure urinary catecholamines and metanephrines in dogs with hypercortisolism before and during Trilostane therapy. Urine samples were collected during initial work up and during therapy with Trilostane in 14 dogs with hypercortisolism and in 25 healthy dogs. Epinephrine, norepinephrine, metanephrine and normetanephrine were measured using high-pressure liquid chromatography and expressed as ratios to urinary creatinine concentration. Untreated dogs with hypercortisolism had significantly higher epinephrine, norepinephrine, and normetanephrine:creatinine ratios compared to healthy dogs. During Trilostane therapy, urinary catecholamines and their metabolites did not decrease significantly. However, dogs with low post-ACTH cortisol concentrations during Trilostane therapy had less increased epinephrine, norepinephrine and normetanephrine:creatinine ratios compared to healthy dogs. There was no correlation of urinary catecholamines and their metabolites with baseline or post-ACTH cortisol or endogenous ACTH concentrations during Trilostane therapy. Influences between steroid hormones and catecholamines seem to occur, as dogs with hypercortisolism have significantly higher urinary epinephrine, norepinephrine, and normetanephrine:creatinine ratios. Once-daily Trilostane therapy does not lead to a significant decrease in catecholamines and their metabolites. Trilostane-treated dogs still have increased urinary epinephrine, norepinephrine and normetanephrine:creatinine ratios during Trilostane therapy.
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Effects of Trilostane on urinary Catecholamines and their metabolites in dogs with Hypercortisolism
BMC, 2017Co-Authors: Nadja S Sieber-ruckstuhl, Elena Salesov, S. Quante, Barbara Riond, Katharina Rentsch, Regina Hofmann-lehmann, Claudia Reusch, Felicitas S. BorettiAbstract:Abstract Background Glucocorticoids influence the synthesis and metabolism of catecholamines (epinephrine and norepinephrine) and metanephrines (metanephrine and normetanephrine). The aim of this study was to measure urinary catecholamines and metanephrines in dogs with hypercortisolism before and during Trilostane therapy. Urine samples were collected during initial work up and during therapy with Trilostane in 14 dogs with hypercortisolism and in 25 healthy dogs. Epinephrine, norepinephrine, metanephrine and normetanephrine were measured using high-pressure liquid chromatography and expressed as ratios to urinary creatinine concentration. Results Untreated dogs with hypercortisolism had significantly higher epinephrine, norepinephrine, and normetanephrine:creatinine ratios compared to healthy dogs. During Trilostane therapy, urinary catecholamines and their metabolites did not decrease significantly. However, dogs with low post-ACTH cortisol concentrations during Trilostane therapy had less increased epinephrine, norepinephrine and normetanephrine:creatinine ratios compared to healthy dogs. There was no correlation of urinary catecholamines and their metabolites with baseline or post-ACTH cortisol or endogenous ACTH concentrations during Trilostane therapy. Conclusion Influences between steroid hormones and catecholamines seem to occur, as dogs with hypercortisolism have significantly higher urinary epinephrine, norepinephrine, and normetanephrine:creatinine ratios. Once-daily Trilostane therapy does not lead to a significant decrease in catecholamines and their metabolites. Trilostane-treated dogs still have increased urinary epinephrine, norepinephrine and normetanephrine:creatinine ratios during Trilostane therapy
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lack of association between clinical signs and laboratory parameters in dogs with hyperadrenocorticism before and during Trilostane treatment
Schweizer Archiv Fur Tierheilkunde, 2016Co-Authors: Felicitas S. Boretti, Claudia E. Reusch, J Holzthum, Nadja S SieberruckstuhlAbstract:INTRODUCTION Trilostane therapy, the treatment of choice for pituitary- dependent hyperadrenocorticism (HAC) in dogs, is monitored by assessing resolution of clinical signs and measuring adrenocortical reserve capacity with an ACTH-stimulation test. The aim of this prospective study was to evaluate agreement between clinical signs reported by owners and cortisol or ACTH concentrations before and during Trilostane therapy (starting dose 1-2 mg/kg once daily). A questionnaire on signs of HAC was used and a clinical score calculated as the sum of the 9 questions. Eighteen questionnaires at diagnosis and 97 during therapy were filled out by owners of 32 dogs. An ACTH-stimulation test was performed at each reevaluation. There were weak correlations between abdominal girth, appetite or weight gain and cortisol concentrations during therapy. However, the clinical score did not correlate with cortisol or cACTH values. In 50% of dogs, Trilostane application had to be changed from once daily to twice daily during the study. Clinical signs reported by owners matched poorly with cortisol or cACTH concentrations at any time point. If low-dose Trilostane is used, treatment frequency often has to be increased.
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evaluation of baseline cortisol endogenous acth and cortisol acth ratio to monitor Trilostane treatment in dogs with pituitary dependent hypercortisolism
Journal of Veterinary Internal Medicine, 2013Co-Authors: W.a. Burkhardt, Felicitas S. Boretti, Claudia E. Reusch, Nadja S SieberruckstuhlAbstract:Background The effectiveness of Trilostane treatment is currently monitored by regular ACTH stimulation tests, which are time-consuming and expensive. Therefore, a monitoring system without a stimulation protocol and with less client expense would be preferable. Hypothesis/Objectives The aim of our study was to evaluate if baseline cortisol, endogenous ACTH (ACTH) concentration or the baseline cortisol to ACTH ratio (cortisol/ACTH ratio) could replace the ACTH stimulation test. Animals Forty Trilostane-treated dogs with pituitary-dependent hypercortisolism (PDH) were included in this prospective study. Methods A total of 148 ACTH stimulation tests and 77 ACTH concentrations and cortisol/ACTH ratios were analyzed. Control of cortisol release was classified according to cortisol concentration after ACTH administration as excessive ( 5.4 μg/dL; group 3). Results Baseline cortisol concentrations had considerable overlap between excessively, adequately, and inadequately controlled dogs. Only baseline cortisol >4.4 μg/dL (in 12% of tests) was a reliable diagnosis of inadequate control. Endogenous ACTH concentrations did not differ between groups. The overlap of the cortisol/ACTH ratio between groups was large. Correct classification was only possible if the cortisol/ACTH ratio was >15, which occurred in 4% of tests. Conclusions and Clinical Importance To monitor Trilostane treatment the ACTH stimulation test cannot be replaced by baseline cortisol, ACTH concentration, or the cortisol/ACTH ratio.
Claudia E. Reusch - One of the best experts on this subject based on the ideXlab platform.
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comparison of two prepill cortisol concentrations in dogs with hypercortisolism treated with Trilostane
BMC Veterinary Research, 2018Co-Authors: Felicitas S. Boretti, Claudia E. Reusch, Barbara Riond, Caterina Musella, Wanda Arabella Burkhardt, Claudia Kuemmerlefraune, Nadja S SieberruckstuhlAbstract:The ideal method for monitoring Trilostane therapy in dogs with hypercortisolism is still open to debate. Recently, determination of the pre-Trilostane (prepill) cortisol concentration has been proposed to be more repeatable than either post-Trilostane or post-ACTH cortisol. The aim of this study was to compare two prepill cortisol concentrations in dogs with hypercortisolism during Trilostane therapy. Sixteen client-owned dogs with naturally occurring hypercortisolism were prospectively included and cortisol concentrations were measured twice, 1 h apart, before the morning Trilostane dose (prepill 1 and 2 cortisol). A total of 47 prepill cortisol measurement pairs were included. Compared to prepill 1, prepill 2 cortisol was higher in 15, equal in 8 and lower in 24 pairs. Group agreement between prepill 1 and 2 cortisol was 70% (moderate agreement - weighted kappa 0.55). In 30% of the pairs, group assignment was discrepant, implying a different therapeutic decision. In some dogs certain circumstances (e.g. excessive barking, difficulties during blood collection, excitement at arrival) were identified as potential factors explaining the discrepancy between prepill 1 and 2 cortisol measurements. In a substantial number of dogs treated with Trilostane, the two prepill cortisol concentrations differed. Part of this difference might be ascribable to stressful events during test performance. When using prepill cortisol measurements to monitor Trilostane therapy, recording of any incident during handling that might affect cortisol release might be helpful to make a reliable decision about a Trilostane dose adaptation.
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effects of Trilostane on urinary catecholamines and their metabolites in dogs with hypercortisolism
BMC Veterinary Research, 2017Co-Authors: Nadja S Sieberruckstuhl, Claudia E. Reusch, Elena Salesov, S. Quante, Barbara Riond, Katharina Rentsch, Regina Hofmannlehmann, Felicitas S. BorettiAbstract:Glucocorticoids influence the synthesis and metabolism of catecholamines (epinephrine and norepinephrine) and metanephrines (metanephrine and normetanephrine). The aim of this study was to measure urinary catecholamines and metanephrines in dogs with hypercortisolism before and during Trilostane therapy. Urine samples were collected during initial work up and during therapy with Trilostane in 14 dogs with hypercortisolism and in 25 healthy dogs. Epinephrine, norepinephrine, metanephrine and normetanephrine were measured using high-pressure liquid chromatography and expressed as ratios to urinary creatinine concentration. Untreated dogs with hypercortisolism had significantly higher epinephrine, norepinephrine, and normetanephrine:creatinine ratios compared to healthy dogs. During Trilostane therapy, urinary catecholamines and their metabolites did not decrease significantly. However, dogs with low post-ACTH cortisol concentrations during Trilostane therapy had less increased epinephrine, norepinephrine and normetanephrine:creatinine ratios compared to healthy dogs. There was no correlation of urinary catecholamines and their metabolites with baseline or post-ACTH cortisol or endogenous ACTH concentrations during Trilostane therapy. Influences between steroid hormones and catecholamines seem to occur, as dogs with hypercortisolism have significantly higher urinary epinephrine, norepinephrine, and normetanephrine:creatinine ratios. Once-daily Trilostane therapy does not lead to a significant decrease in catecholamines and their metabolites. Trilostane-treated dogs still have increased urinary epinephrine, norepinephrine and normetanephrine:creatinine ratios during Trilostane therapy.
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lack of association between clinical signs and laboratory parameters in dogs with hyperadrenocorticism before and during Trilostane treatment
Schweizer Archiv Fur Tierheilkunde, 2016Co-Authors: Felicitas S. Boretti, Claudia E. Reusch, J Holzthum, Nadja S SieberruckstuhlAbstract:INTRODUCTION Trilostane therapy, the treatment of choice for pituitary- dependent hyperadrenocorticism (HAC) in dogs, is monitored by assessing resolution of clinical signs and measuring adrenocortical reserve capacity with an ACTH-stimulation test. The aim of this prospective study was to evaluate agreement between clinical signs reported by owners and cortisol or ACTH concentrations before and during Trilostane therapy (starting dose 1-2 mg/kg once daily). A questionnaire on signs of HAC was used and a clinical score calculated as the sum of the 9 questions. Eighteen questionnaires at diagnosis and 97 during therapy were filled out by owners of 32 dogs. An ACTH-stimulation test was performed at each reevaluation. There were weak correlations between abdominal girth, appetite or weight gain and cortisol concentrations during therapy. However, the clinical score did not correlate with cortisol or cACTH values. In 50% of dogs, Trilostane application had to be changed from once daily to twice daily during the study. Clinical signs reported by owners matched poorly with cortisol or cACTH concentrations at any time point. If low-dose Trilostane is used, treatment frequency often has to be increased.
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evaluation of baseline cortisol endogenous acth and cortisol acth ratio to monitor Trilostane treatment in dogs with pituitary dependent hypercortisolism
Journal of Veterinary Internal Medicine, 2013Co-Authors: W.a. Burkhardt, Felicitas S. Boretti, Claudia E. Reusch, Nadja S SieberruckstuhlAbstract:Background The effectiveness of Trilostane treatment is currently monitored by regular ACTH stimulation tests, which are time-consuming and expensive. Therefore, a monitoring system without a stimulation protocol and with less client expense would be preferable. Hypothesis/Objectives The aim of our study was to evaluate if baseline cortisol, endogenous ACTH (ACTH) concentration or the baseline cortisol to ACTH ratio (cortisol/ACTH ratio) could replace the ACTH stimulation test. Animals Forty Trilostane-treated dogs with pituitary-dependent hypercortisolism (PDH) were included in this prospective study. Methods A total of 148 ACTH stimulation tests and 77 ACTH concentrations and cortisol/ACTH ratios were analyzed. Control of cortisol release was classified according to cortisol concentration after ACTH administration as excessive ( 5.4 μg/dL; group 3). Results Baseline cortisol concentrations had considerable overlap between excessively, adequately, and inadequately controlled dogs. Only baseline cortisol >4.4 μg/dL (in 12% of tests) was a reliable diagnosis of inadequate control. Endogenous ACTH concentrations did not differ between groups. The overlap of the cortisol/ACTH ratio between groups was large. Correct classification was only possible if the cortisol/ACTH ratio was >15, which occurred in 4% of tests. Conclusions and Clinical Importance To monitor Trilostane treatment the ACTH stimulation test cannot be replaced by baseline cortisol, ACTH concentration, or the cortisol/ACTH ratio.
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Adrenocorticotropic hormone, but not Trilostane, causes severe adrenal hemorrhage, vacuolization, and apoptosis in rats
Domestic Animal Endocrinology, 2010Co-Authors: W.a. Burkhardt, Franco Guscetti, A. Ivos Todesco, N. Aldajarov, Thomas A. Lutz, Felicitas S. Boretti, Claudia E. Reusch, Nadja S Sieber-ruckstuhlAbstract:Adrenal necrosis has been reported as a complication of Trilostane application in dogs with hyperadrenocorticism. One suspicion was that necrosis results from the increase of adrenocorticotropic hormone (ACTH) during Trilostane therapy. The aim of the current study was to assess the effects of ACTH and Trilostane on adrenal glands of rats. For experiment 1, 36 rats were divided into 6 groups. Groups 1.1 to 1.4 received ACTH in different doses (60, 40, 20, and 10 μg/d) infused subcutaneously with osmotic minipumps for 16 wk. Group 1.5 received saline, and group 1.6 received no therapy. For experiment 2, 24 rats were divided into 3 groups. Group 2.1 and 2.2 received 5 and 50 mg/kg Trilostane/d orally mixed into chocolate pudding for 16 wk. Eight control rats received pudding alone. At the end of the experiments, adrenal glands were assessed for necrosis by histology and immunohistochemistry; levels of endogenous ACTH and nucleosomes were assessed in the blood. Rats treated with 60 μg ACTH/d showed more hemorrhage and vacuolization and increased numbers of apoptotic cells in the adrenal glands than rats treated with 20 or 10 μg ACTH/d, Trilostane, or control rats. Rats treated with 60 μg ACTH/d had a higher amount of nucleosomes in the blood compared with rats treated with 10 μg ACTH/d, Trilostane, or saline. We conclude that in healthy rats ACTH, but not Trilostane, causes adrenal degeneration in a dose-dependent manner. Results of this study support the hypothesis that adrenal gland lesions seen in Trilostane-treated dogs are caused by ACTH and not by Trilostane.
Ian Ramsey - One of the best experts on this subject based on the ideXlab platform.
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a comparison of once and twice daily administration of Trilostane to dogs with hyperadrenocorticism
Tierärztliche Praxis Ausgabe K: Kleintiere Heimtiere, 2012Co-Authors: Monica Augusto, Reto Neiger, A Burden, Ian RamseyAbstract:Objective: This retrospective study describes the use of Trilostane given once versus twice daily in dogs with hyperadrenocorticism (SID vs. BID-group) in separate clinical trials. Material and methods: The groups were compared over a six month period using laboratory findings, dose required to suppress post-ACTH cortisol, and clinical scores from owner and clinician questionnaires. Results: Ninety-three dogs enrolled the trials but for analysis of the final visit results only 56 dogs filled the inclusion criteria: 30 dogs in the SID-group and 26 dogs in the BID-group. Both treatment groups showed an improvement in clinical scores with time and no significant difference between them. In the BID-group post-ACTH cortisol concentrations went below 250 nmol/l sooner and in a higher proportion of dogs than in the SID-group. Twice-daily administration of Trilostane also achieved a faster and more effective control for comparable daily doses. A higher individual tolerability (based on clinical scores) was found in the SID-group but there were no supporting laboratory findings. No dogs developed serious side-effects. Conclusion: This study reveals only small practical differences between once and twice daily Trilostane administrations in treating hyperadrenocorticism. And the overall benefits of twice daily dosing have to be considered against the effect on the owners and their compliance with treatment.
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a comparison of factors that influence survival in dogs with adrenal dependent hyperadrenocorticism treated with mitotane or Trilostane
Journal of Veterinary Internal Medicine, 2011Co-Authors: Jenny Helm, T D H Parkin, Gerard Mclauchlan, Lisa Boden, P E Frowde, A J Collings, A J Tebb, Clive Elwood, M E Herrtage, Ian RamseyAbstract:Background: Trilostane is a recognized treatment for canine pituitary-dependent hyperadrenocorticism (PDH); however, its efficacy in dogs with adrenal-dependent hyperadrenocorticism (ADH) is unknown. Objectives: To examine factors that might influence survival in the medical management of ADH, with particular emphasis on treatment selection. Animals: Thirty-seven animals referred to 4 centers over a period of 12 years that had been diagnosed with ADH and treated with either Trilostane (22/37), mitotane (13/37), or both (2/37). Methods: Retrospective analysis of clinical records. Results: There was no statistically significant difference between the survival times of 13 dogs treated only with mitotane when compared with 22 dogs treated only with Trilostane. The median survival time for animals treated with Trilostane was 353 days (95% confidence interval [CI] 95–528 days), whereas it was 102 days (95% CI 43–277 days) for mitotane. Metastatic disease was detected in 8 of 37 dogs. There was a significantly lower probability of survival for dogs with metastatic disease when compared with those without metastatic disease (P < .001). Conclusions and Clinical Importance: The choice of medical treatment for ADH may not have a major effect on survival times. However, the presence of metastatic disease considerably decreases survival time regardless of the choice of medical treatment.
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retrospective evaluation of the effect of Trilostane on insulin requirement and fructosamine concentration in eight diabetic dogs with hyperadrenocorticism
Journal of Small Animal Practice, 2010Co-Authors: Gerard Mclauchlan, Y L Mcgrotty, C M Knottenbelt, Monica Augusto, Jenny Helm, Ian RamseyAbstract:Objectives: To describe the effect of Trilostane on insulin requirements and serum fructosamine in dogs with diabetes mellitus (DM) and hyperadrenocorticism (HAC). Methods: Observational retrospective study of eight dogs. Results: Median fructosamine concentration at presentation was 401 μmol/L (range 244 to 554 μmol/L). Median insulin dose at presentation was 1·1 IU/kg/dose (0·4 to 2·1 IU/kg/dose) administered twice daily in five animals and once in three. Four dogs had their insulin dose prospectively reduced at the start of Trilostane therapy. The HAC was controlled within 28 days in seven dogs. The remaining case was controlled by 17 weeks. Two dogs died within 40 days of starting Trilostane. The median fructosamine concentration was 438 μmol/L (range 325 to 600 μmol/L) after stabilisation of the HAC. One case had a consistent reduction in serum fructosamine concentration over the first four months. The median insulin dose after stabilisation of HAC was 1·5 IU/kg dose (range 0·25 to 3·0 IU/kg/dose). Insulin requirements were reduced in two cases after treatment with Trilostane. Four dogs required increased insulin doses. Clinical Significance: Insulin requirements and fructosamine concentrations do not consistently reduce during Trilostane treatment for HAC. Prospective studies are required to provide recommendations regarding reductions in insulin doses with Trilostane treatment.
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monitoring the response of canine hyperadrenocorticism to Trilostane treatment by assessment of acute phase protein concentrations
Journal of Small Animal Practice, 2010Co-Authors: A Arteaga, C M Knottenbelt, A J Tebb, P D Eckersall, Navneet K Dhand, T Mccann, H Evans, Ian RamseyAbstract:Background: Acute phase proteins (APPS) include haptoglobin (Hp), C-reactive protein (CRP) and serum amyloid A (SAA). Increased Hp concentrations may be induced by endogenous or exogenous glucocorticoids in dogs. Objectives: To assess whether control of hyperadrenocorticism (HAC) affects the concentrations of Hp, CRP, SAA, alkaline phosphatase (ALKP) and cholesterol, to determine whether these analytes can be used to assess control of HAC following Trilostane treatment, and whether a combination of these tests offers a valid method of assessing disease control. Methods: Hp, CRP, SAA, ALKP and cholesterol were assessed in 11 dogs with spontaneous HAC before and after treatment with Trilostane. Adequate control of HAC was defined as post-ACTH cortisol less than 150 nmol/l. Results: Significant reductions in Hp, ALKP, cholesterol and SAA (P 0·7) of disease control when compared to adrenocorticotropin or corticotropin (ACTH) stimulation test. SAA and CRP were unhelpful (Se & Sp<0·7). The analysis of the combination of the analytes did not improve the correlation with ACTH stimulation test. Clinical Relevance: Relying on these analytes does not provide additional information over ACTH stimulation test results when assessing control of HAC treated with Trilostane.
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Trilostane in dogs
Veterinary Clinics of North America-small Animal Practice, 2010Co-Authors: Ian RamseyAbstract:Over the last 10 years, Trilostane, a competitive inhibitor of steroid synthesis, is being widely used for the treatment of canine hyperadrenocorticism. Trilostane causes a significant but reversible decrease in cortisol production and a concomitant improvement in clinical signs in most dogs with this common condition. Side effects, though infrequent, can be serious: dogs treated with this drug require regular monitoring. This review summarizes current knowledge of the use of this drug with particular emphasis on its efficacy, safety, adverse reactions, and effects on endocrine parameters. Brief mention is made of its other uses in dogs and other species.
