J.N. Midence, K.J. Drobatz, and R.S. Hess. (2015)
Cortisol Concentrations in Well-Regulated Dogs with Hyperadrenocorticism Treated with Trilostane.
Journal of Veterinary Internal Medicine. 29:1529-1533
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Summary:
This paper is a veterinary research paper on the affects of the drug known as Trilostane. Trilostane is a drug which affects the activity of the hormone ACTH. When ACTH binds to receptors in the adrenal cortex, it stimulates the production and secretion of steroid hormones in a number of ways. One being, the stimulation of gene expression for the enzymes involved in the conversion of cholesterol to steroids such as Cortisol. Trilostane acts on a specific enzyme responsible for the conversion of pregnenolone into progesterone. The name of this enzyme is 3β-Hydroxysteroid dehydrogenase. Trilostane binds to this enzyme and inhibits its activity. Since the creation of progesterone from pregnenolone is a critical step in the synthesis of Cortisol, the binding of Trilostane directly inhibits the creation of the steroid hormone Cortisol.
Figure 1: A pathway diagram illustrating the production of Cortisol and the activity of Trilostane. Original image taken from http://ucsdlabmed.wdfiles.com/local--files/chapter-10/Slide1.jpg
The purpose of the experiment was to determine the effectiveness of Trilostane as a treatment option for hyperadrenocorticism in dogs. Hyperadrenocorticism is a condition in which the dogs pituitary secretes too much ACTH, which causes the excessive secretion of steroid hormones such as Cortisol. Cortisol causes the blood glucose levels to ride, and thus, dogs suffering from hyperadrenocorticism will have an unhealthy level of blood glucose. Symptoms include polyuria, polydipsia, polyphagia, and excessive panting. The scientists predicted that Trilostane treatment would suppress cortisol expression and reduce symptoms associated witht eh condition. In order to test Trilostane as a Cortisol suppressant, the reseachers used approximately 13 different dogs as subjects for the experiment. In order to be considered for the experiment, the dogs must be healthy and their hyperadrenocorticism symptoms were well-regulated. Meaning they had normal urination, drinking, eating, and activity level. Their blood serum was also required to be about < 2.0 μg/dL before the tests started. An approximately even number of both male and female dogs were used with a median age of 9.9 years.
For the procedure, dogs were treated with Trilostane for 152 days before enrollment into the experiment. Researchers continued to give each dog a daily dose of Trilostane averaging 7.3mg/kg of weight. They than took measurements of blood Cortisol and ACTH levels at four different time frames during the days of the experiment and injected synthetic ACTH to stimulate Cortisol production at various points:
Pre1: A measurement taken 3-6 hours after the Trilostane injection, but BEFORE ACTH stimulation.
Post1: A measurement taken 3-6 hours after the Trilostane injection, AFTER the first ACTH stimulant injection.
Pre2: A measurement taken 9-12 hours after the Trilostane injection, BEFORE the second ACTH injection.
Post2: A measurement taken 9-12 hours after the Trilostane injection, AFTER the second ACTH stimulant injection.
This experimental format was used in order to determine the effects of Trilostane over time and under repeated exposure to stimulation of Cortisol production.
Results:
Figure 2: The results summary graph for the experiment, showing measured cortisol levels taken at different time intervals, both before and after ACTH stimulation.
Pre1 Cortisol measurements were lower on average than Pre2 Cortisol levels. Also, Post1 levels of Cortisol were much lower than in Post2 Cortisol measurements. Pre1 and Post1 Cortisol measurements were at similar levels on average. While Post2 levels were much higher than Pre2 levels of Cortisol.
The acceptable range of Cortisol levels for normal functioning in dogs with hyperadrenocorticism is around 4.0 μg/dL. Pre1, Post1, and Pre2 Cortisol measurements were all within range of normality for all dogs measured. Only some of the dogs measure at a Post1 time interval were measured to have Cortisol levels within normal range.
None of the 13 dogs used in the final clinical experiment showed symptoms of hypoadrenocorticism brought on by the treatment of Trilostane.
Findings:
- These results are indicative that Trilostane is effective in normalizing Cortisol levels in dogs hyperadrenocorticism.
- Trilostane can have strong effects in ~75% of tested dogs for a period of up to 12 hours after administered dose.
- Trilostane has high resistance to high ACTH stimulation of the adrenal cortex.
- Trilostane has strong effects in both male and female dogs.
- Trilostane may safely be used in most young dogs without causing symptoms of hypoadrenocorticism.
Critique:
The results obtained definitely align well with the predictions of the research team. After 152 days of treatment with Trilostane, most of the dogs had shown normalized levels of Cortisol in the blood and were no longer showing symptoms of hyperadrenocortisolism. As it turns out, Trilostane is now used as a patented drug called Vyritol for the treatment of Cushing's Syndrome in dogs and cats!
The article was fairly interesting and clearly written. However, I definitely have some criticisms. There was little to no background information provided on the endocrine axis affected by their drug in the article. Knowledge of both the drug mechanism of action, and the hormones involved are critical in understanding how the drug can potentially treat hyperadrenocortisolism. As well, there is only one figure provided in the article, which is the summary graph I have pasted above. The graph is useful for comparison purposes of cortisol levels at different time intervals. However, I believe a clearly organized table with specific cortisol measurement values would be useful in allowing the reader to see the results in the experiment. They currently have these numbers listed in the results section which is somewhat disorganized and hard to read. As well, there is no information provided on dog breeds used in the experiment which may affect the results and effects of the drug.
Future Experiments:
I originally chose this article because I am very interested in both medicine and disease. I think the endocrine axis involved in hyperadrenocorticism is extremely interesting in how it affects the body and how small imbalances can cause problems.
To expand on the research present in this article, I think my first experiment would be to see how Trilostane affects puppies and young dogs. The median age for dogs in this experiment was 9.9. As well, 13 dogs is a small sample size. I would like to see how this medication affects a wider age range and population of dogs. Adjusting dosage within different dogs would be interesting to find the optimal dosasge for treatment. I think I would carry out this experiment by selecting approximately 50 dogs to experiment on over a two year period. 5 dogs from each year of age from 1-10. I would carry out dosage and procedure as in the previous experiment and adjust as necessary with each age group in order to find optimum dosage and identify any side-effects.
Secondly, I would definitely be interested to study a similar disease, hypoadrenocorticism. Dog's with this disease have a lower than normal level of cortisol in the blood as opposed to a higher level. I would like to test different types of synthetic ACTH or glucocorticoid as possible vectors for replacement therapy. The proceure would also be similar to what the researchers in the above article have done, but instead of testing a drug, we would administer synthetic hormone. We would measure levels of this hormone in the blood at various time intervals and determine how often and how effective dosage of the synthetic hormone is in the dogs.
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