Treatment of, and differential diagnosis between, ACTH-dependent cushing's syndrome and ACTH-independent cushing's syndrome
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Solution Overview
Problem
Current methods for differentiating between ACTH-dependent and ACTH-independent Cushing's syndrome are inadequate, leading to potential misdiagnosis and inappropriate treatment, which can be life-threatening if not corrected promptly.
Innovation Solution
Administer a glucocorticoid receptor antagonist (GRA) to patients with basal ACTH levels below 25 pg/mL, and monitor changes in ACTH and cortisol levels to determine whether the patient has ACTH-dependent or ACTH-independent Cushing's syndrome, guiding specific surgical interventions such as transsphenoidal surgery or adrenal surgery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If current diagnostic methods are used to differentiate between ACTH-dependent and ACTH-independent Cushing's syndrome, then the diagnostic process is simple, but the diagnosis accuracy is insufficient leading to potential misdiagnosis
Solution Approach 1:
The patent combines treatment and diagnosis into a single integrated process. The glucocorticoid receptor antagonist (GRA) is administered both to treat Cushing's syndrome and to perform differential diagnosis simultaneously. By measuring ACTH and cortisol levels before and after GRA administration, the system determines whether the patient has ACTH-dependent or ACTH-independent Cushing's syndrome, eliminating the need for separate diagnostic procedures and improving diagnostic accuracy without proportionally increasing complexity
Solution Approach 2:
The patent employs feedback mechanisms by measuring hormone levels (ACTH and cortisol) before and after GRA administration. The change in these levels provides feedback that indicates the type of Cushing's syndrome. Specifically, if ACTH levels increase after GRA administration, it indicates ACTH-dependent Cushing's syndrome; if ACTH levels decrease or remain unchanged, it indicates ACTH-independent Cushing's syndrome. This feedback loop enables accurate differential diagnosis while treating the patient
2Reliability
If differential diagnosis is performed accurately, then appropriate surgical intervention can be selected, but the diagnostic time and complexity increase
Solution Approach 1:
The patent performs preliminary diagnostic action by measuring baseline ACTH and cortisol levels before administering the GRA. This preliminary measurement establishes a reference point that, when compared with post-administration levels, enables accurate differential diagnosis. The preliminary action of baseline measurement is integrated into the treatment protocol, allowing diagnosis to be performed as part of the treatment initiation process rather than as a separate preliminary step
Solution Approach 2:
The GRA administration serves multiple functions simultaneously: it treats the underlying Cushing's syndrome by blocking glucocorticoid receptors, it performs differential diagnosis between ACTH-dependent and ACTH-independent forms, and it provides therapeutic benefit while gathering diagnostic information. This multi-functionality reduces the need for separate diagnostic procedures and minimizes additional time requirements
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Provides accurate differential diagnosis while treating Cushing's syndrome, ensuring appropriate surgical interventions are administered promptly, thereby reducing morbidity and mortality from misdiagnosis.
Implementation Method 1
Mifepristone binds to the GR with high affinity, with a dissociation constant (Kd) of 10-9 M. These antagonists include compositions which, by binding to GR, block the ability of an agonist to effectively bind to and/or activate the GR.
Data Source
AI summary
Methods for treating and differential diagnosis between ACTH-Dependent and ACTH-Independent Cushing's syndrome are disclosed, in which a glucocorticoid receptor antagonist (GRA) is administered to a Cushing's syndrome patient with a basal ACTH level less than about 25 pg/mL. If i) the patient's blood ACTH and ii) the patient's blood cortisol, or adrenal hormone, or adrenal pre-hormone levels rise, or if the ACTH:cortisol ratio increases, then ACTH-Dependent Cushing's syndrome is diagnosed. If those levels do not rise, or if the ACTH:cortisol ratio decreases, then ACTH-Independent Cushing's syndrome is diagnosed. In some instances, the patient is recovering from surgery to remove an ACTH secreting tumor, and the method described herein is used to determine if the tumor resection was successful or complete. The GRA may be mifepristone, or a non-steroidal GRA having a heteroaryl-ketone fused azadecalin backbone, an octahydro fused azadecalin backbone, a cyclohexyl pyrimidine backbone, or a fused azadecalin backbone.