Pasireotide in Cushing's Disease

New England Journal of Medicine (Impact Factor: 55.87). 05/2012; 366(22):2134; author reply 2134-5. DOI: 10.1056/NEJMc1204078#SA1
Source: PubMed
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    • "The use of some inhibitors of ACTH production has been described, but they are ineffective in treating Cushing’s disease [22]. However, it has recently been reported that the use of pasireotide, a somatostatin analogue, has shown success in treating this disease [23], [24]. At the same way, it is essential to prospect for new drugs that could constitute an efficient pharmacological approach to treat Cushing’s disease. "
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    ABSTRACT: Pituitary adenomas comprise approximately 10-15% of intracranial tumors and result in morbidity associated with altered hormonal patterns, therapy and compression of adjacent sella turcica structures. The use of functional foods containing carotenoids contributes to reduce the risk of chronic diseases such as cancer and vascular disorders. In this study, we evaluated the influence of different concentrations of beta-carotene and lycopene on cell viability, colony formation, cell cycle, apoptosis, hormone secretion, intercellular communication and expression of connexin 43, Skp2 and p27(kip1) in ACTH-secreting pituitary adenoma cells, the AtT20 cells, incubated for 48 and 96 h with these carotenoids. We observed a decrease in cell viability caused by the lycopene and beta-carotene treatments; in these conditions, the clonogenic ability of the cells was also significantly decreased. Cell cycle analysis revealed that beta-carotene induced an increase of the cells in S and G2/M phases; furthermore, lycopene increased the proportion of these cells in G0/G1 while decreasing the S and G2/M phases. Also, carotenoids induced apoptosis after 96 h. Lycopene and beta-carotene decreased the secretion of ACTH in AtT20 cells in a dose-dependent manner. Carotenoids blocked the gap junction intercellular communication. In addition, the treatments increased the expression of phosphorylated connexin43. Finally, we also demonstrate decreased expression of S-phase kinase-associated protein 2 (Skp2) and increased expression of p27(kip1) in carotenoid-treated cells. These results show that lycopene and beta-carotene were able to negatively modulate events related to the malignant phenotype of AtT-20 cells, through a mechanism that could involve changes in the expression of connexin 43, Skp2 and p27(kip1); and suggest that these compounds might provide a novel pharmacological approach to the treatment of Cushing's disease.
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    ABSTRACT: Although it is the ideal treatment, pituitary surgery is not always successful, and success is not always lasting. Close surveillance, clinical and biological, will detect immediate failure or late recurrence. The reason must be thoroughly explored with the somewhat dogmatic rule that the patient should be offered the best surgery in expert hands, and a repeat surgical attempt must be systematically discussed. When repeat pituitary surgery is not indicated or has failed, then comes the difficult task to choose between a number of options directed toward different targets: directly suppress tumor ACTH by pituitary radiotherapy (conventional or stereotaxic) or with medications (somatostatin analog such as pasireotide, or dopaminergic drug such as cabergoline), directly suppress adrenocortical activity with medications (inhibitors of adrenal steroidogenesis such as ketoconazole or metyrapone, or the adrenolytic Lysodren), or by surgery (bilateral adrenalectomy), and finally oppose peripheral cortisol action with the antiglucocorticoid mifepristone. No single option is ideal, able to provide at the same time a high success rate and a rapid onset of action, to restore a normal pituitary adrenal axis, and to have good tolerability. Close follow-up and thorough evaluation of the cortisolic status will eventually dictate a switch in treatment options and/or combination strategies over time. The tumor status and its possible oncogenic threat, the severity of the hypercortisolism, and the patient perspectives (wish of fertility) are among the major parameters that can help a multidisciplinary approach toward the best option.
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    ABSTRACT: Pasireotide (Signifor(®)) is a new subcutaneous somatostatin analogue that acts via somatostatin receptors to inhibit the secretion of corticotropin from the pituitary adenoma in patients with Cushing's disease. Pasireotide has a receptor binding profile that is distinct from that of other somatostatin analogues, binding with high affinity to somatostatin receptor subtype 5, which is strongly over expressed in corticotroph adenoma cells. Pasireotide is the first pituitary-directed agent to be approved for use in Cushing's disease. In a phase III clinical trial in patients with Cushing's disease, twice-daily pasireotide 600 or 900 μg for 6 months led to normalization of urinary free cortisol (UFC) levels in up to a quarter of all patients (primary endpoint) and significantly reduced mean UFC levels. The reduction in UFC levels is rapid (within one to two months) and sustained (up to 24 months). Most patients who do not have an early response to pasireotide do not respond at a later time point. Decreases in UFC levels achieved during pasireotide treatment are accompanied by decreases in serum and salivary cortisol levels, as well as improvements in clinical signs and symptoms, including body weight, blood pressure and health-related quality-of-life. Pasireotide has a generally similar tolerability profile to that of other somatostatin analogues, but is associated with a relatively high incidence of hyperglycaemia, requiring the addition or intensification of glucose-lowering medication in a substantial proportion of patients. Thus, pasireotide, together with on-going patient monitoring, provides a promising new option for the medical management of Cushing's disease.
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