Research shows how medicine for the brain can be absorbed through the nose

Research shows how medicine for the brain can be absorbed through the nose
-University of Southern Denmark. "Research shows how medicine for the brain can be absorbed through the nose." Medical News Today. MediLexicon, Intl., 27 Sep. 2013. Web. 27 Sep. 2013.

Editor's notes:
There may be a wonderful use for nasal administration in the treatment of medically resistant pituitary prolactinomas.  These are commonly treated medically by oral administration of the dopamine agonists cabergoline (CAB) or bromocriptine (BRO).  But in some patients normalization of PRL (prolactin) levels is not achieved with even unusually high doses of CAB or BRO. If CAB or BRO can be delivered effectively to the brain via nasal administration, it may be possible to produce higher therapeutic levels of the drug at the pituitary tumor while avoiding the undesired increased exposure to other systems which may be affected: such as the kidneys, pancreas, and immune system.

Cref: Dopamine -Wikipedia

Dopamine agonist-resistant prolactinomas

Dopamine agonist-resistant prolactinomas
-Oh MC, Aghi MK Journal of Neurosurgery 2011 May;114(5):1369-79. published online January 7, 2011; DOI: 10.3171/2010.11.JNS101369.

• "Dopamine agonist-resistant prolactinomas exhibit aggressive behavior and tend to be large, invasive, hyperangiogenic tumors with high mitotic indices, which makes their management via surgery, radiosurgery, or alternative medical therapies challenging, thus underscoring the need for novel medical therapies or treatment regimens that target these lesions."
  
• "...slightly less than 10% of patients with prolactinomas do not experience normalization of their prolactin levels in response to dopamine agonists, and harbor tumors that are resistant to dopamine agonist therapy."
  
• "...a minimum pharmacological definition of dopamine agonist resistance would seem to require a failure to respond to 3 months of treatment with up to 3.5 mg of cabergoline per week."
  
• "Although very rare, secondary or acquired resistance to dopamine agonist therapy has also been described, in which patients who were initially responsive to... either bromocriptine or cabergoline, later develop dopamine agonist resistance, with elevated prolactin levels and sometimes an enlarging tumor volume several years after beginning treatment... According to a recent report... there have been only 5 reported instances of patients who demonstrated secondary resistance to dopamine agonist therapy (2 to bromocriptine and 3 to cabergoline).
  
• DARPs (dopamine agonist resistant prolactinomas) are more likely to exhibit cavernous sinus invasion... [71% vs 10% for dopamine agonist-responsive prolactinomas]."
  
• "DARPs typically do not metastatize."
  
• "Transsphenoidal surgery is recommended for prolactinomas instead of medical treatment if
  • ...2) inadequate prolactin reduction despite high cabergoline doses...
    
  • 3) a female patient desires fertility, which may not occur while on dopamine agonists...
    
  • 5) the patient cannot tolerate dopamine agonist therapy due to side effects.
• transsphenoidal surgery:
  • prolactin was normalized in 36% of patients with DARPs in one study.
    
  • prolactin was normalized in 75% of patients with DARPs that were microprolactinomas.
    
  • "Temozolomide... has been used to treat 3 patients with cabergoline-resistant DARPs... with good results in all 3 cases."

The treatment of sporadic versus MEN1-related pituitary adenomas

The treatment of sporadic versus MEN1-related pituitary adenomas
-Beckers A, et al. Journal of Internal Medicine, 2003; 253: 599-605.

• MEN1-related adenomas [appear to be] more aggressive and less responsive to therapy than their sporadic counterparts."
• "...prolactinomas are over-represented in MEN1."
• [In non-invasive, sporadic cases, about] 92% of cases of prolactinoma or hyperprolactinemia were normalized with Cabergoline.
• 10-15% of patients are resistant to Bromocriptine. Cabergoline normalized PRL in more than 70% of patients intolerant or resistant to Bromocriptine.
• "In the future, somatostatin analogues with greater affinity to receptors subtype 5 (SSTR5) -frequently present at the cell surface of prolactinomas- may be tried.
• "Malignancy does not appear a characteristic of pituitary tumours in MEN1."
• "it appears therefore probable that MEN1 pituitary adenomas are more aggressive than the sporadic counterpart."
• In MEN1 patients with pituitary adenomas, "aggressive therapy is more frequently needed!"

Drug-resistant hyperprolactinemia

MEN1 frequently involves pituitary disease. One study found pituitary disease occurred in 42% of MEN1 patients.⁽¹⁾ Depending on the specific type of pituitary disorder, treatment may include the surgical removal of an adenoma, the use of hormones or drugs to normalize pituitary function, or radiotherapy.

A prolactinoma, for example, is a non-cancerous pituitary tumor that produces the hormone prolactin; it's the most common form of pituitary tumor.⁽²⁾ Prolactinomas tend to cause hyperprolactinemia, abnormally high blood levels of prolactin. This can cause a variety of symptoms, including interfering with normal ovulatory function in women.

Normally, prolactin-producing cells are down-regulated, or inhibited, by dopamine signals from the hypothalamus.⁽³⁾ Therefore, hyperprolactinemia often is treated by dopamine agonists, usually Cabergoline or Bromocriptine.

Cabergoline usually is more effective than Bromocriptine at normalizing prolactin levels and restoring gonadal function.⁽⁴⁾ Yet it is not always successful in lowering prolactin to normal levels.

One particular patient, "P", was found to have hyperprolactinemia which then prompted an MRI scan and diagnosis of a pituitary adenoma. Treatment with Cabergoline was started. Within four months, the adenoma shrank and was no longer detectable via MRI, and P's prolactin level dropped to normal levels. But not for long. The prolactin level began to rise, and P's doctor responded with increasing dosage of Cabergoline. This went on for eight years, with Caborgoline dosage of up to 2.5mg/wk and prolactin levels typically about 50-100 mg/dL. When Cabergoline was discontinued, the prolactin would shoot up to about 180, and when Cabergoline was resumed, prolactin would reduce but not normalize. Periodic MRIs suggested possible empty sella syndrome and no sign of adenoma.

P's treatment subsequently was switched to Bromocriptine for a year, but her prolactin did not respond as well as it did to Cabergoline, and so Cabergoline was resumed.

What is there to do for a patient whose hyperprolactinemia does not respond sufficiently to dopamine agonist therapy, and who does not exhibit an operable adenoma?
__________

⁽¹⁾ Bruno Vergès, et al. Pituitary Disease in MEN Type 1 (MEN1): Data from the France-Belgium MEN1 Multicenter Study. The Journal of Clinical Endocrinology & Metabolism February 1, 2002 vol. 87 no. 2, 457-465.
⁽²⁾ http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001377/
⁽³⁾ http://en.wikipedia.org/wiki/Dopamine#Regulating_prolactin_secretion
⁽⁴⁾ Webster, et al. A Comparison of Cabergoline and Bromocriptine in the Treatment of Hyperprolactinemic Amenorrhea. N Engl J Med 1994; 331:904-909