QUINAGOLIDE (NORPROLAC(R)) - A NOVEL NONERGOT PROLACTIN INHIBITOR

Quinagolide (Norprolac(R)) is a novel, long-acting dopaminergic drug d esigned for use in hyperprolactinemia. The molecule is a octahydrobenz o[g]quino-line, which has neither an ergot nor an ergoline structure, and thus represents a third-generation prolactin inhibitor. Unique amo ng pituitary hormones, normal levels of prolactin are maintained throu gh negative feedback action by the hypothalamic prolactin inhibiting f actor, which is the neurotransmitter dopamine. Among the dopamine rece ptor subtypes, the dopamine D-2 receptor on the pituitary lactotrope i s specific to prolactin regulation. Hence, the use of dopaminergic dru gs as pro[actin inhibitors, and the rationale for the design of a D-2 receptor-specific drug. Prolactin oversecretion can be caused by multi ple factors that lead to dysfunction of the hypothalamic-pituitary reg ulatory system and result in uncontrolled activity of the lactotropes, with or without adenomatous tumor growth. Clinical manifestations of hyperprolactinemia appear as disturbances of reproductive function, sp ecifically menstrual cycle dysfunction, decreased libido in women and in men, impotence and sometimes galactorrhea. Large tumors may expand beyond the pituitary fossa, causing neurological as well as endocrinol ogical symptoms. The goals of treatment with a dopaminergic drug are t o relieve symptoms, restore gonadal function and, when a large prolact inoma is present, to shrink the tumor. Preclinical studies with quinag olide show it to be a potent and selective dopaminergic drug. The spec ificity of quinagolide for the D-2 receptor was demonstrated by recept or binding studies and by the use of selective and nonselective antago nists to reverse the quinagolide-induced prolactin inhibition by pitui tary cells in vitro. Quinagolide shows no action on adrenergic or sero tonin receptors, and its oral and parenteral activity in prolactin inh ibition tests is 35-200 times greater than that of bromocriptine. Earl y-phase studies in healthy volunteers show that quinagolide possesses 24-hour prolactin suppressant action? and that the drug's activity is specific to the pituitary lactotropic cells. In short- and long-term d ose ranging trials in patients with idiopathic or microadenoma-induced hyperprolactine-mia, quinagolide produced strong and sustained pro[ac tin suppression in up to 93% of patients, with associated relief of ga lactorrhea and return of ovulatory menses in up to 97%. These studies showed that quinagolide is effective in lowering prolactin levels over a broad dose range, and that treatment should begin with a 1-week tit ration scheme followed by a basic maintenance dose of 0.075 mg once da ily. At this dose, 70% of patients normalize, 75% of them within the f irst month. Titration to individual need can be done at approximately monthly intervals without affecting tolerability or safety. The clinic al efficacy and tolerability of quinagoilde in hyperprolactinemic wome n with or without microadenoma was compared with the action of bromocr iptine in a multicenter study with a double-blind phase of 6 months. A fter 6 months, all patients continued open-label treatment with quinag olide up to 24 months. The results of the double-blind period show tha t quinagolide is at least as effective as bromocriptine in suppressing prolactin in and alleviating the symptoms of prolactin oversecretion. With quinagolide treatment alone, prolactin normalization occurred in 88% of patients by month 24, while regular menses were established an d galactorrhea relieved in up to 95%, at doses similar to those of the earlier studies; Quinagolide was judged by patients and physicians to be better tolerated than bromocriptine, and there were statistically significantly fewer discontinuations (p < 0.03) in the quinagolide gro up. In 72% of patients with macroadenomas (>10 mm in diameter), prolac tin was normalized at quinagolide doses less than 0.3 mg daily in the majority of patients. Clinical complaints disappeared as normo-prolact inemia was attained; Tumor shrinkage of more than 50% was registered i n about 70% of the tumors, no direct correlation being observed betwee n baseline tumor size or prolactin level, or length of quinagolide tre atment. The prolactin normalization rate in patients who do not tolera te other dopaminergic drugs is 93%, and 57% in patients who are resist ant to other drugs, pre-dominantly bromocriptine. In studies using rad iolabeled drug, quinagolide was shown to be rapidly and well absorbed after oral administration. The compound is extensively metabolized dur ing its first pass, and more than 95% is excreted via urine and feces. With therapeutic doses, a clinically significant prolactin-lowering e ffect occurs within 2 hours after ingestion, reaches a maximum within -4-6 hours, and is maintained for 24 hours. The effective bioavailabil ity is almost 100%. No drug accumulation occurs during long-term treat ment, and no loss of therapeutic effect is seen when patients are swit ched without treatment interruption from bromocriptine to quinagolide. About 95% of patients are able to tolerate quinagolide. Adverse event s are similar to those of other dopamine agonists, but are reported le ss often, are less severe, and tend to be self-limiting. Adverse event s include nausea, headache and fatigue in more than 10% of patients, a nd abdominal discomfort, constipation and nasal stuffiness in fewer th an 10%. Orthostatic hypotension has been rarely documented; No evidenc e of drug toxicity to any organ system has been recorded. The only cli nically notable long-term effect has been a trend towards normalizatio n in lipid metabolism when serum lipids were elevated at the beginning of quinagolide ide treatment. The course and outcome of 169 pregnanci es occurring during quinagolide development studies indicate that expo sure to the drug during gestation does not increase the rates of spont aneous abortion, multiple pregnancy or fetal abnormalities. In summary , quinagolide represents clear progress in dopamine agonist therapy be cause of its broad clinical efficacy and improved tolerability profile .