Preparation of liposomes by reverse-phase evaporation using alternative organic solvents.

The organic solvents employed in liposome preparation, such as chlorinated solvents, diethyl ether or methanol, although usually removed by evaporation, may remain as traces in the final formulation representing a possible risk for human health and influencing the stability of the vesicles. In order to solve the above mentioned disadvantages, this paper describes the use of different organic solvents, namely ethanol, ethyl acetate and two mixtures of ethanol/ethyl acetate, for the production of liposomes by the reverse phase evaporation technique. After preparation, liposomes were extruded through polycarbonate filters and then characterized by size and encapsulation efficacy. As model drugs retinyl acetate and sodium cromoglycate have been used. The association yield for the hydrophilic drug and the encapsulation yield for the hydrophilic model drug were found, in all the liposome preparations, to be satisfactory. In particular, the use of more polar organic solvents (with respect to diethyl ether) appear to enhance the encapsulation of the hydrophilic drug, sodium cromoglycate. The use of alternative organic solvents to diethyl ether can be proposed with the aim of reducing the toxic problems associated with the presence of residual traces of organic solvents in the final liposome formulation.

Failure of nomifensine administration to discriminate between tumorous and nontumorous hyperprolactinemia.

It has recently been claimed that the PRL-lowering response to nomifensine administration (200 mg, orally) reliably discriminates patients with PRL-secreting tumors from those with so-called functional hyperprolactinemia. In the present study, this test was performed in 15 healthy controls, 7 hyperprolactinemic subjects without evidence of pituitary tumor, and 16 patients with prolactinoma. A decrease of serum PRL to below 65% of basal levels, which seemed to be the cut-off point in the previous study, was obtained in 11 subjects of the first group, in 4 subjects of the second group, and in 4 subjects of the third group. The decrease of mean serum PRL concentration after nomifensine was only significant in the first and second groups. Analysis of variance showed a significant difference in the PRL inhibition by nomifensine between the tumor group and the two groups without evidence of pituitary adenoma. Nevertheless, this study shows that the nomifensine test is unable to discriminate in the individual patient the tumorous or nontumorous origin of excessive PRL secretion.

Hyperprolactinemic primary amenorrhea: case report with successful prolactin-lowering treatment and review of the literature.

A 19-year-old girl with primary amenorrhea, galactorrhea, and hyperprolactinemia is described. Her high serum prolactin levels (95 ng/ml) did not increase after thyrotropin-releasing hormone and sulpiride, but markedly decreased after acute bromocriptine and metergoline administration. The results of other pituitary function tests were normal. Tomography of the sella turcica and CT scan of the skull were also normal. The patient was treated with metergoline, a prolactin-lowering drug which is believed to act as a serotonin antagonist, for 30 months. Serum prolactin rapidly decreased after institution of treatment, with actual normalization (less than 20 ng/ml) by the 3rd month. At this time the low serum luteinizing hormone levels began to rise and fluctuate in the normal follicular range. Galactorrhea disappeared, and menarche occurred during the 15th month of treatment. 15 further menstrual bleedings ensued over the following 15 months, albeit at irregular time intervals; ovulation was suggested by finding elevated serum progesterone levels in the presumed luteal phase by about 1 year following the menarche. The available data on 38 patients with primary amenorrhea and hyperprolactinemia reported in the literature are reviewed. 15 of them were treated with bromocriptine, and either pregnancy or cyclic menses occurred in 11. Hyperprolactinemic primary amenorrhea may be more common than previously recognized, and it may probably be successfully treated by prolactin-lowering drugs or by surgical ablation of a pituitary adenoma in a high percentage of cases.

Effect of two antiserotoninergic drugs, methysergide and metergoline, on gastric acid secretion and gastrin release in healthy man.

The effects of acute oral administration of the antiserotoninergic drugs methysergide (3 mg) and metergoline (4 mg) on basal, submaximal (0.6 micrograms/kg i. m.) and maximal (6 micrograms/kg) pentagastrin-stimulated gastric acid secretion, as well as on basal and food-induced gastrin release, have been evaluated in healthy volunteers. Methysergide significantly increased basal and submaximal pentagastrin-stimulated gastric acid secretion, and metergoline significantly inhibited gastric acidity in all experiments. Basal and stimulated serum gastrin concentrations were not modified by either drug. The effect of methysergide on gastric acid secretion was opposed to that of serotonin and was probably dependent on its antiserotoninergic action, but the decrease in gastric acidity caused by metergoline is not easily explained. Although the effect is similar to that of a dopamine infusion, it does not depend on dopamine infusion, it does not depend on dopamine receptor stimulation, since it was not influenced by pretreatment with metoclopramide. It is suggested that it might be due to the weak anticholinergic and/or antihistaminic properties of metergoline.

Inhibition of prolactin release by serotonin antagonists in hyperprolactinemic subjects.

Metergoline (4 mg) and methysergide (3 mg), two serotonin antagonists known to inhibit prolactin secretion in normal subjects, and the dopaminergic agonist, bromocriptine (2.5 mg) were orally administered in hyperprolactinemic patients. Mean serum prolactin concentration was significantly decreased between 120 and 240 min following the ingestion of all three drugs in comparison with a placebo; a consistent reduction to below 50% of basal values occurred in 10 of 14 patients after metergoline, in 5 of 10 after methysergide, and in 11 of 14 after bromocriptine administration. These data indicate that serotonin antagonists may acutely lower serum prolactin levels in hyperprolactinemic patients similarly to bromocriptine, though their mechanism of action is most likely different.

Restoration of cyclic ovarian function by metergoline treatment in a patient with a prolactin-secreting pituitary microadenoma.

A patient with amenorrhea due to a prolactin-secreting pituitary microadenoma was treated with the antiserotoninergic drug metergoline for 8 months. The first menstruation occurred after 1 month of therapy, and it was followed by regular menses by the 3rd month. Presumptive evidence of ovulation was obtained in at least some instances by serum progesterone and gonadotropin determination. Serum prolactin was only slightly lowered by treatment. The patient had menses and possibly ovulation in the 2 months following drug withdrawal. Metergoline might restore ovarian function in hyperprolactinemic amenorrhea either by prolactin suppression or perhaps by direct stimulation of gonadotropin release.

Prolactin suppression by serotonin antagonists in man: further evidence for serotoninergic control of prolactin secretion.

To further investigate the role of serotonin in human prolactin (Prl) secretion, serotonin antagonists have been administered to healthy volunteers in basal conditions and after pretreatment with the selective blocker of dopamine receptors, pimozide (Pim). Highly significant falls (p less than 0.001) in serum Prl were observed at 120, 180, and 240 min following the oral administration of metergoline (Met) (4 mg; N = 34) and methysergide (Meth) (3 mg; N = 20) in comparison with placebo. No significant difference was found in the degree of Prl suppression induced by these two serotonin antagonists and by hte dopaminergic drug bromocriptine (Br) (2.5 mg; N = 20). After Pim pretreatment (1 mg every 6 h for 7 days) the elevated serum Prl levels were reduced to 27.1% +/- 8.1 (SEM) of basal after Met and to 54.5% +/- 8.9 after Meth administration (N = 5 for each study). It is concluded that Met and Meth inhibit Prl secretion by mechanisms which are not or only partially related to dopaminergic receptors. These data are consistent with a stimulatory role for serotonin in human Prl release.