Treatment of macroprolactinoma with cabergoline: a study of 85 patients.

OBJECTIVE: Cabergoline is now established as an effective and well-tolerated treatment for prolactinoma. However, there are relatively few published data on the treatment of macro-, as opposed to micro-, prolactinoma. We have therefore reviewed the efficiency and safety of cabergoline in the treatment of patients with prolactin-secreting macroadenomas treated on a compassionate basis. STUDY DESIGN AND PATIENTS: Eighty-five patients with prolactin-secreting macroadenomas were treated with cabergoline 0.25 to 10.5 mg per week (median 1 mg) given to one to seven doses. Treatment durations ranged between 3 months and 8 years. Sixty-five patients (32 intolerant, 16 resistant) had been treated previously with other dopamine agonists. Pretreatment prolactin levels ranged between 80 and 8300 micrograms/I and tumour maximum diameters were between 11 and 42 mm. MEASUREMENTS: Serum prolactin, visual fields if initially abnormal, occurrence of menses or return of libido and potency, blood chemistry and adverse events were assessed at 1 month and then at 3-month intervals during treatment. Pituitary computed tomography or magnetic resonance imaging was usually repeated at 3 months and 1 year, then yearly, in most patients (n = 62). RESULTS: Normalization of prolactin levels was achieved in 52 patients (61.2%) and a prolactin decrease of at least 75% of pretreatment values occurred in 24 others (28.2%). Of the 20 de novo patients, 17 had prolactin normalized and the remainder had at least 75% reduction. Disappearance of tumour image was found in eight of 62 evaluable patients (12.9%) and reduction of the largest diameter by at least 25% in another 33 (53.2%), with an overall success rate of 66.1%; among the 17 evaluable de novo patients the success rate was 82.3%. Fifteen of 21 patients who failed to show tumour shrinkage had previously demonstrated resistance/intolerance to other prolactin-lowering treatments. Of the 12 patients with visual field defects at baseline, six normalized and two showed an improvement. Menses resumed during cabergoline treatment in 79.5% of premenopausal women. Restoration of potency was reported by seven of eight evaluable men. Adverse events were recorded in 24.7% of cases, four of whom (4.7%) discontinued treatment. CONCLUSIONS: Although the present data were not obtained in a formal study we conclude that cabergoline is an effective and well-tolerated treatment for macroprolactinoma patients.

Pregnancy outcome after treatment with the ergot derivative, cabergoline.

The goal of this article is to assess the reproductive safety of cabergoline, a new ergot derivative proposed in hyperprolactinemic disorders. Investigated in different animal species, the drug showed no teratogenic or embryotoxic effects on rabbits. Considering the dose envisaged for humans, large safety margins exist. Our sample consists of 226 pregnancies occuring in 205 women. Follow-up is available for 204. There were 24 miscarriages and three abortions induced because of major malformations (one Down syndrome in a 42-year-old woman, one limb-body wall complex, one hydrocephalus). Two of the 148 single liveborn infants had significant malformations: one megaureter, one scaphocephaly. This series shows no increase in miscarriage rate, a distribution of birthweights and sex ratio within the expected range, and no increased rate of congenital malformations. Follow-up of babies, limited to 107 cases, thus far indicates normal physical and mental development.

Pharmacokinetics of acipimox and of its N-deoxy metabolite following single and repeated oral administration to healthy volunteers.

The aim of the present study was to evaluate the plasma pharmacokinetics of acipimox and of its N-deoxy metabolite (5-methylpyrazine-2-carboxylic acid, MPCA) following single and repeated administration of 250 mg acipimox (thrice daily, for 6 days) to ten healthy volunteers. Mean maximum concentration, the corresponding time, area under the curve extrapolated to infinity and elimination half-life values of acipimox after single administration were equal to 5.74 micrograms/ml (range 2.56-8.38 micrograms/ml), 1.7 h (1-3 h), 16.99 micrograms/ml.h (11.28-22.17 micrograms/ml.h) and 1.15 h (0.79-1.48 h), respectively. Mean area under the curve over one dosing interval (8 h) and elimination half-life values of acipimox after repeated dosing were not significantly different from the corresponding values after the single dose. No significant accumulation was observed following the repeated treatment, since the mean accumulation ratio was 1.08 (range 0.74-1.52). The mean maximum concentration and corresponding time values in the 7 out of 10 subjects with detectable metabolite levels after the single dose were 0.19 microgram/ml (0.10-0.34 microgram/ml) and 6.7 h (3-12 h), respectively, whilst after the repeated treatment, detectable concentrations of the metabolite were observed in all subjects, the mean maximum concentration value being equal to 0.48 micrograms/ml (0.11-1.19 microgram/ml). The average ratio of the parent/metabolite area under the curve values (8 h) after repeated dosing was equal to 14 (range 2-56). Inter-subject variability in the extent of metabolite formation was very high.

Plasma free fatty acids and serum insulin in subjects feeding at 12-hour intervals; effects of methionyl growth hormone and of acipimox, an inhibitor of lipolysis.

In normal men, plasma free fatty acids (FFA) are influenced by feeding and by fasting; in addition, iv infusions of methionyl growth hormone (met-GH), so far performed during morning hours, induce an FFA rise that can be blocked by acipimox (ACX), a nicotinic acid analogue. The aims of the present study were to evaluate, in the absence of food interferences, the following aspects: i) Fasting FFA, glycerol, and insulin (IRI) in the morning and in the evening, and their response to met-GH ii) The effect of ACX and of a sustained release ACX formulation (ACX-SR) on fasting and met-GH induced lipolysis and on IRI levels. In a double blind study, 6 normal men received 50% cal at 09:30 h and 50% at 21:30 h; during placebo administrations FFA, glycerol, and IRI levels were lower at 06:30 h than at 18:30 h, and an iv met-GH infusion (160 ng/kg/min lasting 180 min) had a similar effect on FFA and on glycerol at 06:30 h and at 18:30 h. ACX-SR, administered at 21:30 h and 09:30 h, lowered FFA and glycerol in the morning as well as in the evening, and prevented met-GH induced lipolysis in the morning, but not in the evening.(ABSTRACT TRUNCATED AT 250 WORDS)

Acipimox-induced facial skin flush: frequency, thermographic evaluation and relationship to plasma acipimox level.

Facial skin flush is the most frequent adverse effect induced by acipimox (ACX), a nicotinic acid analogue used in the management of hyperlipidaemia. The aims of the study were to evaluate the frequency, magnitude and reproducibility of the ACX flush in previously unexposed healthy subjects and to assess any possible relationship with the dose and plasma level of ACX. Seventy four healthy subjects received, on two different mornings, ACX 250 mg and placebo (P), according to a single blind, randomized, cross-over design; 33 had a clear flush after ACX and not after P.25 of those subjects were retested on five different mornings, with P, and with ACX 31.2, 62.5, 125.0, 250.0 mg, according to a double blind, randomized, cross-over design. Any increase in the local skin temperature was recorded by a thermocouple fixed to the left check. Subjective and objective assessment of the flush were strongly correlated with thermographic recordings. They indicated that a 120 min flush occurred after doses of ACX greater than 62.5 mg. In 12 of the 25 subjects, 6 with the highest and 6 with the lowest thermographic recordings, plasma ACX levels were determined. Subjects with different thermographic records had superimposable plasma ACX levels after all doses of ACX. Only the 6 subjects with the highest skin temperatures showed a significant relationship between the thermographic record and the plasma ACX. The data indicate that flush is a frequent, reproducible and dose-related adverse effect of ACX.

Acipimox stimulates skin blood flow by a cyclo-oxygenase-dependent mechanism.

The blood flow in the skin and the urinary excretion of the PGI2 metabolite 2,3-dinor-6-keto-PGF1a (PGI-M) were determined in the nine healthy subjects randomly assigned to double-blind oral treatment with a) placebo and acipimox (AC) 500 mg, b) acetylsalicylic acid 1500 mg and AC 500 mg, or c) placebo and nicotinic acid (NIC) 500 mg, on three different occasions. After treatment with placebo and AC there was a transient increase in the skin blood flow, up to about four-times the basal level, and a concomitant increase in skin temperature. After acetylsalicylic acid and AC no increase in skin flow rate or temperature was found. Urinary excretion of PGI-M was insignificantly increased by AC, but fell after acetylsalicylic acid pretreatment. NIC elicited a more marked increase in skin blood flow than AC, and in parallel the urinary excretion of PGI-M was more than doubled. It is concluded that cutaneous flushing induced by AC is cyclo-oxygenase dependent. In comparison to NIC, however, AC appears as a weak stimulant of vascular prostacyclin formation.

Plasma lipid lowering activity of acipimox in patients with type II and type IV hyperlipoproteinemia. Results of a multicenter trial.

A multicenter study was carried out in 130 out-patients to assess the plasma lipid lowering activity of acipimox in type IIa, IIb and IV hyperlipoproteinemia. The study consisted of two periods, an 8-week randomized, double-blind comparison of active drug versus placebo and a 16-week open follow-up with acipimox (400 mg and 250 mg t.i.d., respectively, in type II and IV patients). During the double-blind phase acipimox, compared to placebo, showed a highly significant triglyceride lowering effect in type IV patients (-43% vs. +4%, P less than 0.01), while reducing plasma cholesterol significantly in type II patients (-7% vs. -3%, P less than 0.05). Further reductions in plasma lipids were obtained in both types of hyperlipoproteinemia after the 16-week follow-up. In type II patients, total cholesterol fell by 9% in the former acipimox group and 17% in the former placebo group, whereas a 34% reduction in triglycerides was found in type IV patients previously treated with placebo. Treatment had to be discontinued in 4 patients during the double-blind phase and in 5 patients during follow-up, because of adverse events such as skin reactions and gastric disturbances. Statistical analysis of hematological and biochemical variables expressing safety did not show any significant change during treatment.

Vaginal treatment with a prostaglandin F2 alpha derivative (alfaprostol) for inducing labor in pregnancy at term.

The effectiveness and acceptability of Alfaprostol (an analog of PGF2 alpha) in inducing labor were assessed in 20 pregnant women at term. All subjects had no spontaneous uterine activity before treatment and the mean (M +/- SE) Bishop score was 2.45 +/- 0.21. The drug was administered by vaginal route at the dose of 10 mg every 3 hours. Regular uterine contractions appeared in all patients and delivery occurred in 85% of the patients after a mean time of 9h50min +/- 0h55min following the start of treatment. The mean dose of Alfaprostol utilized to achieve delivery was 29.4 +/- 2.0 mg. No major side effects were noted in the mothers and their fetuses at any time during treatment. Two patients exhibited vomiting. The Apgar score of all newborns at birth was 8 or more. These results suggest the usefulness of Alfaprostol to induce labor in pregnant women at term, as it has oxytocic activity without adverse effects on either the mother or the fetus.

Reduced triglyceridemia and increased high density lipoprotein cholesterol levels after treatment with acipimox, a new inhibitor of lipolysis.

Acipimox (5-methylpyrazine carboxylic acid 4-oxide) is a new inhibitor of lipolysis with long-lasting activity, whose plasma lipid lowering potential was demonstrated in early clinical trials. The hypolipidemic effect of acipimox was investigated in two double-blind cross-over trials versus placebo. The first trial, carried out in 12 type IV patients, showed a significant triglyceride lowering effect (-35%) following 4 weeks of drug administration at a 250 tid dose. The same regimen, maintained for 9 weeks in 18 type IIA patients, failed to induce a significant reduction of total cholesterolemia. However, in 10 subjects, in whom lipoprotein cholesterol fractionation was carried out, a significant reduction of low density and highly significant increase in high density lipoprotein cholesterol levels (respectively -11% and +20%) were observed.

Bioavailability and pharmacokinetics in man of acipimox, a new antilipolytic and hypolipemic agent.

Two separate studies were performed: in the first study for healthy male volunteers received three single oral doses (150, 250 and 400 mg) of 5-methylpyrazine carboxylic acid 4-oxide (acipimox) according to a randomized sequence. Plasma levels of the drug were determined by RIA and urinary excretion by HPLC. In the second trial the effect of food on the drug bioavailability and pharmacokinetics during repeated administration was investigated in six volunteers. The RIA method was adopted to measure plasma and urine levels. Acipimox was rapidly and almost completely absorbed after the three single doses. About 90% of the administered dose was recovered as unchanges drug in urine collected up to 24 h. Peak plasma levels, area under plasma levels curves and urinary excretion were linearly related to the administered dose. The presence of food in the gastro-intestinal tract did not adversely affect the bioavailability of the drug. No significant changes were noted in the rate of elimination after 6 days of treatment with 250 mg t.i.d. Plasma levels determined after the 19th dose were in good agreement with those predicted on the assumption of linear pharmacokinetics and a one-compartment open model, with a half-life of about 2 h.

Inhibition of lipolysis by nicotinic acid and by acipimox.

Acipimox (5-methylpyrazinecarboxylic acid 4-oxide) is a new lipolysis inhibitor that has a distant chemical relationship with nicotinic acid (NA). The tritiated compound (100 mg) is rapidly absorbed, peak plasma radioactivity being reached after 2 hr, with an almost total elimination unchanged in urine. A comparison of th antilipolytic activity of three doses of acipimox and three doses of NA showed acipimox to be 20 times as potent as NA. There was a correlation between intensity and duration of effect for acipimox, but not for NA. Plasma acipimox levels correlated with inhibition of lipolysis. In consideration of the very good subjective tolerability of acipimox at all doses tested, this drug may be suitable for control of lipolysis in hyperlipidemias.