Philippe Jaquet

Sandostatin® LAR®: A promising therapeutic tool in the management of acromegalic patients

A stable and sustained suppression of growth hormone (GH) secretion was noted in 101 patients treated long term with individual doses (20 and 30 mg in 89 patients, 40 mg in 12 patients) of Sandostatin LAR (Sandoz Pharma Ltd, Basel, Switzerland). Doses of 20 mg and 30 mg at 4-week intervals delivered average octreotide concentrations of 1,348 +/- 483 ng/L and 2,631 +/- 1,026 ng/L, respectively, in steady-state conditions and provided adequate control of patients who had been well controlled during treatment with 0.1 mg and 0.2 mg thrice-daily subcutaneous (SC) Sandostatin. Suppression of GH serum concentrations to less than 5 micrograms, 2 micrograms, and even 1 microgram/L was recorded in more patients and more consistently during long-term treatment with Sandostatin LAR than Sandostatin. A marked decrease or even a normalization of insulin-like growth factor-1 (IGF-1) serum concentrations was observed after the first double-blind 10-, 20-, or 30-mg dose of Sandostatin LAR. A progressive improvement was recorded during long-term treatment, with normalization of IGF-1 serum concentrations in 65.3% of patients. A marked clinical improvement was observed in parallel, with 36 of 101 patients (35.6%) becoming asymptomatic after the nineteenth injection of Sandostatin LAR. A greater than 20% shrinkage of the GH-secreting adenoma was also recorded in 12 of 14 patients treated with Sandostatin LAR after receiving only 2 to 4 weeks of treatment with SC Sandostatin and in 11 of 18 patients receiving Sandostatin LAR as adjuvant therapy after failure of surgery. The systemic tolerability of Sandostatin LAR was good, and most adverse events were mild and short term (1 to 2 days). No impairment of thyroid function was detected. Newly occurring gallstones were recorded in four of 101 patients and microlithiasis in four of 101 after up to 30 months of treatment with Sandostatin LAR. Due to its excellent efficacy, good tolerability, convenience of administration, and acceptability by patients, Sandostatin LAR is considered a promising therapeutic tool in the management of acromegalic patients.

Sandostatin LAR®: Pharmacokinetics, pharmacodynamics, efficacy, and tolerability in acromegalic patients

Abstract Sandostatin LAR® was developed by incorporating octreotide in microspheres of the biodegradable polymer poly( dl -lactide-coglycolide glucose). One hundred acromegalics, 85 of whom were known to be “responders” to octreotide (subcutaneous [SC] Sandostatin® 0.1 to 0.2 mg three times daily), as measured by mean 12-hour growth hormone (GH) serum concentrations below 5 μg/L, were switched after a washout period of at least 3 days to single doses of 3, 6, 9, 12, 10, 20, and 30 mg Sandostatin LAR®. Octreotide and GH serum concentrations were assessed hourly from 8 am to 8 pm , during screening, at baseline (after washout), and on days 1 (day of injection), 7, 14, 21, 28, 35, 42 (for doses of 3, 6, 9, and 12 mg), and 60 (for doses of 10, 20, and 30 mg). The pattern of octreotide release was similar for all doses tested. A rapid increase in octreotide serum concentrations was noted after the intramuscular (IM) injection of Sandostatin LAR®, with a peak occurring within 1 hour of injection and followed by a progressive decrease to low octreotide levels within 12 hours. On days 2 through 7, after single doses of Sandostatin LAR®, lower octreotide serum concentrations were recorded. Thereafter, an increase in the serum octreotide concentration occurred and dose-dependent plateau concentrations were observed between days 14 and 42, followed by a progressive decrease from day 42 onward. In the plateau phase (days 14 to 42), daily average octreotide plasma concentrations remained very stable over the 12-hour observation period, comparing well with those seen after continuous SC infusion. The peak level on day 1 (for the 10-, 20-, and 30-mg doses) was lower than plateau octreotide concentrations, and the area under the peak on the Sandostatin LAR® injection day was no greater than 0.5% of the total area under the curve ([AUC] 0 to 60 days). A dose-dependent increase in the octreotide maximum concentration and AUC occurred in the dose range of 10 to 30 mg. There is an almost linear relationship between plateau octreotide concentrations and the dose administered. Plateau octreotide concentrations were approximately 350 ng/L for the 10-mg dose, 750 for the 20-mg dose, and 1,300 for the 30-mg dose. No accumulation of octreotide was noted after repeated injections at 4-week intervals in 40 patients who received up to seven injections of Sandostatin LAR®. Steady-state octreotide serum concentrations were reached after multiple injections (three injections at 4-week intervals) and were higher by a factor of 1.6 in comparison to plateau octreotide levels noted after the first injection. Plateau octreotide concentrations lasting for a period of 20 to 30 days point to once-a-month dosing in long-term treatment. The pattern of GH secretion irrespective of dose showed an initial suppression for 8 to 12 hours, followed by a return to almost preinjection values on days 2, 3, and 7 after the first injection. From days 14 to 42, the maximum suppression of GH secretion was recorded for each dose tested. Reproducible and stable suppression of GH secretion was noted after single-dose administration of 10, 20, or 30 mg and repeated injections of 20, 30, or 40 mg Sandostatin LAR®, and this mirrored the consistent and stable octreotide concentration. A trend toward progressive suppression of GH secretion and insulin-like growth factor-I (IGF-I) serum concentrations was noted during long-term treatment (up to 35 weeks) with repeated (up to seven) IM injections of Sandostatin LAR®. Administered at 4-week intervals, the 20- and 30-mg doses provided a very good clinical control of acromegalic symptoms/signs in all patients, including the “partial responders” (with GH concentrations not suppressed to below 5 μg/L). The local tolerability was very good, with mild to moderate local pain on injection days. Systemic tolerability of Sandostatin LAR®, including gallstone formation, compared well with the SC treatment with Sandostatin®. As a result of the convenience of administration, very good acceptance, very stable and consistent octreotide serum concentrations in long-term treatment, and very good biological and clinical efficacy, it is expected that Sandostatin LAR® will become the medical treatment of choice in acromegalic patients.

A Potential Inhibitory Role for the New Truncated Variant of Somatostatin Receptor 5, sst5TMD4, in Pituitary Adenomas Poorly Responsive to Somatostatin Analogs

CONTEXT Somatostatin (SST) receptors, specially sst2 and sst5, provide a valuable target to inhibit excessive hormone release and cell growth in pituitary tumors by using SST analogs (SSAs). Unfortunately, an appreciable proportion of tumors fail to respond to SSA despite expressing high levels of one or more ssts. Recently we identified two novel truncated sst5 variants, sst5TMD5, and sst5TMD4, absent in normal pituitary but expressed in pituitary tumors. OBJECTIVE AND DESIGN We aimed at exploring the potential role of sst5TMD5 and sst5TMD4 in the poor response of some tumors to SSA in vivo and in vitro. Specifically, 25 somatotropinomas showing different responses to octreotide in vivo and sst2 (BIM-23197)- and sst5(BIM-23268)-selective compounds in vitro were screened for sst5TMD5/sst5TMD4 expression by real-time PCR. Relationships between ssts expression and in vivo and in vitro secretory response of the corresponding pituitary samples were assessed. RESULTS sst5TMD5 was absent in all samples analyzed. sst5TMD4 was found in 85% of tumors, and its expression was positively correlated to that of sst5 (R(2) = 0.79, P < 0.001). Expression of sst5TMD4 was negatively correlated with the ability of octreotide to reduce GH levels in vivo and partially negatively correlated with inhibition of GH secretion by an sst5 selective agonist (BIM-23268) in vitro. CONCLUSIONS These results indicate that sst5TMD4 is related to the reduced ability of octreotide at normalizing hormone secretion in poorly responsive tumors in vivo. Further studies will help to evaluate the potential use of sst5TMD4 expression in surgically removed pituitary adenomas as a predictor of the subsequent response of different pituitary tumors to SSA therapy.

Somatostatin and Dopamine-Somatostatin Multiple Ligands Directed towards Somatostatin and Dopamine Receptors in Pituitary Adenomas

Aim: We report the comparative efficacy of octreotide, cabergoline and multiple ligands directed towards the different somatostatin subtypes (ssts), such as BIM-23A779 and SOM-230, and of chimeric analogs which bind both somatostatin and the dopamine D2 receptors (D2R), such as BIM-23A760 and BIM-23A781, in cell cultures from human growth hormone (GH)-secreting pituitary adenomas. Procedures: RT-PCR analysis of the quantitative expression of the different ssts and D2R mRNAs was performed on tumor fragments of 22 GH-secreting adenomas collected after surgery. Pharmacological studies, using the different ligands, were performed on cell cultures of such tumors. Results: sst2, sst5 and D2R were constantly coexpressed in all tumors, in variable amounts. The levels of expression of sst2 and D2R mRNAs were significantly correlated with the maximal GH suppression by either octreotide or cabergoline (p < 0.001). In each tumor tested, 3 patterns of response, in terms of GH suppression, were observed. GH secretion was preferentially inhibited by the sst2 preferential compound octreotide in 61% of the tumors. In 19% of the tumors, the maximal inhibition of GH release was achieved with the sst5 preferential compound BIM-23268. The dopamine analog cabergoline was the most effective inhibitor of GH secretion in 21% of cases. Among the compounds tested, the most potent inhibitors of GH secretion were the sst2, sst5, D2R chimeric compound BIM-23A760, followed by the sst universal ligand SOM-230. Conclusions: The variable patterns of response to sst2, sst5 and dopamine D2 analogs may explain the greater efficacy of drugs which bind to the 3 receptors in suppressing GH secretion. The biological potency (EC50) and efficacy of the chimeric compound BIM-23A760 on GH secretion can be partly explained by its high affinity for sst2. The effect of multiple receptor activation on the functions of other pituitary tumor types, such as prolactinomas and corticotropinomas, is not presently analyzed, and the efficacy of multireceptor ligands remains to be elucidated.

Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas

OBJECTIVE Ten percent of patients with prolactinoma fail to respond with normalization of prolactin (PRL) and tumor shrinkage under dopamine agonist (DA) therapy. The resistance to treatment is linked to a loss of dopamine receptor 2 (D2DR). Prolactinomas express somatostatin (SST) receptor subtypes, SSTR1, 2, and 5. The aim of this study was to determine whether different SST compounds could overcome the resistance to DA in prolactinomas. DESIGN AND METHODS The efficacy of SSTR1, SSTR2, and SSTR5 ligands; the universal SST ligand, SOM230; and the chimeric SST-DA compound, BIM-23A760, was compared with cabergoline in suppressing PRL secretion from primary cultures of ten prolactinomas (six DA responders and four DA resistant). Receptor mRNAs were assessed by quantitative PCR. RESULTS The mean mRNA levels for D2DR, SSTR1, SSTR2, and SSTR5 were 92.3+/-47.3, 2.2+/-1.4, 1.1+/-0.7, and 1.6+/-0.6 copy/copy beta-glucuronidase (beta-Gus) respectively. The SSTR1 agonist, BIM-23926, did not suppress PRL in prolactinomas. In a DA-resistant prolactinoma, it did not inhibit [(3)H]thymidine incorporation. The SSTR5 compound, BIM-23206, produced a dose-dependent inhibition of PRL release similar to that of cabergoline in three DA-sensitive prolactinomas. BIM-23A760 produced a maximal PRL inhibition superimposable to that obtained with cabergoline with a lower EC(50) (0.5+/-0.1 vs 2.5+/-1.5 pmol/l). In DA-resistant prolactinomas, BIM-23206 and SOM230 were ineffective. Cabergoline and BIM-23A760 produced a partial inhibition of PRL secretion (19+/-6 and 21+/-3% respectively). CONCLUSION Although the SSTRs are expressed in prolactinomas, the somatostatinergic ligands analyzed do not appear to be highly effective in suppressing PRL. D2DR remains the primary target for effective treatment of prolactinomas.

Somatostatin-dopamine ligands in the treatment of pituitary adenomas

Somatostatin receptors (sst1–5) and dopamine receptor 2 (D2DR) are well expressed and co-localized in several human pituitary adenomas, suggesting possible functional interactions in the control of hormonal hypersecretion and tumor cell growth. The present review describes the expression and functionality of these receptors in the different classes of human pituitary adenomas. The sst2 agonists, octreotide and lanreotide, control GH hypersecretion and tumor growth in about 65% of somatotropinomas. The D2DR agonists, bromocriptine and cabergoline, control about 90% of prolactinomas. Such drugs are much less effective in the control of the others pituitary adenomas also expressing ssts and D2DR receptors. The second part summarizes the current knowledge on new chimeric compounds with sst2, sst5, and D2DR affinity. Such ligands bearing distinct ssts and DRD2 pharmacophores may synergistically produce an increased control of secretion and/or of proliferation in the different types of pituitary adenomas. The mechanisms of action of such chimeric molecules through increased binding affinities, prolonged bioavailability, ligand-induced modulation of receptors heterodimerization, are discussed.

Hormonal Regulation of Prolactin Release by Human Prolactinoma Cells Cultured in Serum-Free Conditions

Thyrotropin-releasing hormone (TRH) stimulates the prolactin (PRL) release from normal lactotrophs or tumoral cell line GH3. This effect is not observed in many patients with PRL-secreting tumors. We examined in vitro the PRL response to TRH on cultured human PRL-secreting tumor cells (n = 10) maintained on an extracellular matrix in a minimum medium (DME + insulin, transferrin, selenium). Addition of 10(-8) M TRH to 4 X 10(4) cells produced either no stimulation of PRL release (n = 6) or a mild PRL rise of 32 +/- (SE) 11% (n = 4) when measured 1, 2 and 24 h after TRH addition. When tumor cells were preincubated for 24 h with 5 X 10(-11) M bromocriptine, a 47 +/- 4% inhibition of PRL release was obtained. When TRH (10(-8) M) was added, 24 h after bromocriptine, it produced a 85 +/- 25% increase of PRL release (n = 8). This stimulation of PRL release was evident when measured 1 h after TRH addition and persisted for 48 h. The half maximal stimulatory effect of TRH was 2 X 10(-10) M and the maximal effect was achieved at 10(-9) M TRH. When tumor cells were pretreated with various concentrations of triiodothyronine (T3), the PRL release was inhibited by 50% with 5 X 10(-11) M T3 and by 80% with 10(-9) M T3. Successive addition of TRH (10(-8) M) was unable to stimulate PRL release at any concentration of T3. The addition of 10(-8) M estradiol for up to 16 days either stimulated or had no effect upon the PRL basal release according to the cases. In all cases tested (n = 4), preincubation of the tumor cells with estradiol (10(-8) M) modified the inhibition of PRL release induced by bromocriptine with a half-inhibitory concentration displaced from 3 X 10(-11) M (control) to 3 X 10(-10) M (estradiol). These data demonstrate that the absence of TRH effect observed in some human prolactinomas is not linked to the absence of TRH receptor in such tumor cells. TRH responsiveness is always restored in the presence of dopamine (DA) at appropriate concentration. This TRH/DA interaction seems specific while not observed under T3 inhibition of PRL. Furthermore, estrogens, while presenting a variable stimulatory effect upon basal PRL, antagonize the dopaminergic inhibition of PRL release.

Resistance to somatostatin (SRIH) analog therapy in acromegaly. Re-evaluation of the correlation between the SRIH receptor status of the pituitary tumor and the in vivo inhibition of GH secretion in response to SRIH analog.

The development of a long-acting somatostatin (SRIH) analog (octreotide, Sandoz) has been a major breakthrough in the treatment of acromegaly. However, in 20-30% of the patients, growth hormone (GH) plasma levels remain elevated (> 10 micrograms/l) despite treatment with octreotide. This raised the concept of resistance to SRIH analog therapy in acromegaly. Indeed, in vivo response to SRIH analogs varies greatly among acromegalic patients. According to the reviews in the literature and our own autoradiographic data, no direct correlation can be established between the GH response to octreotide and the number or affinity of the SRIH receptors located on the tumor. In our series a greater density of SRIH receptors is present on tumors from patients very sensitive to the SRIH agonist. A subset of patients resistant to octreotide could result from a very low density of SRIH receptor although this type of GH-secreting tumor constitutes certainly a rare case. A subset of GH-secreting pituitary tumors can be characterized by a mutation on the alpha subunit of the guanine nucleotide-dependent protein coupled to the stimulation of adenylate cyclase (G alpha s). This mutation results in a high basal adenylate cyclase activity and a low GHRH-stimulated activity. However, when the adenomas are separated according to their basal adenylate cyclase activity, SRIH is able to decrease cAMP levels in both types of tumor. In addition, in our series no direct correlation is observed between the SRIH inhibition of adenylate cyclase and the amount of SRIH-binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

A long-acting repeatable form of bromocriptine as long-term treatment of prolactin-secreting macroadenomas : a multicenter study

OBJECTIVE To assess the efficacy and tolerability of monthly injections of the long-acting repeatable bromocriptine in patients with macroprolactinomas. DESIGN Open and prospective trial. SETTING This multicenter trial was carried out in seven university hospitals. PATIENTS Forty-two patients with prolactin (PRL)-secreting macroadenomas. INTERVENTIONS Fifty to 200 mg of the drug were administered intragluteally every 28 days for 6 to 24 months. MAIN OUTCOME MEASURES The efficacy was assessed by repetitive plasma PRL measurements, visual field determinations, and computed tomography scan examinations. RESULTS After the first 50-mg injection, the mean percentage decrease of PRL levels was 71% from baseline on day 14; between days 1 and 28, PRL levels were suppressed to normal in nine cases, and a clear tumor shrinkage was documented in 21% of the patients. Normalization of PRL secretion was obtained in 62%, and a clear-cut reduction in tumor size in 50% of the patients after 6 months of treatment. CONCLUSIONS The long-acting repeatable form of bromocriptine was a well tolerated and quickly effective treatment in most of these patients with macroprolactinomas.

PATTERN OF PROLACTIN DIURNAL SECRETION IN NORMAL HUMANS : EVIDENCE FOR NONLINEAR DYNAMICS

Prolactin (PRL) circadian profiles were analyzed using methods of nonlinear dynamics, directly from the experimental data, by combining in a single time-series (432 measurements), six individual 24-hour PRL profiles (72 measurements per profile, sampling interval = 20 min), obtained from young healthy human volunteers (4 males, 2 females), under basal conditions. Significant autocorrelation exists between any given point of the time series and a limited number of its successors. Fourier analysis showed a dominant frequency of 1 cycle/24 h, without sub-24-hour harmonics. Poincaré section indicated the presence of a fractal attractor and a sketch of the attractor revealed a highly convoluted geometric structure with a conical contour. The box-counting dimension (D0), information dimension (D1) and correlation dimension (D2) of the attractor had low, fractal values, did not differ significantly from each other, and exhibited saturation at an embedding dimension of 2. The evidence taken together suggests that, under basal conditions, the daily changes in the peripheral blood levels of PRL are governed by nonlinear deterministic dynamics, with a dominant rhythm of 1 cycle/day mixed with a higher-frequency, low-amplitude signal.