[Treatment of acromegaly with sustained-release lanreotide. A new somatostatin analog]. / Traitement de l'acromégalie par une forme à libération prolongée du lanréotide. Un nouvel analogue de la somatostatine.

The recovery of acromegaly is not obtained in about 50 percent of cases treated with radiotherapy and/or transsphenoidal surgery. Somatostatin analogs prescribed in such cases are effective but need either several subcutaneous injections a day or continuous infusions with pumps. Long-acting formulations of the new somatostatin analog lanreotide should avoid such drawbacks. Nine acromegalics, not cured by pituitary surgery (associated with radiotherapy in 7) received on IM injection of a long acting formulation of lanreotide twice a month for one year. Basal evaluation included: clinical examination, routine analyses, gall bladder ultrasonography, hormonal investigation of pituitary function including GH and IgF-1 measurements, visual field evaluation and pituitary scanning. A similar evaluation was performed on months 6 and 12 of treatment. The clinical symptoms of acromegaly progressively improved during therapy. Plasma GH levels decreased significantly (P < 0.01) from 24.2 +/- 2.1 to 9.3 +/- 1.2, 6.4 +/- 1.4 and 7.9 +/- 1.1 micrograms/l on months 3, 6 and 12, respectively. Plasma IgF-1 levels were normalized, decreasing from 676 +/- 40 to 331 +/- 30, 350 +/- 36, and 317 +/- 29 ng/ml on months 3, 6 and 12, respectively. Plasma lanreotide levels remained stable throughout the treatment. Side-effects included slight and transient diarrhoea and abdominal cramps which disappeared after 6 months of treatment. No gallstones appeared during treatment. These results show that one injection, twice a month, of a long-acting formulation containing 30 mg lanreotide is able to control the evolutivity of acromegalies not cured by pituitary radiotherapy and/or transsphenoidal surgery. Such formulations are well tolerated and avoid the drawbacks of either several subcutaneous injections a day or continuous infusions of somatostatin analogs.

Effect of long-term treatment with platelet-activating factor on IL-1 and IL-2 production by rat spleen cells.

To study the effect of the in vivo administration of platelet-activating factor (PAF) on cytokine production, alzet minipumps loaded with the mediator or solvent alone were connected to the jugular vein and placed under the skin of Sprague-Dawley rats. Over 7 days the animals received total doses of 0.5, 1, 4.5, 9, or 28 micrograms PAF or the solvent alone. The spleen mononuclear cells isolated from Ficoll gradients and the adherent cell fraction were separated before determination of basal and mitogen-stimulated IL-1 and IL-2 production, respectively. Adherent splenocytes from rats having received 28 micrograms PAF exhibited a decreased capability to produce IL-1, as compared to those from vehicle-treated animals. In contrast, adherent splenocytes from rats having received 9 and 4.5 micrograms PAF yielded higher amounts of released and cell-associated IL-1 activity upon LPS stimulation, as compared to those from solvent-treated animals. The PAF antagonist, BN 52021, given orally (5 mg/kg, twice a day throughout the experiments) inhibited the in vivo effect of 28 micrograms PAF. Statistically significant 144 +/- 43% (p less than 0.001, n = 5) and 73 +/- 33%, (p less than 0.01, n = 3) increases in IL-2 production were observed when whole spleen mononuclear cells from rats administered with 1 and 4.5 micrograms PAF, respectively, were stimulated with Con A. BN 52021 markedly inhibited the in vivo effect of 1 microgram PAF on the IL-2 release. Our study demonstrates that PAF can modulate immune functions in vivo and suggests that the specific PAF antagonist, BN 52021, may be used as an immunomodulatory agent.

Modulation of the priming effects of platelet-activating factor on the release of interleukin-1 from lipopolysaccharide-stimulated rat spleen macrophages.

The pharmacologic modulation of the effect of platelet-activating factor (PAF) on the interleukin-1 (IL-1) activity present in the supernatants from lipopolysaccharide (LPS)-stimulated macrophages was investigated. Rat spleen macrophages were isolated by centrifugation on a Ficoll-Hypaque gradient followed by adherence on plastic petri dishes for 60 min at 37 degrees C under a 5% CO2/95% air atmosphere. The IL-1 content in the cell-free supernatants was assessed using the mouse thymocyte proliferation assay. Preincubation of macrophages for 10 min with 10 fM PAF prior to stimulation with 20 micrograms/ml LPS for 24 h markedly increased the IL-1 activity present in the supernatants from macrophages whereas no direct effect of PAF was noted. Although they had no direct effect, addition of L-651,392 (10 microM), a lipoxygenase inhibitor, or the oxygen-derived free radical scavenger mannitol (10 microM) during the 10-min preincubation period with PAF reversed by 105.0% and 79.9%, respectively, the action of the autacoid on IL-1 activity. Pertussis toxin (PT, 1 microgram/ml) decreased by 30% the LPS-induced IL-1 activity. Association of PT with PAF suppressed the enhancing effect of 10 fM PAF on the IL-1 activity present in the supernatants from LPS-stimulated macrophages. Thus, the enhancing effect of PAF on IL-1 release appears to be due to the production of lipoxygenase metabolites, leading to superoxide production and alterations of cAMP levels.

Effect of long-term treatment with platelet-activating factor on cytokine production by rat spleen cells.

The long-term in vivo effect of platelet-activating factor (PAF) production of interleukin-1 and -2 (IL-1, IL-2) was investigated. Alzet infusion minipumps loaded with PAF or solvent were placed under the back skin of Sprague-Dawley rats and connected to the jugular vein. Lymphocytes from animals having received 1, 4.5 or 9 micrograms PAF/7 days showed an increased capacity to produce IL-1 and IL-2. In contrast, splenocytes from rats receiving 28 micrograms PAF/7 days exhibited decreased capacity to produce IL-1, whereas IL-2 was unaffected. The decrease in IL-1 synthesis induced by 28 micrograms PAF and the increase in IL-2 production evoked by 1 microgram PAF were not observed in rats treated daily with the PAF antagonist, BN 52021. Thus, PAF appears to play a role in the regulation of the immune response. The reversal of the effect of PAF by BN 52021 indicates that the mediator is acting via specific binding sites similar to those reported on other cell types. These data also suggest that PAF antagonists may be used as immunomodulatory drugs.

Effect of platelet-activating factor (PAF-acether) and its specific receptor antagonist, BN 52021, on interleukin 1 (IL1) release and synthesis by rat spleen adherent monocytes.

PAF-acether, at doses ranging from 1pM to 0.1 microM did not induce a significative release and/or synthesis of IL1 from monocytes. In contrast, depending upon the dose of the mediator, adverse effects on the lipopolysaccharide (LPS)-induced IL1 release and synthesis were observed. PAF-acether at 1pM increased IL1 release by 120 +/- 39% and synthesis by 87 +/- 27% whereas at 0.1 microM a decrease of IL1 release of 52 +/- 9% and synthesis of 46 +/- 6% were observed. BN 52021, a specific PAF-acether receptor antagonist, reversed by more than 70% the increase of inhibition of LPS-induced IL1 release and synthesis induced by 1pM and 0.1 microM of the autacoid, respectively. No direct effect of BN 52021 on IL1 release and synthesis from adherent monocytes was noted. These results indicate that PAF-acether modulates monocytes functions, possibly via specific binding sites.