Four-year follow-up of acromegalic patients treated with the new long-acting formulation of Lanreotide (Lanreotide Autogel).

Lanreotide Autogel (Ipsen) is a long-acting somatostatin analogue (SA) in a new galenic formulation suitable for subcutaneous (s.c.) injection. In our department, 11 patients with therapy-resistant acromegaly were treated with Lanreotide Autogel for 48 months. 10/11 patients had previously undergone transsphenoidal surgery. For a median duration of 1.4 years prior to Lanreotide Autogel, the patients received Lanreotide PR 30 mg every 7, 10, or 14 days. 60, 90, or 120 mg of Lanreotide Autogel was administered by deep s.c. injection every 28 days, with the higher dosage being given to those with the previously shortest injection interval under Lanreotide PR. Dose was adjusted on the basis of Growth Hormone (GH) level after 4, 8, and 12 months with a minimum dose of 60 mg and a maximum dose of 120 mg. The efficacy of Lanreotide Autogel treatment was evaluated by measuring GH concentrations (4 hour profiles) and IGF-I levels. Before switching to Lanreotide Autogel, the multiple of the upper limit of normal (xULN) of IGF-I levels was 1.2 (median) and the median GH level was 1.3 microg/l. 3 out of 11 patients had an IGF-I within the age- and sex-adjusted normal range. After 48 months of treatment with Lanreotide Autogel, six patients had an IGF-I within the normal range. Median GH levels were at 1.3 microg/l and xULN of IGF-I was at 1.0 compared to Lanreotide PR 30 mg treatment (p < 0.001). At the end of the study, 8 patients received 120 mg Lanreotide Autogel, 2 patients 90 mg and 1 patient 60 mg, respectively. There was slight but significant deterioration of glucose metabolism with an increase of HbA1c. In conclusion, the new galenic formulation of Lanreotide improves not only the control of biochemical markers of acromegaly compared to the conventional PR formulation, but is also easier to administer given its deep s.c. method of administration. Glucose metabolism has to be followed carefully in patients on high-dose Lanreotide Autogel.     

Comparison of gonadotropin-releasing hormone and gonadotropin therapy in male patients with idiopathic hypothalamic hypogonadism.

OBJECTIVE: To compare pulsatile gonadotropin-releasing hormone (GnRH) therapy with gonadotropin therapy in male patients with idiopathic hypothalamic hypogonadism. DESIGN: Prospective study. Patients had free choice between the two forms of therapy. SETTING: Patients were treated on an outpatient basis in our department. PATIENTS: Eighteen patients of matched age (mean [+/- SD] age: 21.1 +/- 3.0 years and 23.6 +/- 7.3 years) and similar testicular volume were treated in each group. INTERVENTIONS: Pulsatile GnRH therapy was started with 4 micrograms GnRH subcutaneously every 2 hours using a portable pump and gonadotropin therapy with 3 x 2,500 IU human chorionic gonadotropin (hCG) weekly injected intramuscularly. After 8 to 12 weeks of hCG treatment, 150 IU human menopausal gonadotropin two to four times weekly were added. RESULTS: Testosterone (T) and estradiol (E2) levels increased significantly higher (T: P less than 0.03; E2; P less than 0.001) in the gonadotropin group than in the GnRH group (T: 22.5 +/- 8.1 versus 16.8 +/- 5.5 nmol/L; E2: 150 +/- 70 versus 88. +/- 59 pmol/L). Five patients developed gynecomastia during gonadotropin therapy. The rise of testicular volume was significantly more pronounced (P less than 0.001) in the GnRH group (delta testicular volume = 8.1 +/- 2.0 mL) than in the gonadotropin group (delta testicular volume = 4.8 +/- 1.8 mL). Ten patients of the GnRH and 8 of the gonadotropin group had positive sperm counts, ranging from 1.5 to 26 x 10(6) spermatozoa/mL. The latter was achieved more rapidly in the GnRH group (12 +/- 1.6 versus 20 +/- 2.3 months: P less than 0.02). CONCLUSIONS: Endocrine and exocrine testicular function can be normalized by both forms of therapy. Gonadotropin therapy has more side effects. Gonadotropin-releasing hormone leads to a higher testicular volume and a more rapid initiation of spermatogenesis compared with gonadotropin therapy.     

Selectins and integrins but not platelet-endothelial cell adhesion molecule-1 regulate opioid inhibition of inflammatory pain

1.Control of inflammatory pain can result from activation of opioid receptors on peripheral sensory nerves by opioid peptides secreted from leukocytes in response to stress (e.g. experimental swim stress or surgery). The extravasation of immunocytes to injured tissues involves rolling, adhesion and transmigration through the vessel wall, orchestrated by various adhesion molecules. 2. Here we evaluate the relative contribution of selectins, integrins alpha(4) and beta(2), and platelet-endothelial cell adhesion molecule-1 (PECAM-1) to the opioid-mediated inhibition of inflammatory pain. 3. We use flow cytometry, double immunofluorescence and nociceptive (paw pressure) testing in rats with unilateral hind paw inflammation induced by complete Freund's adjuvant. 4. In inflamed tissue, 43-58% of hematopoietic cells (CD45(+)) expressed opioid peptides. L-selectin and beta(2) were coexpressed by 7 and 98% of opioid-containing leukocytes, respectively. Alpha(4) integrin was expressed in low levels by the majority of leukocytes. Opioid-containing cells, vascular P- and E-selectin and PECAM-1 were simultaneously upregulated. 5. Swim stress produced potent opioid-mediated antinociception in inflamed tissue, unaffected by blockade of PECAM-1. However, blockade of L- and P-selectins by fucoidin, or of alpha(4) and beta(2) by monoclonal antibodies completely abolished peripheral stress-induced antinociception. This coincided with a 40% decrease in the migration of opioid-containing leukocytes to inflamed tissue. 6. These findings establish selectins and integrins alpha(4) and beta(2), but not PECAM-1, as important molecules involved in stress-induced opioid-mediated antinociception in inflammation. They point to a cautious use of anti-inflammatory treatments applying anti-selectin, anti-alpha(4) and anti-beta(2) strategies because they may impair intrinsic pain inhibition.     

Comparison of glucose and lipid metabolism and bone mineralization in patients with growth hormone deficiency with and without long-term growth hormone replacement

The effects of long-term growth hormone (GH) substitution in pituitary-insufficient patients with GH deficiency (GHD-pats) on glucose and lipid metabolism and bone mineral density (BMD) have yet to be ascertained. We performed this cross-sectional study comparing GHD-pats with and without long-term GH substitution. We measured lipid parameters at baseline and glucose and insulin concentrations for 3 hours during oral glucose tolerance test in 52 GHD-pats (21 female and 31 male; median age, 51.5 years [27-82]). Twenty-two GHD-pats were on constant GH substitution (GH-Subs) for a median of 10 years (2-42 years). Thirty GHD-pats had not been substituted for at least 2 years (non-Subs). For analyses of β-cell function, insulin resistance (IR), and sensitivity, homeostatic model assessment (HOMA)-β , HOMA-IR, and insulin sensitivity index were used, respectively. Body composition and BMD were measured by dual-energy x-ray absorptiometry. Age and body mass index did not differ significantly between groups. Fasting glucose was significantly lower for GH-Subs than non-Subs (87 mg/dL [71-103] vs non-Subs 89 mg/dL [71-113], P < .05), whereas basal insulin did not differ significantly (10 μU/mL (4-42) vs non-Subs 10μU/mL [4-63]). Glucose and insulin levels at 120 minutes as well as patients' area under the curve, C-peptide, hemoglobin A_1c, waist-hip ratio, HOMA-β, HOMA-IR, insulin sensitivity index, lipid parameters, and BMD did not differ significantly; but total fat mass was significantly higher in non-Subs (37% [20%-52%] vs GH-sub 31% [13%-54%], P < .01). More non-Subs had abnormal glucose tolerance (19 [63%] vs GH-Subs 9 [41%]). Long-term GH substitution trends to beneficially influence fasting glucose and glucose tolerance, although differences are sparse. Growth hormone substitution alone does not seem to significantly impact on insulin sensitivity, lipid metabolism, and BMD in patients with pituitary insufficiency.     

Prophylactic endovascular radiotherapy to prevent intimal hyperplasia after stent implantation in femoropopliteal arteries

Purpose: Recurrent stenosis or occlusion by intimal hyperplasia occurs in up to 40% of patients with tantalum stent implantations in femoropopliteal arteries and greatly restricts their usefulness. We evaluated the effect of prophylactic endovascular radiotherapy on stenosed/occluded\ stents. Methods: We investigated prophylactic endovascular radiotherapy with a surface dose of 12 Gy using an iridium 192 source as a means to reduce or eliminate recurrent stenosis in 4 patients with stenosed/occluded stents, 6–8 months after the original implantation. Confirmatory diagnostic atherectomy, PTA or laser recanalization and endovascular radiotherapy were performed. Results: None of the four has developed recurrent obstruction within 23 to 30 months after this treatment, which up to now shows no short-term or long-term complications. Conclusion: We conclude that this limited experience is promising enough to warrant further study.     

Effects of theophylline infusion on the growth hormone (GH) and prolactin response to GH-releasing hormone administration in acromegaly

Since theophylline has been shown to blunt the GH response to growth hormone-releasing hormone (GHRH) in normal subjects, we investigated whether the same effect of theophylline administration could be reproduced in patients with active acromegaly. Ten acromegalic patients received on two different days 100 micrograms GHRH iv alone and the same GHRH dose during a constant infusion of theophylline (3.56 mg/min), beginning 2 h before GHRH administration. In the whole group theophylline did not affect basal GH secretion significantly (from a mean of 44.6 +/- 14.4 at 0 min to 41.8 +/- 13.5 ng/ml at 120 min). However, the amount of GH released after GHRH stimulation was lower when theophylline was concomitantly infused (7525 +/- 3709 ng min/ml vs. 12038 +/- 6337 ng min/ml; p less than 0.05). The inhibitory effect of theophylline was not homogeneous, since either marked or minimal reductions of the GHRH-stimulated GH secretion occurred. Serum PRL levels increased after GHRH administration in 6 patients and theophylline infusion had no influence upon this response. Peak GHRH levels were not different in both studies (14.9 +/- 1.7 and 17.1 +/- 4.0 ng/ml, respectively). Free fatty acid levels rose progressively during theophylline administration (from 0.66 +/- 0.10 at 0 min to 1.04 +/- 0.10 mEq/l at 240 min) and were significantly higher than after GHRH stimulation alone from 180 min up to the end of the test. Our results demonstrate that in active acromegaly theophylline blunts the GH response to GHRH, though this effect is not uniformly seen in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

NSE and S-100B are not sufficiently predictive of neurologic outcome after therapeutic hypothermia for cardiac arrest

Introduction

Prognostication of cardiac arrest survivors is challenging since therapeutic hypothermia (TH) has been introduced. We evaluated serum biomarkers and motor response.

Methods

This was a retrospective data analysis including patients in the years 2007–2012. Blood was drawn and a neurological examination was performed on admission and every morning. Outcomes were evaluated 6 months after discharge and dichotomized into good (cerebral performance category (CPC) = 1 or 2) and poor (CPC = 3, 4 or 5).

Results

123 patients (79.7% male, 63 ± 14 years) received TH; 50% had a good outcome. On admission, S-100B (P = 0.004) was significantly associated with the outcome, as well as neuron-specific enolase (NSE; P = 0.020) and S-100B (P = 0.004) on day 1 after admission. NSE on day 2, NSE progression from day 1 to 2 and motor response on day 3 also predicted the outcome (all P < 0.001).NSE > 33 μg l⁻¹ only predicted a poor outcome with a specificity of 76%. An absent motor response on day 3 was the most sensitive marker (94%). NSE > 41.1 μg l⁻¹ combined with S-100B > 0.461 μg l⁻¹ on day 1 was the most specific marker (96%).

Conclusion

Although NSE and S-100B levels are associated with the outcome, the use of previously described cut-off values was insufficiently predictive of neurologic outcome. Caution should be exercised in the use of these tests to provide neuroprognostication.