G. Corsini

Influence of β-endorphin on phytohemagglutinin-induced lymphocyte proliferation and on the expression of mononuclear cell surface antigens in vitro

Recent evidence suggests that opiates can modulate the immune responses. In particular it has been shown that beta-endorphin and morphine are able to depress some T lymphocyte functions in humans. In the present study, experiments were designed to evaluate the effect of beta-endorphin phytohemagglutinin-induced lymphocyte proliferation and determine the mechanism of this action. The ability of naloxone to block the effect of beta-endorphin was also investigated, and the influence of beta-endorphin on the expression of mononuclear cell surface antigens using the OKT3, OKT4, OKT8, anti-HLA-DR and anti-beta 2-microglobulin monoclonal antibodies was evaluated. Phytohemagglutinin-induced lymphocyte proliferation was significantly inhibited by beta-endorphin. This effect occurred when beta-endorphin was added to cells at the beginning of the culture period (30 min before, simultaneously or 30 min after phytohemagglutinin), but not when added after 48 h of incubation. The preincubation of cells with BEP for 1 h, 4 h or 24 h did not affect lymphocyte activation by phytohemagglutinin. A ten-fold excess of naloxone, added to cultures 30 min prior to beta-endorphin, did not block the inhibitory effect. Incubation with beta-endorphin had different effects on each surface antigen tested. The OKT8+ and beta 2-microglobulin+ cells did not show significant variations. The OKT4+ cells significantly decreased, after 4 h of incubation with beta-endorphin, both in mononuclear cell and in purified T lymphocyte cultures and, after 24 h, in mononuclear cell cultures only. The OKT3+ cells decreased, in mononuclear cell cultures only, after 24 h beta-endorphin incubation.(ABSTRACT TRUNCATED AT 250 WORDS)

Twenty-four-hour variation in serum leptin in the elderly

To investigate the possibility that the aging process may affect the diurnal variation in serum leptin in humans, serum leptin levels were measured by a sensitive radioimmunoassay method in 12 elderly (aged 72 to 87 years) and 10 middle-aged (35 to 50 years) lean male subjects. Fasting blood samples (4 mL) were drawn at 8:00 AM, and then every 4 hours until 10:00 PM and every 2 hours from 12:00 midnight to 8:00 AM of the next morning. Circadian rhythmicity analysis was performed using the cosinor method. In elderly subjects, serum leptin levels showed a significant diurnal rhythm, which was similar to that observed in controls. Single cosinor analysis showed a significant rhythm in eight of 12 elderly subjects and in all middle-aged subjects but one. Compared with middle-aged subjects, similar mesor mean values (7.8 +/- 1.0 v 8.1 +/- 0.8 ng/mL) but a decreased amplitude (1.4 +/- 0.3 v 2.3 +/- 0.2 ng/mL) and an earlier acrophase (11:56 PM v 2:04 AM) were observed in the elderly. The data demonstrate that the diurnal variation in serum leptin is generally preserved in the elderly. However, the amplitude of leptin diurnal excursion undergoes a reduction with advancing age. It can be speculated that the blunted diurnal variation in serum leptin observed in the elderly may result in an alteration of the afferent signal in the adipose tissue-central nervous system homeostatic loop.

Calcitonin and β-endorphin secretion

Abstract Calcitonin is a peptide hormone secreted by the C-cells of the thyroid gland. This hormone mainly acts in preventing bone resorption. Furthermore, calcitonin is involved in other biological actions, and in particular it is able to relieve pain independently of its peripheral effects on bone. Here, we examine the possible mechanisms of calcitonin-induced analgesia, with particular regard to the opioid system involvement. Several studies in animals and in humans demonstrate that calcitonin increases plasma beta-endorphin levels, acting at the hypothalamic and/or at the pituitary level, either directly or indirectly, through monoaminergic neurotransmitters. However, this calcitonin-induced beta-endorphin release has not always been observed. These different results are discussed, and a possible implication of sex and/or calcitonin dose employed has been examined. We conclude that the analgesic effects of calcitonin are multifactorial, and beta-endorphin plays its own specific role.

Lack of variation of plasma beta-endorphin after clodronate infusion in patients with increased bone resorption

Twenty patients with increased bone resorption (osteoporosis, 6; Pagets disease, 2; multiple myeloma, 5; cancer, 7) received clodronate 300 mg by 1-hr infusion for 7 days. There was a significant decrease in serum calcium, alkaline phosphatase, and urinary hydroxyproline in all patients, and a prompt improvement of bone pain occurred concomitantly. No significant changes in circulating beta-endorphin concentration during the week of therapy were observed. Changes in the beta-endorphin concentrations were evaluated by a 2-hr period of blood sampling during and after the drug infusion and by daily determinations. Data suggest that the clodronate-induced analgesic effect is probably due to a peripheral action on osteoclasts in absence of any central effect.

Effects of acute administration of recombinant interferon alpha 2b on pituitary hormone secretion in patients with chronic active hepatitis

Abstract The effect of a single intramuscular (IM) dose of 10 × 10 6 IU of recombinant interferon alpha-2b (alpha IFN) on adrenocorticotropin (ACTH), beta-endorphin (β-EP), thyrotropin (TSH), growth hormone (GH), luteotropin (LH), and prolactin (PRL) was evaluated in seven patients suffering from chronic viral hepatitis (CVH). Alpha IFN increased ACTH (from 11.2 ± 1.1 ng/L to 16.3 ± 2.6 ng/L) and β-EP (from 25.0 ± 1.9 ng/L to 37.6 ± 1.7 ng/L) plasma concentrations and lowered plasma TSH concentrations (from 2.4 ± 0.4 mIU/L to 1.0 ± 0.2 mIU/L). These effects were recorded between the fourth and the 12th hour after alpha IFN administration and occurred without significant variations in the remaining plasma hormonal levels. In seven additional patients who received a 3 × 10 6 -IU IM dose of the same IFN, no significant variations in ACTH, β-EP, or TSH plasma levels were found. Data indicate that alpha IFN may influence the neural mechanisms controlling anterior pituitary secretion. However, high alpha IFN doses are required for this effect to occur.

Effect of the 5-HT3 receptor antagonist ondansetron on plasma AVP secretion : a study in cancer patients

The aim of the present study was to investigate the effects of a serotonin subtype 3 receptor antagonist, ondansetron, on arginine vasopressin secretion in humans. Plasma vasopressin concentrations were determined in 24 breast cancer patients undergoing adjuvant chemotherapy, before and after ondansetron intravenous (i.v.) administration. Ondansetron (8 mg i.v. at time 0 and 8 mg po at time 240 min) was administered alone in 12 patients and afterwards in combination with chemotherapy in all patients. No changes in hormone levels were found after ondansetron alone and in 17 patients who did not claim nausea and/or emesis after chemotherapy. In seven patients who experienced nausea and /or emesis, vasopressin levels significantly (P < 0.01) increased (from 6.3 +/- 0.9 ng/L in basal conditions to 15.1 +/- 3.3 ng/L at 10 h; P < 0.05 vs baseline). The results suggest the possibility that in humans, serotoninergic mechanisms, which modulate vasopressin secretion, may involve the activation of the serotonin receptors recognised by ondansetron.

Effect of interferon therapy on serum alpha-fetoprotein levels in patients with chronic hepatitis C virus infection

Serum alpha-fetoprotein (AFP) levels were determined monthly for 1 year in 30 patients with biopsy-proven chronic hepatitis C virus (HCV) infection before, during, and after recombinant interferon alfa-2b (IFN) therapy. On the basis of their response to therapy, as evaluated by serum alanine aminotransferase levels, patients were classified as responders (10 patients), partial responders (10), and nonresponders (10). Ten healthy subjects comprised the control group. In patients with chronic HCV infection, baseline serum AFP levels (7.2 ± 1.0 ng/mL, 5.2 ± 0.4 ng/mL, and 6.2 ± 0.7 ng/mL in responders, partial responders, and nonresponders, respectively) were slightly but significantly higher than those recorded in healthy subjects (2.2 ± 0.3 ng/mL). Furthermore, IFN therapy caused a decrease in serum AFP levels that was more evident and prolonged in responders but that also occurred in partial responders and nonresponders. However, in the latter groups, this reduction in serum AFP levels was evident only during IFN therapy. These data suggest that IFN therapy may affect AFP secretion, possibly throughout the improvement of hepatic necrosis and, consequently, of hepatic regeneration.

Somatostatin release in response to glucose is impaired in chronic renal failure

In order to evaluate somatostatin (SRIH) secretion in uremia, plasma SRIH concentrations were determined in basal conditions and after an oral glucose tolerance test (OGTT) in 14 non-dialysed patients with chronic renal failure (CRF), seven of whom had normal glucose tolerance (NGT) and seven impaired glucose tolerance (IGT). Plasma insulin, C-peptide and glucagon and blood glucose concentrations were also evaluated. The results were compared with those obtained in a group of age- and sex-matched normal subjects. In CRF patients, plasma SRIH fasting values (8.6 +/- 0.6 and 7.8 +/- 0.6 pmol/L in NGT and IGT patients, respectively) were comparable to those recorded in controls (7.7 +/- 0.5 pmol/L). SRIH response to OGTT, evaluated as area under curves (AUC) above basal, was similar in both groups of CRF patients (412.9 +/- 84.5 and 415.6 +/- 51.9 pmol/L per min), and significantly lower than in controls (660.1 +/- 58.5 pmol/L per min). Data indicate that chronic uremia induces a loss of SRIH secretory cell responsiveness to glucose. A possible effect of impaired SRIH secretion on glucose metabolism in CRF is discussed.

Valproate-induced encephalopathy in a comorbid elderly woman

Valproate (VPA) is used to prevent migraines and to treat seizures, mania, and children with attention deficit hyperactivity disorder. VPA may be also considered an off-label treatment for behavioural disturbances in dementia. It is generally considered a drug with a good tolerability profile in elderly subjects, even if, so far, there has been a lack of evidencebased results in the older segment of the population. There have been few case reports of VPA-related hyperammonaemic encephalopathy (VHE), and it is considered a rare clinical complication. VHE has been predominantly described in children and adults at the onset of the therapy. To date, only anecdotal case reports have been described in elderly patients. Here, we report the clinical case of an elderly patient who developed VHE during long-term treatment with VPA for schizoaffective disorder, despite previous good tolerability and adequate therapeutic compliance. A 62-year-old woman was admitted to the emergency department for lethargy and acute confusional state. The patient had been affected by a schizoaffective disorder since adolescence. She also had diabetes mellitus type 2 and chronic diarrhoea of an undetermined origin, and had undergone a recent coronary stenting for myocardial infarction (4 months before emergency department admittance). The patient’s drug regimen included VPA 500 mg/day (long-term therapy); acetylsalicylic acid 100 mg/day, clopidogrel 75 mg/day, lansoprazole 30 mg/day, and atorvastatin 40 mg/day had been recently introduced after the myocardial infarction. The patient had moderate comorbidity (cumulative illness rating scale, index of comorbidity: 4/13), a polypharmacy of 14 drugs, and severe functional dependence (Activities of Daily Living Scale: 5/6). The patient’s physical examination showed lethargy without any neurological focal sign. Vital signs were normal (blood pressure: 120/60 mmHg; cardiac rate: sinus rhythm with 80 bpm; temperature: 36.6 C). Brain computed tomography was unremarkable. Electroencephalogram excluded the presence of seizures. Neither drugs nor alcohol abuse was considered a potential cause for lethargy because of the patient’s institutionalization with adequate supervision by a nurse. Blood plasma showed high levels of ammonia (114 μmol/L), normal liver enzymes (aspartate aminotransferase 13 U/L, alanine aminotransferase 9 U/L, gamma-glutamyl transpeptidase 6 U/L, and alkaline phosphatase 56 U/L), and subtherapeutic levels of VPA (48.7 mg/L); modest thrombocytopenia (platelets 127 × 10/L) and hypoalbuminaemia (26.2 g/L) were also reported. Unabsorbed faeces were observed with a faecal sampling. The diagnostic work-up excluded the most common causes of hyperammonaemia (cirrhosis, acute bleeding, systemic acid–base alterations, thyroid malfunctioning, calcium deficits). Metabolic encephalopathy was suspected so VPA was discontinued. The patient showed progressive clinical improvement after 48 h with hyperammonaemia, thrombocytopenia, and diarrhoea resolving within 5–7 days. The patient’s score of 7 on the Naranjo scale indicated a probable causal relationship between her altered consciousness and VPA. VPA-induced encephalopathy is a rare, lifethreatening clinical syndrome; its pathogenesis is commonly associated with hyperammonaemia and normal liver function. Hyperammonaemia may be considered the metabolic result of the liver and renal effects of VPA: a VPA metabolite stimulates glutaminase in the renal cortex and another one is known to indirectly inhibit the hepatic mitochondrial carbamoyl phosphate synthetase-I, the first urea cycle enzyme. Additionally, it is important to note that VPA is for

Effect of granulocyte colony-stimulating factor on secretion of prolactin, growth hormone, thyroid-stimulating hormone, and cortisol in humans

Abstract In order to assess the endocrine effects of acute and short-term granulocyte colony-stimulating factor (G-CSF), we studied seven patients with myelo- and lymphoproliferative disorders who were given G-CSF to prevent chemotherapy-induced neutropenia. On day 0, the patients received a placebo; on days 1 to 4, they received recombinant human G-CSF (300 μg, subcutaneously). Plasma prolactin, growth hormone, thyroid-stimulating hormone, and cortisol levels were determined at baseline and hourly for 8 hours on days 0 and 1. Additional blood samples were collected at 12 hours on days 0 and 1, and at 9:00 am on days 2 to 5 of the study. After administration of G-CSF, no significant variations in circulating hormone levels were observed with respect to baseline and corresponding placebo levels. The data indicate that short-term G-CSF administration does not cause endocrine abnormalities in patients undergoing this cytokine treatment