Simonetta Bossoni

Short-Term Administration of Captopril and Nifedipine and Exercise-Induced Albuminuria in Normotensive Diabetic Patients With Early-Stage Nephropathy

Recent studies have demonstrated that short-term angiotensin converting enzyme (ACE) inhibition with captopril can reduce urinary albumin excretion rate (UAER) after exercise in normotensive diabetic patients with early-stage nephropathy. The aim of this study was to investigate whether this effect of ACE inhibition was due to a systemic hypotensive action or a specific action at the intrarenal level. Thus, we compared the acute effects of captopril and the Ca2+-channel blocker nifedipine on exercise-induced UAER in normotensive (blood pressure <165/95 mmHg) diabetic patients who were normoalbuminuric or microalbuminuric at rest (stage 2 or 3 of diabetic nephropathy). Twenty-five stage 2 diabetic nephropathy patients, 39 stage 3 diabetic nephropathy patients, and 12 nondiabetic subjects performed five submaximal cycloergometric exercises (90% of theoretical heart rate) on nonconsecutive days. The first two exercises were performed in basal conditions; the next three exercises were performed 24 h after administration of captopril (25 mg twice daily) or nifedipine AR (20 mg twice daily) or placebo (1 tablet twice daily) according to a randomized double-blind crossover trial. After placebo, blood pressure and UAER did not change at rest or 1 h after exercise. After captopril, blood pressure at rest and during exercise was similar to that observed after placebo. UAER at rest was not modified, whereas 1 h after exercise, it was significantly decreased both in stage 2 and stage 3 diabetic nephropathy patients (P < 0.001). After nifedipine, blood pressure decreased significantly at rest and during exercise in respect to placebo and captopril. UAER at rest did not change significantly. UAER 1 h after exercise was significantly decreased both in stage 2 and stage 3 diabetic nephropathy patients (P < 0.01 vs. placebo), but it was significantly higher than that observed after captopril (P < 0.01). Captopril is more effective than nifedipine in reducing exercise-induced UAER in normotensive diabetic patients even though it does not influence blood pressure response to exercise. The effects of captopril on UAER induced by exercise may be due to a specific action at the intrarenal level.

Pyridostigmine enhances even if it does not normalize the growth hormone responses to growth hormone-releasing hormone in patients with Cushing's disease.

Subjects with Cushings disease have diminished growth hormone (GH) response to growth hormone-releasing hormone (GHRH). The aim of our study was to investigate the underlying mechanism of this diminished GH response in these patients using pyridostigmine (PD), an acetylcholinesterase inhibitor, which is reported to increase GH secretion by reducing somatostatin tone. Eight subjects with untreated Cushings disease (caused by a pituitary adenoma) and 6 control subjects received GHRH 100 micrograms in 1 ml of saline, as intravenous bolus injection 60 min after (1) placebo (2 tablets, p.o.) or (2) PD (120 mg, p.o.). After GHRH plus placebo, the GH peak (mean +/- SEM) was significantly lower in subjects with Cushings disease (2.4 +/- 0.5 micrograms/l) compared to control subjects (25.1 +/- 1.8 micrograms/l, p less than 0.05). After GHRH plus PD, the GH peak was significantly enhanced both in subjects with Cushings disease (7.1 +/- 2.3 micrograms/l, p less than 0.05) and in control subjects (42.3 +/- 4.3 micrograms/l, p less than 0.05). In patients with Cushings disease, the GH response to GHRH plus PD was lower with respect to the GH response to GHRH alone in normal subjects. We conclude that hypercortisolism may cause a decrease in central cholinergic tone which is in turn hypothesized to be responsible of an enhanced somatostatin release from the hypothalamus. However, other metabolic or central nervous system alterations may act synergistically with hypercortisolism in causing GH inhibition in patients with Cushings disease.

Effect of galanin on the growth hormone (GH) response to GH-releasing hormone in patients with Cushing's disease

Attenuated plasma GH secretion during sleep and blunted GH responses to provocative stimuli have been observed in patients with Cushings disease. Synthetic porcine galanin elicits GH secretion when given alone, and enhances the GH response to GHRH in normal human subjects. The aim of our study was to investigate the effects of galanin on the GH response to GHRH in patients with Cushings disease. We studied 5 female subjects with untreated active Cushings disease caused by micro-pituitary adenomas (age 43 +/- 6.7 years; BMI 30 +/- 0.7 kg/m2). Four normal adult females, matched for age and body weight with the patients with Cushings disease, were studied as controls. Subjects underwent in random order: (1) infusion of synthetic porcine galanin IV, 500 micrograms in 100 mL; (2) infusion of saline, IV, 100 mL. A bolus of human GHRH(1-29)NH2 (Geref, Serono, Italy), 100 micrograms in 1 mL saline, was injected IV at 0 minutes. Patients with Cushings disease showed blunted GH peaks after GHRH (1.2 +/- 0.4 micrograms/L) during saline infusion, as compared to normal controls (24.6 +/- 4.6 micrograms/L; p < 0.05). During galanin infusion a significantly enhanced GH response to GHRH, as compared with saline infusion, was observed in control subjects (GH peak: 51.4 +/- 9.8 micrograms/L; p < 0.05), but not in patients with Cushings disease (GH peak: 2.3 +/- 0.6 micrograms/L). GH levels were significantly lower both after saline and after galanin in patients with Cushings disease as compared to normal controls. Our data demonstrate that galanin is not able to enhance the GH response to GHRH in patients with Cushings disease. That galanin cannot reverse this effect suggests that the mechanism of action of galanin is not via a decrease in somatostatin release by the hypothalamus.

Growth hormone treatment in aging: state of the art and perspectives

The regulation of GH secretion in the aged human is still not clearly understood. Results from a large number of studies suggest that aging decreases both spontaneous pulsatile GH secretory activity, and baseline serum GH concentrations. In addition, the GH response to physiological and pharmacological stimuli, including the administration of exogenous GH-releasing hormone (GHRH) have also been reported to be decreased in aged subjects. Recent studies have suggested that the inhibitory effect of aging on GH secretion may be due to an enhancement of hypothalamic somatostatin release both in the rat and in man. Shortly after the documentation of decreases in GH secretion in humans, other studies showed that the amplitude of spontaneous GH pulses decreased with age in rodents and that these changes were associated with a decline in plasma IGF-I. These studies immediately progressed to an investigation of the mechanisms responsible for the decline in GH secretion. Research efforts were eventually directed to the level of hypothalamic releasing (GHRH) and inhibiting (somatostatin) hormones. Results of these studies provided evidence that increased somatostatin tone and decreased GHRH tone at the hypothalamic level may both be a contributing factor in the decline in GH secretion with age. These conclusions were supported by research in humans, where administration of cho

A single dose of aztreonam in the prevention of urinary tract infections in elderly catheterized patients.

We have compared the effects of aztreonam and placebo in the prevention of urinary tract infections (UTI) in elderly hospitalized patients who needed urethral catheterization. 162 patients (96 males, 66 females; age range 60-91 years) were randomly allocated to receive double-blind a single dose of aztreonam (2 g i.m. 80 patients) or placebo (4 ml lidocaine 2%, 82 patients) three hours before catheterization. All patients were followed-up for 7 days. Urine culture was performed before, at the first, third and seventh day of catheterization. At the end of follow-up 71/80 patients (88.7%) who received a single preventing dose of aztreonam had negative urine culture without clinical signs of UTI. On the contrary, in the group treated with placebo at the end of follow-up only 38/82 patients (46.3%) had negative urine without clinical signs of UTI. In conclusion, our data suggest that a single 2g i.m. dose of aztreonam is effective in preventing UTI in elderly patients needing indwelling urethral catheterization.

Short-term effect of captopril and nifedipine on micro-albuminuria induced by exercise in hypertensive diabetic patients.

Physical exercise can induce micro-albuminuria, a urinary albumin excretion rate of 20-200 micrograms/min, in diabetics without micro-albuminuria at rest (stage II of diabetic nephropathy). The aim of the present study was to evaluate the acute effects of captopril, an angiotensin converting enzyme (ACE) inhibitor, and nifedipine, a calcium channel blocker, on exercise-induced micro-albuminuria in hypertensive diabetics with stage II nephropathy. Eleven hypertensive World Health Organisation (WHO) stages I-II non-obese diabetics (five insulin-dependent diabetics, six non-insulin dependent diabetics) underwent five submaximal cycloergometric tests, the first two in basal conditions, the other three after 24-h administration of captopril (25 mg twice a day), placebo (1 tablet twice a day) or nifedipine AR (20 mg twice a day) according to a randomized double-blind design. Our results demonstrate that despite a lower reduction in exercise blood pressure, captopril is more effective than nifedipine in blunting diabetic exercise-induced micro-albuminuria.

TREATMENT WITH METFORMIN IS PROTECTIVE AGAINST LIMITATIONS IN INSTRUMENTAL ACTIVITIES OF DAILY LIVING IN OLDER SUBJECTS WITH TYPE 2 DIABETES MELLITUS

for basic activities of daily living, and flexion contractures had developed in her arms and legs. She directed severe agitation and aggression toward nursing staff during toileting, bathing, and transfers but remained calm when unattended during the remainder of the day and slept well most nights. Rigorous nursing care planning and environmental and behavioral management strategies were ineffective. Identification and treatment of potential triggers such as pain failed to extinguish the agitation and aggression. Management of pain included injection of flexion contractures with Botox by a physiatrist and gabapentin titrated up to the maximum tolerated dose (600 mg twice a day) in addition to regular dosing of acetaminophen 1,000 mg every 6 hours. The patient had a disappointing response to pharmacotherapy specifically targeting response agitation. This included quetiapine up to 150 mg daily (ineffective and oversedating), citalopram up to 30 mg daily (ineffective), a low dose of zuclopenthixol (a 72-hour depot-typical antipsychotic; 5 mg intramuscularly) (caused severe extrapyramidal side-effects), pre-care lorazepam use at the minimum effective dose (caused 6–8 hours or more of daytime oversedation), and olanzapine (pre-care use was ineffective and oversedating). Midazolam oral solution was prepared at a concentration of 2 mg/mL. The dosage was started at 2 mg and titrated gradually (over the course of 2 weeks) up to 6 mg given 15 to 30 minutes before personal care or transfers. The patient’s response agitation and aggression resolved with no consequent daytime oversedation, and all antipsychotics were discontinued. Midazolam is an ultra-brief-acting benzodiazepine with a half-life of 1.5 to 6 hours. It is commonly used for conscious sedation in emergency departments, in minor procedures such as endoscopy, and for uncooperative patients such as in pediatric dentistry. It has an oral bioavailability of 35% to 40% when given orally and greater than 90% when given parenterally. Parenteral routes are usually limited to emergency department and intensive care settings. Dosage reductions are required with parenteral administration. It undergoes hepatic metabolism and renal excretion. In this patient, the use of oral midazolam was associated with marked improvement in severe dementia-related response agitation. Based on this case study, preparation of a midazolam oral solution with a concentration of 2 to 3 mg/mL is recommended. Nursing staff should be requested to shake the solution to ensure proper constitution before administration. Starting at a dose of 1 to 2 mg given orally 15 to 30 minutes before personal care or transfers is suggested, titrating in increments of 1 to 2 mg as tolerated to induce the required level of sedation. It is anticipated that the usual effective dose would be in the range of 2 to 8 mg. Careful monitoring for respiratory depression is recommended, with a precaution to avoid administration of midazolam to patients with preexisting respiratory compromise, low baseline respiratory rate, or concurrent use of opioid-based medications. Midazolam-related oversedation can be reversed with the benzodiazepine inverseagonist flumazenil. Michael J. Passmore, MD Les Sheldon, MD Stuart Lax, MD Michael Wilkins-Ho, MD Martin Illing, MD Department of Psychiatry Division of Geriatric Psychiatry University of British Columbia Vancouver, British Columbia, Canada

Effect of the combined administration of galanin and clonidine on serum growth hormone levels in normal subjects and in patients under chronic glucocorticoid treatment.

Aim of our study was to investigate the effect of clonidine and galanin (alone or in combination) on growth hormone (GH) secretion in normal subjects and in adult patients with increased somatostatin tone due to chronic daily immunosuppressive glucocorticoid treatment. We studied 7 adult patients undergoing long-term (no less than 6 months) immunosuppressive glucocorticoid treatment for non endocrine diseases (4F, 3M; age 49.7 +/- 6.3 years). Six normal adult nonobese subjects (3F, 3M; age 34 +/- 2.7 years) served as controls. All subjects underwent the following three tests in random order: 1) iv infusion of clonidine, 150 micrograms in 10 mL of saline, from time 0 to 10 min; 2) iv infusion of synthetic porcine galanin, 500 micrograms in 100 mL of saline from -15 to 30 min; 3) iv infusion of clonidine from 0 to 10 min combined with synthetic porcine galanin iv infusion from -15 to 30 min. Blood samples for GH assay were taken at -15, 0, 15, 30, 45, 60, 90, 120 min. No significant differences in GH absolute values were observed at any time between the three different tests within each group of subjects. Normal subjects showed significantly (p < 0.05) higher GH peaks and GH absolute values from 15 to 90 min after galanin alone, clonidine alone and clonidine+galanin with respect to the glucocorticoid-treated patients. The absence of any either synergistic or at least additive effect on GH secretion of galanin and clonidine in conditions of both normal and increased somatostatin tone suggests that also in man, as well as in the rat, the action of galanin on the GH axis may be mediated through alpha-adrenergic pathways.

Variability in the growth hormone response to growth hormone-releasing hormone alone or combined with pyridostigmine in type 1 diabetic patients.

In man the GH response to GHRH is variable within and between subjects. Pyridostigmine (PD), an acetylcholinesterase inhibitor, has been shown to reduce the variability of the GH response to GHRH in normal subjects. The aim of this study was to assess the existence of either inter- or intraindividual variability in the GH response to GHRH in type 1 diabetic patients. Moreover, we investigated the effect of PD on such variability in the same patients. Seven (4 females-3 males) nonobese type 1 diabetic patients underwent two experiments performed in consecutive days according to a single-blind protocol: 1) 120 mg oral PD 60 min before iv injection of human (h) GHRH-(1-29) NH2, 100 μg in 2 ml of sterile water; 2) oral placebo 60 min before iv injection of 100 μg hGHRH. The two experiments were then repeated, following the same procedure, one and two weeks after the start of the study. The GH peaks after GHRH were variable within different subjects but also in the same subject on different occasions. However, the mean GH peak levels after GHRH in the three tests were not significantly different (14.2±3.5, 15.3±3, 16.5±6.4 μg/L, respectively), the coefficient of variation for each test was 65%, 51.8%, 102.4%, respectively (mean 73.1±15.1%). The GH response to GHRH was always significantly enhanced by PD administration: the mean GH peak levels in the three tests were 31.9±7.1, 44.8±10.4, 49.9±13.1 μg/L, respectively, without significant differences between tests. After PD+GHRH the interindividual variability in the GH response was still present but significantly lower than after GHRH alone. The coefficient of variation for each test was 58.7%, 61.3%, 69.3%, respectively (mean 63.1±3.2%). It can be hypothesized that PD may reduce the interindividual variability of the GH response to GHRH in the diabetic population by decreasing somatostatin tone only in diabetic patients with normal-high hypothalamic somatostatin.

Effects of Metoclopramide on the Paradoxical Growth Hormone Response to Galanin in Acromegaly

Galanin is able to enhance growth hormone (GH)-releasing hormone stimulated GH secretion in normal man. In acromegaly circulating GH levels are elevated and the GH response to GHRH may be exaggerated. Galanin has been recently shown to decrease circulating GH levels in acromegaly. Dopaminergic drugs were the only previously known agents able to cause a paradoxical GH fall in acromegaly. Aim of our study was to investigate the effects of a potent central dopaminergic receptor blocker, metoclopramide (MCP), on the galanin-induced paradoxical GH secretion in acromegalic subjects. Two male and three female patients with active acromegaly (age range 44-66 years, body mass index range 24.6-28 Kg/m2) were studied after 45 min i.v. infusion of porcine galanin (0.5 mg in 100 ml of saline) from 0 to 45 min combined with a 60 min i.v. infusion of a) saline (100 ml) or b) MCP (10 mg in 100 ml of saline) from -15 to 45 min. After galanin, GH values fell from baseline (27.5 +/- 10 micrograms/L) to a mean nadir of 16.4 +/- 6.1 micrograms/L; after galanin + MCP, circulating GH levels were also decreased (mean nadir 17.3 +/- 8.1 micrograms/L) in all the patients with respect to baseline (23.6 +/- 9.7 micrograms/L). No significant differences were found in absolute or percent of baseline GH levels after galanin+saline vs galanin + MCP. Our results suggest that the paradoxical GH fall after galanin in acromegalic patients is not mediated through dopaminergic receptor. It can be hypothesized that galanin may interact at the pituitary level with its own receptors expressed by GH-secreting adenomatous cells.