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Obesity represents the single greatest ongoing roadblock to improving cardiovascular health. Prolonged obesity is associated with fundamental changes in the integrative control of energy balance, including the development of selective leptin resistance, which is thought to contribute to obesity-associated hypertension, and adaptation of resting metabolic rate (RMR) when excess weight is reduced. Leptin and the melanocortin system within the hypothalamus contribute to the control of both energy balance and blood pressure. While the development of drugs to stimulate RMR and thereby reverse obesity through activation of the melanocortin system has been pursued, most of the resulting compounds simultaneously cause hypertension. Evidence supports the concept that although feeding behaviors, RMR, and blood pressure are controlled through mechanisms that utilize similar molecular mediators, these mechanisms exist in anatomically dissociable networks. New evidence supports a major change in molecular signaling within AgRP (Agouti-related peptide) neurons of the arcuate nucleus of the hypothalamus during prolonged obesity and the existence of multiple distinct subtypes of AgRP neurons that individually contribute to control of feeding, RMR, or blood pressure. Finally, ongoing work by our laboratory and others support a unique role for AT 1 (angiotensin II type 1 receptor) within one specific subtype of AgRP neuron for the control of RMR. We propose that understanding the unique biology of the AT 1 -expressing, RMR-controlling subtype of AgRP neurons will help to resolve the selective dysfunctions in RMR control that develop during prolonged obesity and potentially point toward novel druggable antiobesity targets that will not simultaneously cause hypertension.

Perception of weight loss requirements before bariatric surgery varies among patients, physicians, and health insurance payers. Current clinical guidelines do not require preoperative weight loss because of a lack of scientific support regarding its benefits.To examine the association of preoperative body mass index (BMI) and weight loss with 30-day mortality after bariatric surgery.This cohort study used data from 480 075 patients who underwent bariatric surgery from 2015 to 2017 in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program, which covers more than 90% of all bariatric surgery programs in the United States and Canada. Clinical and demographic data were collected at all participating institutions using a standardized protocol. Data analysis was performed from December 2018 to November 2019.Preoperative BMI and weight loss.30-day mortality after bariatric surgery.Of the 480 075 patients (mean [SD] age 45.1 [12.0] years; 383 265 [79.8%] women), 511 deaths (0.1%) occurred within 30 days of bariatric surgery. Compared with patients with a preoperative BMI of 35.0 to 39.9, the multivariable-adjusted odds ratios for 30-day mortality for patients with preoperative BMI of 40.0 to 44.9, 45.0 to 49.9, 50.0 to 54.9, and 55.0 and greater were 1.37 (95% CI, 1.02-1.83), 2.19 (95% CI, 1.64-2.92), 2.61 (95% CI, 1.90-3.58), and 5.03 (95% CI, 3.78-6.68), respectively (P for trend .001). Moreover, compared with no preoperative weight loss, the multivariable-adjusted odds ratios for 30-day mortality for patients with weight loss of more than 0% to less than 5.0%, 5.0% to 9.9%, and 10.0% and greater were 0.76 (95% CI, 0.60-0.96), 0.69 (95% CI, 0.53-0.90), and 0.58 (95% CI, 0.41-0.82), respectively (P for trend = .003).In this study, even moderate weight loss (ie,0% to5%) before bariatric surgery was associated with a lower risk of 30-day mortality. These findings may help inform future updates of clinical guidelines regarding bariatric surgery.

PURPOSE OF REVIEW: Here we review the current understanding of the functional neuroanatomy of neurons expressing Agouti-related peptide (AgRP) and the angiotensin 1A receptor (AT(1A)) within the arcuate nucleus (ARC) in the control of energy balance. RECENT FINDINGS: The development and maintenance of obesity involves suppression of resting metabolic rate (RMR). RMR control is integrated via AgRP and proopiomelanocortin neurons within the ARC. Their projections to other hypothalamic and extrahypothalamic nuclei contribute to RMR control, though relatively little is known about the contributions of individual projections and the neurotransmitters involved. Recent studies highlight a role for AT(1A), localized to AgRP neurons, but the specific function of AT(1A) within these cells remains unclear. SUMMARY: AT(1A) functions within AgRP neurons to control RMR, but additional work is required to clarify its role within subpopulations of AgRP neurons projecting to distinct second-order nuclei, and the molecular mediators of its signaling within these cells.

Study Objectives Severe sleep restriction results in elevated evening cortisol levels. We examined whether this relative hypercortisolism is associated with alterations in the pituitary-adrenocortical response to evening corticotropin-releasing hormone (CRH) stimulation. Methods Eleven subjects participated in 2 sessions (2 nights of 10 hours vs. 4 hours in bed) in randomized order. Sleep was polygraphically recorded. After the second night of each session, blood was sampled at 20-minute intervals from 09:00 to 24:00 for adrenocorticotropic hormone (ACTH) and cortisol measurements, and perceived stress was assessed hourly. Ovine CRH was injected at 18:00 (1 µg/kg body weight). Results Prior to CRH injection, baseline ACTH, but not cortisol, levels were elevated after sleep restriction. Relative to the well-rested condition, sleep restriction resulted in a 27% decrease in overall ACTH response to CRH (estimated by the incremental area under the curve from 18:00 to 24:00; p = .002) while the cortisol response was decreased by 21% (p = .083). Further, the magnitude of these decreases was correlated with the individual amount of sleep loss (ACTH: rSp = -0.65, p = .032; cortisol: rSp = -0.71, p = .015). The acute post-CRH increment of cortisol was reduced (p = .002) without changes in ACTH reactivity, suggesting decreased adrenal sensitivity. The rate of decline from peak post-injection levels was reduced for cortisol (p = .032), but not for ACTH. Scores of perceived stress were unaffected by CRH injection and were low and similar under both sleep conditions. Conclusions Sleep restriction is associated with a reduction of the overall ACTH and cortisol responses to evening CRH stimulation, and a reduced reactivity and slower recovery of the cortisol response.

Electronic portal imaging (EPI) is commonly used to identify and correct for inter-fraction variability in tangential breast irradiation. Based on the institutional policy, EPI registration is performed by either radiation oncologist or therapist. Little data is available on the inter-observer agreement in EPI registration among different health practitioners. The aim of our study was to analyze inter-observer agreement among radiation oncologists and therapists in the evaluation of EPI for breast cancer radiotherapy verification. EPI data of 40 patients treated with tangential fields were independently reviewed by a radiation oncologist (on-line, just before treatment) and off-line by junior and senior therapists. Displacement of each EPI image with respect to the digital reconstructed radiographs (DRRs) was quantified using manual EPI registration based on bony marks with the corresponding DRRs. Agreement between observers was evaluated using weighted Cohen's Kappa statistics. In 95% out of 720 EPI-DRR comparisons, the EPI-DRR misalignment was < 5 mm. The difference between observers was < 2 mm in 666 (92.5%) out of all 720 delta values. High inter-observer agreement was found, with weighted Cohen's Kappa values attesting evaluation overlaps ranging from moderate (among therapists) to almost perfect (among radiation oncologist and therapists). The high agreement among the observers demonstrated the precision of breast localization using EPI. These findings suggest that routine EPI-based patient set-up verification in breast cancer radiotherapy can be safely entrusted to trained therapists (supervision should be assured based on the local tasks definition). Our study might be useful in quality assurance and in the optimization of workload in the radiotherapy departments. They might allow for wider implementation of complex and evolving radiotherapy technologies.

Diltiazem, as well as other calcium entry blockers, is widely prescribed for the treatment of various types of angina. This review summarizes the current state of knowledge of the pharmacokinetics of diltiazem and of two other calcium entry blockers: verapamil and nifedipine. Although unrelated in their chemical structure, these three drugs have common features. They are highly lipophilic and have a large volume of distribution, are mainly cleared by metabolism and undergo an extensive first-pass extraction. On the other hand, as expected from their quite dissimilar structures, they have their own particular kinetic characteristics. For example, metabolism of diltiazem and verapamil gives rise to active metabolites; repeated administration influences the kinetic profile of verapamil but not those of diltiazem and nifedipine. Absorption, distribution and elimination of these three drugs are differently affected by age and pathological conditions. The possible drug interactions involving diltiazem and the other calcium entry blockers are discussed, particularly that with digoxin. Due to its large therapeutic index, there is no need for treatment monitoring of diltiazem. Nevertheless, this procedure may provide useful information for optimizing the dosage regimen of each patient as the pathological condition and drug therapy may be quite complex.

Cystatin C (Cys C) is a cysteine protease inhibitor produced at a constant rate by nucleated cells, filtered through the glomerular membrane and reabsorbed by kidney tubular cells. Aim of this cross-sectional and longitudinal study was to assess serum Cys C and creatinine (Crea) concentrations in thyroid dysfunction. One hundred and eighty-one patients, 26 with untreated non-toxic nodular goiter, 58 with hyperthyroidism, 31 on L-T4 suppressive therapy for non-toxic nodular goiter, 35 with short-term hypothyroidism after L-T4 withdrawal to perform whole body scan for thyroid cancer, 11 with long-term hypothyroidism due to chronic autoimmune thyroiditis and 20 patients with mild hypothyroidism were enrolled in the study. Fifty-seven age- and sex-matched normal subjects served as controls. Serum Cys C, Crea, free T4 (FT4), FT3 and TSH were assessed. Thirty hyperthyroid patients and 35 short-term hypothyroid patients were followed prospectively until euthyroidism was reached by methimazole or L-T4 therapy. The cross-sectional study showed that mean serum Crea concentrations were significantly reduced in overt hyperthyroid or subclinical hyperthyroid patients, while it was increased in overt hypothyroid patients, but not in mild hypothyroidism. Conversely, serum Cys C levels were significantly increased in overt hyperthyroid patients compared to controls (p

Odorous compounds from a landfill have been characterised by gas-chromatography-mass-spectrometry, identifying about 100 volatile organic compounds. Air samples from different landfill sites and from the environment have been analysed after a solid-phase microextraction on a three-phase fiber, DVB/Carboxen/PDMS, which allowed a preconcentration and the chromatographic data obtained from the most significant emission sources have been submitted to chemometric analysis in order to better establish specific markers of olfactory pollution. For example limonene was a typical tracer of fresh wastes, while p-cymene was characteristic of leachate and biogas. By the developed analytical procedure it has been evaluated the efficiency of a scrubber plant utilised in the landfill in order to remove malodour compounds. The average removal efficiency was not very high (about 23.5%) due to scarce ability in removing low polarity compounds. Furthermore, it has been demonstrated the suitability of a microgas chromatograph for the continuous on-site monitoring of air pollution in order to rapidly individuate emission sources of olfactive nuisances.

Insufficient sleep is associated with increased cardiometabolic risk. Alterations in hypothalamic-pituitary-adrenal axis may underlie this link.Our objective was to examine the impact of restricted sleep on daytime profiles of ACTH and cortisol concentrations.Thirteen subjects participated in 2 laboratory sessions (2 nights of 10 hours in bed versus 2 nights of 4 hours in bed) in a randomized crossover design. Sleep was polygraphically recorded. After the second night of each session, blood was sampled at 20-minute intervals from 9:00 am to midnight to measure ACTH and total cortisol. Saliva was collected every 20 minutes from 2:00 pm to midnight to measure free cortisol. Perceived stress, hunger, and appetite were assessed at hourly intervals by validated scales.Sleep restriction was associated with a 19% increase in overall ACTH levels (P.03) that was correlated with the individual amount of sleep loss (rSp = 0.63, P.02). Overall total cortisol levels were also elevated (+21%; P = .10). Pulse frequency was unchanged for both ACTH and cortisol. Morning levels of ACTH were higher after sleep restriction (P.04) without concomitant elevation of cortisol. In contrast, evening ACTH levels were unchanged while total and free cortisol increased by, respectively, 30% (P.03) and 200% (P.04). Thus, the amplitude of the circadian cortisol decline was dampened by sleep restriction (-21%; P.05). Sleep restriction was not associated with higher perceived stress but resulted in an increase in appetite that was correlated with the increase in total cortisol.The impact of sleep loss on hypothalamic-pituitary-adrenal activity is dependent on time of day. Insufficient sleep dampens the circadian rhythm of cortisol, a major internal synchronizer of central and peripheral clocks.

ObjectivesWe previously reported that adult patients with GH deficiency (GHD) due to a confirmed or likely pituitary defect, compared with healthy controls individually matched for age, gender, and BMI, have more slow-wave sleep (SWS) and higher delta activity (a marker of SWS intensity). Here, we examined the impact of recombinant human GH (rhGH) therapy, compared with placebo, on objective sleep quality in a subset of patients from the same cohort.DesignSingle-blind, randomized, crossover design study.MethodsFourteen patients with untreated GHD of confirmed or likely pituitary origin, aged 22–74 years, participated in the study. Patients with associated hormonal deficiencies were on appropriate replacement therapy. Polygraphic sleep recordings, with bedtimes individually tailored to habitual sleep times, were performed after 4 months on rhGH or placebo.ResultsValid data were obtained in 13 patients. At the end of the rhGH treatment period, patients had a shorter sleep period time than at the end of the placebo period (479±11 vs 431±19 min respectively;P=0.005), primarily due to an earlier wake-up time, and a decrease in the intensity of SWS (delta activity) (559±125 vs 794±219 μV2respectively;P=0.048).ConclusionsFour months of rhGH replacement therapy partly reversed sleep disturbances previously observed in untreated patients. The decrease in delta activity associated with rhGH treatment adds further evidence to the hypothesis that the excess of high-intensity SWS observed in untreated pituitary GHD patients is likely to result from overactivity of the hypothalamic GHRH system due to the lack of negative feedback inhibition by GH.

Evidence for the role of sleep on metabolic and endocrine function has been reported more than four decades ago. In the past 30 years, the prevalence of obesity and diabetes has greatly increased in industrialized countries, and self-imposed sleep curtailment, now very common, is starting to be recognized as a contributing factor, alongside with increased caloric intake and decreased physical activity. Furthermore, obstructive sleep apnea, a chronic condition characterized by recurrent upper airway obstruction leading to intermittent hypoxemia and sleep fragmentation, has also become highly prevalent as a consequence of the epidemic of obesity and has been shown to contribute, in a vicious circle, to the metabolic disturbances observed in obese patients. In this article, we summarize the current data supporting the role of sleep in the regulation of glucose homeostasis and the hormones involved in the regulation of appetite. We also review the results of the epidemiologic and laboratory studies that investigated the impact of sleep duration and quality on the risk of developing diabetes and obesity, as well as the mechanisms underlying this increased risk. Finally, we discuss how obstructive sleep apnea affects glucose metabolism and the beneficial impact of its treatment, the continuous positive airway pressure. In conclusion, the data available in the literature highlight the importance of getting enough good sleep for metabolic health.

Sleep curtailment has become a common behavior in modern society. This review summarizes the current laboratory evidence indicating that sleep loss may contribute to the pathophysiology of diabetes mellitus and obesity. Experimentally induced sleep loss in healthy volunteers decreases insulin sensitivity without adequate compensation in beta-cell function, resulting in impaired glucose tolerance and increased diabetes risk. Lack of sleep also down-regulates the satiety hormone leptin, up-regulates the appetite-stimulating hormone ghrelin, and increases hunger and food intake. Taken together with the epidemiologic evidence for an association between short sleep and the prevalence or incidence of diabetes mellitus and/or obesity, these results support a role for reduced sleep duration in the current epidemic of these metabolic disorders. Screening for habitual sleep patterns in patients with "diabesity" is therefore of great importance. Studies are warranted to investigate the putative therapeutic impact of extending sleep in habitual short sleepers with metabolic disorders.

Low energy and fatigue are frequent complaints in subjects with GH deficiency (GHD). Because interrelations between sleep and GH regulation are well documented, these complaints could partly reflect alterations of sleep quality.The objective of the study was to determine objective and subjective sleep quality and daytime sleepiness in adult GHD patients.Thirty patients, aged 19-74 yr, with untreated GHD (primary pituitary defects confirmed or likely in 26 patients, hypothalamic origin in four patients), and 30 healthy controls individually matched for gender, age, and body mass index participated in the study. Patients with associated pituitary deficiencies (n = 28) were on hormonal replacement therapy.Polygraphic sleep recordings, assessment of Pittsburgh Sleep Quality Index, and Quality of Life Assessment for GHD in Adults were measured.Irrespective of etiology, GHD patients had a Pittsburgh Sleep Quality Index score above the clinical cutoff for poor sleep and lower Quality of Life Assessment for GHD in Adults scores than controls, with tiredness being the most affected domain. Patients with pituitary GHD spent more time in slow-wave sleep (SWS) and had a higher intensity of SWS than their controls. Among these patients, older individuals obtained less total sleep than controls, and their late sleep was more fragmented. Contrasting with pituitary GHD, the four patients with hypothalamic GHD had lower intensity of SWS than their controls.GHD is associated with sleep disorders that may be caused by specific hormonal alterations as well as with poor subjective sleep quality and daytime sleepiness. Disturbed sleep is likely to be partly responsible for increased tiredness, a major component of quality of life in GHD.

SUMMARY: In a double-blind, cross-over trial, progabide (PGB) and placebo were compared as add-on therapy in 59 patients with moderate to severe epilepsy. Eight patients did not complete the study, 4 because of adverse drug reactions (elevation of liver transaminases, 2; gastritis, 1; and acute psychosis, 1) and 4 because of administrative reasons. Among the remaining 51 patients, seizure frequency was reduced >50% in 18 patients with PGB treatment and in 8 patients with placebo (p

Neurodegenerative diseases are a major focus of scientific and clinical interest because of their increasing medical and social importance. Due to the intimate connections between central nervous and endocrine systems, it is reasonable to suspect that important, and in some cases clinically relevant, endocrine modifications may accompany the progression of neurodegenerative diseases. Data on endocrine modifications in different neurodegenerative diseases have been reported, but results have often been non-conclusive, or conflicting. Accumulating evidence suggests that the GH/IGF-I axis is involved in the regulation of brain growth, development, and metabolism and in the regulation of muscle function. Dysfunctions in GH/IGF-I axis in most of neurodegenerative diseases are therefore reviewed. Alterations of this system could be actors in the complex network leading to (at least some) neurodegenerative diseases. A thorough effort in investigating every possible involvement is warranted, in the light of future therapeutic strategies.

Impaired GH secretion is a common finding in patients with primary hyperparathyroidism (PHP). Ghrelin displays strong GH-releasing action, mainly at the hypothalamic level.To evaluate secretory response of GH to ghrelin in PHP patients.Fifteen patients [11 women/4 men, mean age 54 years, range 32-70 years, body mass index (BMI) 25.0 +/- 0.7 kg/m(2)] affected with PHP due to single parathyroid adenoma and 35 normal age-matched subjects (23 women/12 men, mean age 58 years, range 35-68 years, BMI 24.1 +/- 1.1 kg/m(2)).A measure of 1 microg/kg body weight i.v. acylated ghrelin or 1 microg/kg body weight i.v. GH releasing hormone (GHRH) followed by 0.5 g/kg body weight i.v. arginine (ARG) hydrochloride were administered to all subjects on alternate days in order to evaluate GH response.Mean serum GH peak after GHRH + ARG was 32.6 +/- 7.8 and 17.4 +/- 4.0 microg/l, in controls and PHP patients, respectively (P0.05). Mean serum GH peak after ghrelin was 70.4 +/- 31.5 and 16.8 +/- 1.9 microg/l, in controls and PHP patients, respectively, (P0.001). Using ROC curves, a serum GH peak22 microg/l after ghrelin stimulation might be considered as a cut-off value for identifying normal subjects. Ten (67%) PHP patients have impaired GH response to GHRH + ARG and 13 (87%) to ghrelin. Serum GH peak after ghrelin or GHRH + ARG was unrelated to serum IGF-1, PTH or ionized calcium concentrations.The present data confirm that GH secretion is impaired in PHP patients using the potent GH secretagogue ghrelin and suggest that impaired GH secretion is likely due to a deleterious effect of hypercalcaemia at the hypothalamic level in PHP patients.

Twenty two pregnant women with mild to moderate hypertension were treated with betaxolol (10-40 mg/day), a cardioselective beta adrenoceptor blocking agent. The analysis of the changes from the baseline confirmed the antihypertensive effect of the drug with a mean decrease in SBP of 11.8 mm Hg and in DBP of 8.3 mm Hg. A diastolic BP less than 90 mm Hg was obtained in 20 patients after the first day of therapy. Fetal safety, assessed by ultrasonography and cardiotocographic recording was excellent. The 22 mothers gave birth to 23 live born babies (one twin pregnancy). Mean Apgar scores were 8.3 and 9.1 at 1 and 5 min. Only 1 newborn had an Apgar score less than 7. Three newborns suffered from fetal distress and 1 from threat for causes not related to therapy. At 9 months follow-up, all 23 babies were in good health. These data suggest that betaxolol is effective in reducing maternal blood pressure without any deleterious effect on the foetus and the newborn.

Betaxolol levels in blood were monitored in the perinatal period in 28 pregnant hypertensive women and in their babies. In the mothers betaxolol concentrations at delivery ranged from less than 1 to 115 ng.ml-1 after doses of 10 to 40 mg.day-1. The apparent blood half-life was 15.6 to 22.1 h mean (19 h). Umbilical cord levels indicated a rapid equilibrium between fetal and maternal units (ratio 0.93) within few hours after dosing. Milk betaxolol concentrations, measured in few cases, exceeded those in blood by a factor of 3. Amniotic fluid concentrations were similar to those observed in maternal venous blood and umbilical cord blood. In neonates, the blood betaxolol half-life ranged from 14.8 to 38.5 h, with a definite trend towards a negative correlation with gestational age. A 11-61% rise in the betaxolol concentration was observed in 64% of the neonates during the first 12 h of extrauterine life. The data indicate that betaxolol kinetics is not altered in pregnant women and they stress the need for careful and prolonged (72-96 h) intensive monitoring of neonates born to hypertensive mothers treated with beta-blocking agents.

Background: Circulating antipituitary antibodies (APA) are markers of autoimmune hypophysitis, which may cause deficient pituitary function. The prevalence of APA in autoimmune thyroid disorders (AITD) is uncertain. Objectives: The aims of this study were 1) to evaluate APA prevalence in a large series of patients with AITD and non-AITD and 2) to investigate the functional significance of APA by assessing pituitary function in APA-positive patients. Design and Setting: We conducted a health survey on consecutive AITD and non-AITD patients at a tertiary referral center (Department of Endocrinology, Pisa). Patients: Subjects, including 1290 consecutive patients with thyroid disorders (961 AITD and 329 non-AITD) and 135 controls, were enrolled in the study. Methods: APA (indirect immunofluorescence), free T4, free T3, TSH, and organ-specific autoantibodies were assayed in all patients. Functional pituitary evaluation was performed in most APA-positive patients. Results: APA frequency was higher in AITD (11.4%) than in nonAITD (0.9%; P 0.0001) patients; all control subjects had negative APA tests. APA were more frequently found in Hashimoto’s thyroiditis (13%) than in Graves’ disease (7.1%; P 0.05). Of 110 APApositive AITD patients, 20 (18.2%) had autoimmune polyglandular syndrome, whereas 90 (81.8%) had apparently isolated AITD. APA positivity increased percentage of autoimmune polyglandular syndrome in our series from 10.4 to 13.5%. Of 110 APA-positive patients, 102 were submitted to dynamic testing for functional pituitary assessment; 36 patients (35.2%) had mild or severe GH deficiency (GHD). No additional anterior pituitary hormone deficiencies were found; one patient had central diabetes insipidus. Pituitary abnormalities at magnetic resonance imaging were found in most APApositive GHD patients. Conclusions: APA are frequently present in patients with AITD. Patients should be tested for APA because positive tests are associated with GHD. (J Clin Endocrinol Metab 92: 2176–2181, 2007)

Summary Objective ALS is the most common motor neurone disorder in human adults. Scanty data on endocrine abnormalities have been reported. The aim of the present study was to investigate the GH-IGF-I axis in ALS patients. Patients Tw enty-two ALS patients (12 men, 10 women), mean age 61 years, and 25 normal age- and sex-matched subjects. No patient was under riluzole therapy. Measurements Patients and controls underwent a GHRH plus arginine test. IGF-I was determined at baseline. A complete evaluation of pituitary function was also performed. Results Mean ( ± SD) basal GH levels were significantly reduced compared with normal controls (0·2 ± 0·3 vs 1·6 ± 1·8 ng/ml, P < 0·01), as well as peak GH concentrations after GHRH + arginine administration (12·6 ± 8·9 vs 39·9 ± 18·7 ng/ml, P < 0·001). Six (27%) patients showed a normal GH response to stimulus; 7 (32%) patients displayed a moderate GH deficiency; in 9 (40%) patients GH response was markedly deficient. IGF-I levels were normal in the majority of patients (mean ± SD: 143·6 ± 63·8 ng /ml). No significant correlation was observed between peak GH concentrations and age, BMI, disease duration, severity or clinical form. A higher incidence of GH deficiency was observed in male compared to female patients (83% vs 60%), with a peak GH response in males significantly lower than in females (8·9 ± 6·6 vs 17 ± 9·6 ng/ml, P = 0·03). Eighteen patients repeated the test after 5 months and similar results were obtained. Conclusions The present data indicate a reduction of GH secretion in ALS patients.

PTH-related peptide (PTHrP), a member of the PTH family, is widely expressed in foetal and adult tissues, and it has been found in benign and malignant tumors, including GH and PRL-secreting adenomas. Conflicting data are reported in literature on serum PTHrP concentrations in patients with Cushing's disease. The aim of the present study was to further evaluate peripheral and inferior petrosal sinus (IPS) serum PTHrP concentrations before and after CRH, in a group of consecutive patients with ACTH-dependent Cushing's disease. Nine patients with active ACTH-dependent Cushing's disease (8 women and 1 man, age +/- SD 41 +/- 13 yr) were submitted to peripheral and IPS sampling under fluoroscopic control before and after iv administration of CRH. All patients were subsequently submitted to transsphenoidal surgery and an ACTH-secreting microadenoma was found in all cases. In all patients, serum IPS and peripheral ACTH measurement were in keeping with the diagnosis of ACTH-dependent Cushing's disease. Serum PTHrP concentrations before and after CRH stimulation were below the sensitivity limit of the assay in all samples, and no gradient between IPS and peripheral sampling was observed. Our data, combined with others reported in literature, indicate that PTHrP release by ACTH-secreting tumors is not a common occurrence. Therefore, we conclude that IPS and peripheral PTHrP are of little clinical usefulness.

Prostate-specific antigen (PSA) is a serine proteases produced by prostatic epithelial cells detectable in male serum and seminal plasma. PSA is also expressed in some female tissues and fluids and is increased in hirsute women showing a positive correlation with androgens. Accordingly, it has been suggested that PSA might be a marker of androgen action in women. The aim of this observational study was to assess serum PSA concentration in acro megalic women with active disease, in remission or during somatostatin analogs therapy. Forty-four acromegalic women, 15 with active disease, 10 in remission and 19 under long-acting somatostatin analogs therapy were enrolled in the study; 273 normal women matched for age, body mass index, with no signs of hirsutism, served as controls. Serum PSA, 3a-androstanediol (3alpha-AG), total testosterone (T), DHEAS, LH, FSH and estradiol were assessed. No patient or control had been given estrogen or antiandrogen drugs; no acromegalic women had hyperprolactinemia or hypopituitarism. Serum PSA concentration was significantly higher in acromegalic patients than in control subjects (p < 0.0001). Patients with active acromegaly or under somatostatin analogs therapy had significant higher serum PSA concentration than controls, while patients in remission after adenomectomy did not differ. Serum PSA was detectable in serum of 75% acromegalic women and 45% of controls. In addition 24% of acromegalic women had serum PSA concentrations higher than the mean +/- 2SD of control subjects. Differences in serum PSA levels did not reach statistical significance in the different acromegalic subgroups possibly because of the small number of subjects, but patients with active acromegaly had higher serum PSA levels than patients under somatostatin analogs therapy or in remission. Acromegalic women had significantly higher serum PSA concentrations than controls both before and after menopause (p < 0.01). 3alpha-AG (p < 0.05) and T (p < 0.01) were higher in acromegalic than in control subjects in pre-menopause (PM) but not in post-menopause (M). A correlation was found in the whole group of acromegalic patients between serum PSA and 3a-AG concentrations (r = 0.3, p < 0.01). In conclusion, acromegalic is associated with an increase in serum PSA concentrations as a group, although this increase is observed, at an individual level, in only 24% of cases. Patients whose disease is controlled by somatostatin analogs or has been cured by pituitary adenomectomy tend to have lower serum PSA levels than patients with active disease. M patients tend to have lower PSA values than PM women, consistent with the main androgen control of PSA production. However, the observation that M women still have higher serum PSA levels than controls suggest that in acromegaly PSA is regulated not only by androgens but also by the GH/IGF-I system itself.

Background. Self-report data obtained from members of advocate groups for patients with anxiety or mood disorders in 11 countries were used to study time to initial professional help-seeking after incident episodes.Method. Data were taken from 3516 self-administered questionnaires completed by members of GAMIAN, an international consortium of mental health patient advocate groups. Reports about age at onset and age at first seeking treatment were obtained retrospectively.Results. Approximately 40% of respondents reported that they sought treatment in the same year as the first onset of their disorder. The median delay in help-seeking was 8 years for the remainder of respondents. Synthetic cohort analysis suggests that delays have decreased in recent cohorts. However, time to initial help-seeking in all cohorts and all countries was found to be inversely related to age at onset.Conclusions. Although caution is needed in generalizing the results beyond members of patient advocate groups, the key patterns found here were also found in previous analyses of general population surveys carried out in the US and Canada. The critical and consistent finding in all these studies is that presumably curable adolescents with early-onset disorders are, in effect, ignored by the treatment system in these countries. Aggressive outreach and intervention among early-onset cases might prove to be a cost-effective approach both to prevent the onset of secondary disorders and to improve success in treating primary disorders.

The attempt has been made to define the optimal dose regimen of clonazepam in newborns suffering from neonatal convulsions. Results obtained from 22 patients (GA 28-41 weeks; PNA 4 h to 23 days) indicated that a dose of 0.1 mg/kg every 24 h was satisfactory in the majority of the patients. It is recommended as a starting regimen.

A representative sample of 5,622 subjects between 15 and 96 years of age from the noninstitutionalized general population of France were interviewed by telephone concerning their sleeping habits and sleep disorders. The interviews were conducted using the Sleep-Eval knowledge-based system, a nonmonotonic, level 2 expert system with a causal reasoning mode. Questions investigated nightmares, based on the Diagnostic and Statistical Manual, fourth edition (DSM-IV), definition, psychopathological traits, and included 12 other groups of information, including sociodemographics, sleep-wake schedule, daytime functioning, psychiatric and medical history, and drug intake. The data from 1,049 subjects suffering from insomnia were considered for this analysis. Bivariate analyses, logistic regression analysis using the method of indicator contrasts for the investigation of independent variables, and calculation of significant odds ratios were performed. Nightmares were reported in 18.3% of the surveyed insomniac population and were two times higher in women than in men. The following factors were found to be significantly associated with nightmares 1) sleep with many awakenings, 2) abnormally long sleep onset, 3) daytime memory impairment following poor nocturnal sleep, 4) daytime anxiety following poor nocturnal sleep, and 5) being a woman. There was a strong association between the report of nightmares in women and the presence of either a depressive disorder, anxiety disorder, or both disorders together. When the effects of major psychiatric disorders were controlled for, nightmares were significantly associated with being a woman, feeling depressed after a poor night's sleep, and complaining of a long sleep latency. Nightmares can lead to a negative conditioning toward sleep and to chronic sleep complaints. Considering the frequency of nightmares in an adult insomniac population and the significant relationship between nightmares and certain subgroups, nightmares should receive more attention in patients, especially women complaining of disrupted sleep, as high rates of psychiatric disorders were found in this specific group.

In a parallel-group, placebo-controlled, polysomnographic study with randomization, the possible occurrence of rebound insomnia was evaluated in 24 patients suffering from moderate to severe chronic insomnia and receiving either triazolam 0.5 mg, zolpidem 10 mg, or placebo. Treatment duration was 27 nights, followed by three placebo-controlled withdrawal nights. Both drugs showed significant efficacy compared to placebo during the active treatment period. A trend toward tolerance was noted in the triazolam group but not in the zolpidem one. The increase in total sleep time in the zolpidem group was accompanied by an increase in the number of sleep cycles. When active treatment was discontinued, clear rebound insomnia was present in the triazolam group while it was not possible to observe any rebound in the placebo and zolpidem groups. Subjective feelings of the patients, which were assessed by means of visual analog scales, correlated well with polysomnographic data. Our findings tend to indicate that, even after long-term treatment, zolpidem does not induce rebound insomnia or daytime anxiety.

Zolpidem is an imidazopyridine which binds specifically to the omega 1 receptor. Zolpidem demonstrated potent hypnotic activity at a dose of 10 mg. Pharmacodynamics and pharmacokinetics of zolpidem were studied after daytime administration in a randomised, double-blind, placebo-controlled, cross-over trial. Single doses of zolpidem (10 mg IV as a 3-min infusion and 20 mg orally) and placebo were firstly tested in 12 healthy young male volunteers. Two other doses (5 mg IV and orally) were then evaluated in 6 out of these 12 subjects. EEG (4 leads = Fp2-T4, Fp1-T3, T4-02 and T3-01), and Stanford Sleepiness Scale (SSS) were measured up to 5 h postdosing. Blood samples were also collected up to 24 h. The time course of the hypnotic activity of zolpidem, assessed by the score obtained on SSS, showed a similar profile whatever the route or the dose administered: slightly earlier onset after IV but sedative scores were reached at 30 min and the effect peaked between 1 and 1.5 h and lasted 4 h in both conditions. The EEG profile of zolpidem was characterised by a decrease of alpha activity and an increase in delta and in beta activity. The effect on beta activity was marked within the first hour and then disappeared. The time course of delta and alpha activities indicated a rapid onset (10 min after IV, 30 min after oral route) and a duration of 3-4 h. The amplitude of these relative EEG changes and their duration were independent of the route of administration and the dose administered. AUC and Cmax increased proportionally to the administered dose and elimination half life (2h), clearance and volume of distribution did not change according to the dose or the route of administration.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Litoxetine is a selective serotonin reuptake inhibitor with antidepressant activity in animal models and in depressed patients. 2. This double-blind, cross-over, placebo-controlled study was carried out in 12 healthy young male volunteers. The aim was to assess the EEG profile of litoxetine in parallel with its pharmacokinetics after a single dose or multiple administrations for 4 days (6 doses) of two dosages (10 mg and 25 mg). Spectral analysis of four EEG leads (F4-T4, F3-T3, T4-02 and T3-01) was done up to 12 h post-dose. 3. In single or multiple doses, litoxetine induced EEG changes characterised by a dose-related increase in fast beta energies, mainly beta 2, without any changes in slow waves (delta and theta). A slight reduction in alpha activity occurred only after repeated doses. 4. EEG changes occurred after a single oral administration and lasted at least 12 h with litoxetine blood concentrations ranging from 4 to 10 ng ml-1. With repeated administrations, the pharmacodynamic steady-state was achieved as the increase in beta 2 energies was the same before and 12 h post-dose. These effects occurred with litoxetine blood concentrations ranging from 3 to 7 ng ml-1 with the 10 mg dosage and from 8 to 18 ng ml-1 with the 25 mg dosage. The EEG profile did not change after 4 days of repeated administration, indicating that tolerance did not develop. 5. Cmax and AUC showed proportionality between the administered dosages of 10 and 25 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Twelve healthy subjects were enrolled in a double-blind placebo controlled cross-over study in order to assess the possible anticholinergic effects of four doses of a new antihistamine compound, mizolastine, compared with hyoscine butylbromide (HBB) used as a reference anticholinergic drug. 2. Although mizolastine, a potent and selective H1-receptor blocker has no affinity for muscarinic receptors and does not antagonize the effects of carbachol in rodents, a study was initiated to investigate its effects on various effectors possessing muscarinic receptors (eye, heart, sweat gland, salivary gland). 3. HBB (40 mg, s.c.) impaired accommodation, decreased salivary flow and inhibited cardiac sinus arrhythmia. Pupil diameter and maximum constriction speed, carbachol-induced skin sweating and Valsalva ratio were unaffected. 4. Mizolastine (5, 10, 20, 40 mg p.o.) did not affect any parameter at any time point, demonstrating a lack of anticholinergic effect.

The antihistaminic activity, clinical safety, and pharmacokinetics of mizolastine (SL 85.0324) were studied in a 5-way, double-blind crossover study of ten healthy volunteers with doses of 1 to 75 mg. Inhibition of the histamine-induced wheal and flare showed clear dose-dependent antihistaminic activity beginning from the 2-mg dose with a maximum attained between 10 and 20 mg. The onset of action was rapid (one hour) and the effect persisted for more than 24 hours after a 10-mg dose or more. Mizolastine was well tolerated at doses up to 75 mg; subjective and objective signs of transient sedative activity were not observed at doses below 30 mg. The pharmacokinetic profile (rapid absorption with Tmax congruent to 1 h and elimination T1/2 of about eight hours) parallels the pharmacodynamic activity. Within the considered dose range, the pharmacokinetics was linear with no saturation phenomena.

The safety and efficacy of 10 or 20 mg/day zolpidem, a new hypnotic belonging to the imidazopyridine class, were studied over a 180-day period in 96 patients with sleep disorders. The treatment was continued for a further 180 days by 49 of these patients. Follow-up information from 21 patients who discontinued treatment after 180 days showed no rebound insomnia or withdrawal signs. Efficacy of treatment with respect to reduction of sleep onset latency and number of nocturnal wakenings, and improvement in duration of sleep, quality of sleep and morning wakenings was found in nearly 90% of patients and was maintained in those patients who continued treatment for 360 days. This efficacy was achieved with a stable percentage of patients receiving 10 mg/day and 20 mg/day zolpidem from day 30 to the final visit. Zolpidem, therefore, has been shown to be an effective and safe hypnotic, and to be devoid of rebound and withdrawal effects. La sécurité d'utilisation et l'efficacité du 10 ou 20 mg par jour de zolpidem, un nouvel hypnotique appartenant à la classe des imidazopyridines, ont été étudiées sur une période de 180 jours chez 96 patients souffrant de troubles du sommeil. Le traitement s'est poursuivi pendant 180 jours supplémentaires chez 49 de ces patients. Le suivi de 21 patients ayant cessé le traitement au bout de 180 jours n'a montré ni rebond d'insomnie, ni syndrome de sevrage. L'efficacité du traitement se mesure par la reduction du temp d'endormissement et le nombre de réveils noctures, ainsi que l'amélioration de la durée du sommeil, de la qualité du sommeil et du réveil au matin ont été retrouvés chez près de 90% des patients; ces effets se sont maintenus chez les patients qui ont poursuivi le traitement pendant 360 jours. Cette efficacité a été obtenue pour un pourcentage assez constant de patients qui ont reçu 10 mg par jour de zolpidem, puis 20 mg par jour du 30 ème jour à la fin du traitement. Pour ces raisons, le zolpidem, s'est donc révélé être un hypnotique efficace et sûr, dépourvu d'effets de rebond et de sevrage.

Diltiazem undergoes extensive first-pass metabolism; extrapolation from single to repeated administration thus underestimates plasma concentration values. In order to validate the hypothesis of a partially saturable first-pass effect, four single doses of diltiazem (10, 20, 40, and 120 mg) were administered at weekly intervals to eight healthy volunteers. Results showed that: (a) the inter-subject variability was highest at the lowest dose and lowest at the highest dose; (b) bioavailability was almost nil in 3 of 8 of the subjects after the administration of the 10 mg dose; (c) the mean bioavailability increased with the dose from 11·8 ± 2·5 per cent after 10 mg to 28·2 per cent after 120 mg; (d) the elimination half-life was dose-related; (e) the renal excretion of diltiazem increased with the administered dose from 1.0 ± 0·3 per cent after 10 mg to 3·0 ± 0·5 per cent after 120 mg; (f) the greatest amounts of circulating metabolites were present after the lowest doses. These results are consistent with a partially saturable first-pass effect for diltiazem.

We studied 142 patients (121 males, 21 females) survivors of a first non complicated acute myocardial infarction (AMI) treated with thrombolytic therapy between March 1988 and December 1989. Dipyridamole echocardiography test (DET, 67 patients) and exercise electrocardiography test (EET, 104 patients) were performed to assess sensitivity and specificity in identifying patients at risk for an unfavorable clinical outcome and subsequent cardiac events: 67 patients underwent coronary arteriography within 4 weeks after AMI. DET positivity was related to the detection of a new transient asynergy of contraction either in infarct area or in remote zones. The mean follow-up period was 12 months (range 4-20). Clinical follow-up end-points of the study included death, re-AMI, angina. Sensitivity and specificity of EET and DET were 75 and 68%, 53 and 71% respectively. If EET plus DET were considered, sensitivity was 81% and specificity 60%. The fairly good DET sensitivity and specificity could be partially explained by some stunned myocardium exhibiting prolonged contractile dysfunction despite myocardial reperfusion. EET sensitivity and specificity is comparable to previous observations in AMI not treated with thrombolytic therapy. DET seems to be a useful and safe test in prognostic evaluation of asymptomatic patients after thrombolysed AMI, but its value is improved in association with EET.

Overnight blood sampling for repeated growth hormone (GH) assays, regarded as the most physiological assessment of GH status, may induce some disturbances in patients' sleep and then in the evaluation of GH secretion. We studied the influence of a hypnotic drug, zolpidem (10 mg), on nocturnal GH profiles (GH peak, time to first and maximum GH peak, area under the curve, mean integrated concentration) over two nights at a 7-day interval, in a double-blind cross-over design in a group of 12 young adult volunteers (27.9 +/- 4.3 years), and in a group of 12 children (10.8 +/- 2.3 years) with short stature, in a parallel double-blind study. Mean GH profiles showed no difference between zolpidem-treated subjects and placebo-treated controls, either in adults or in children. Although in these experimental conditions, sleep onset latency was significantly reduced with zolpidem in the adult volunteers, the mean time to first GH peak remained unchanged. Furthermore, GH profile did not relate with sleep duration, sleep onset latency or number of awakenings. A hypnotic drug, such as zolpidem, given at bedtime, is therefore devoided of effect on nocturnal GH profile and may be used in young children for overnight blood sampling when needed.

In a double-blind, placebo-controlled, cross-over experiment in 21 healthy male volunteers, aged 19 to 27 y, the pharmacokinetics and tolerance of the new anxiolytic drug alpidem (SL80.0342) and its three major metabolites were studied after single doses of 25, 50, 100 and 200 mg. Plasma concentrations of alpidem (in 20 subjects) and metabolites (in 6 subjects) were measured by HPLC over a period of 54 h after dosing. Cmax, tmax and AUC(0-54) and, when possible, t1/2 were determined for alpidem and metabolites and the dose linearity of the parameters was investigated. The time to peak of alpidem was dose independent in most subjects and was short (1-4 h); the mean values at the four dosing levels were 1.9, 1.7, 1.6 and 1.8 h. The peak concentration increased with the dose, the mean values being 17, 34, 88 and 115 ng.ml-1, respectively. In 50% of the subjects Cmax tended to stabilize between the 100 and 200 mg dose. Dose linearity was also present for the AUC, which plateaued between the 100 and 200 mg dose in only 3 out of 20 subjects; the mean AUC was 119, 281, 669 and 1117 ng.ml-1.h, respectively. The apparent half-life of elimination appeared to be dose independent, mean values at the increasing dosing levels being 18.7, 19.9, 18.1, and 17.9 h. A similar relationship between the kinetics parameters and dose of the alpidem was observed for the metabolites SL83.0912, SL80.0522 and SL83.0725. The formation of metabolites was not saturated as their AUCs relative to corresponding alpidem AUCs were not dose related.(ABSTRACT TRUNCATED AT 250 WORDS)

The results of a double-blind clinical trial of fengabine vs clomipramine in depressed outpatients are reported. Fengabine, a new GABAergic agent, seems to be as effective as the reference drug, with a faster onset of action and a more marked effect on cognitive disturbances and retardation. The new drug is free of any significant anticholinergic or cardiovascular effect, and it is not sedative.

1. Cicloprolol is a partial beta 1-adrenoceptor agonist considered for the treatment of patients with coronary artery disease and impaired left ventricular function. In such patients, digoxin remains in widespread use. 2. We assessed the pharmacokinetic and pharmacodynamic interaction between oral cicloprolol 50 mg day-1 and oral digoxin 0.25 mg day-1 in 10 healthy male volunteers, using a double-blind, randomised protocol, during three 8 day periods. Digoxin was given alone during the first period to reach steady state; then digoxin was given with cicloprolol or placebo during the second and third periods, according to a cross-over design. 3. No significant adverse effects were observed. 4. The pharmacokinetics of digoxin were not different significantly at the end of the placebo-digoxin and cicloprolol-digoxin periods. 5. A significant increase in minimum heart rate and mean nocturnal heart rate, assessed by 24 h Holter recordings, was observed at the end of the cicloprolol-digoxin period as compared with the placebo-digoxin period (means +/- s.e. mean, 57.1 +/- 3.2 beats min-1 vs 52.2 +/- 3.1 beats min-1, P less than 0.01; and 65.6 +/- 3.8 beats min-1 vs 59.9 +/- 3.9 beats min-1, P less than 0.01, respectively). 6. A significant increase in left ventricular ejection fraction and shortening fraction, assessed by echocardiography, was noted at the end of the cicloprolol-digoxin period as compared with the placebo-digoxin period (means +/- s.e. mean, 66.4 +/- 1.4% vs 61.3 +/- 1.2%, P less than 0.05; and 37.0 +/- 1.1% vs 33.3 +/- 0.9%, P less than 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

In this double-blind study, alpidem, a new imidazo-pyridine anxiolytic drug, was compared with placebo in order to test its efficacy and safety in chronic schizophrenic in-patients suffering from anxiety not directly related to the schizophrenic process. Sixty-six patients aged from 18 to 65 entered the trial. They also scored at least 18 on the Hamilton Rating Scale for Anxiety (HRSA) after a seven-day placebo run-in. Improvement in symptoms was evaluated by means of the HRSA, the Brief Psychiatric Rating Scale (BPRS), a Visual Analogue Scale (VAS), and the Clinical Global Impression score (CGI). Thirty-three patients were randomly allocated to alpidem and 33 to placebo. Alpidem was significantly more effective (P less than 0.0001) than placebo in improving HRSA scores (total score and factorial scores for somatic and psychic anxiety), BPRS, and VAS. Considering the results of CGI at 21 day, more patients were moderately to markedly improved on alpidem (30/33) than on placebo (2/33) (P less than 0.0001). The efficacy index, according to CGI, was significantly better (P less than 0.001 at least) for alpidem than for placebo. Side-effects were negligible in both groups.

Diazepam (DZ) placental transfer in pregnant women at term, following single or repeated drug administration by various routes, was evaluated. DZ and its metabolite N-demethyldiazepam (NDZ) were constantly present in umbilical cord plasma at concentrations comparable to the mother's shortly after drug administration. N-methyloxazepam (MOX) was detected in cord plasma only in a limited number of cases following chronic DZ treatment. Postmortem analysis of fetal tissue concentrations showed accumulation of NDZ in heart and lungs. Differences in NDZ concentrations between venous cord (VC) and arterial cord (AC) plasms suggest metabolic degradation of DZ in the fetus. The DZ apparent plasma half-life in the newborn was found to be longer (31 plus or minus 2 hr) than previously observed in infants and children. The low drug clearance appears to be linked to reduced urinary excretion of hydroxylated metabolites, suggesting limited capability to dispose of DZ in the newborn.

The results of two trials conducted in human dyskinesia with progabide, a specific gamma-aminobutyric acid (GABA) receptor agonist, are reviewed. In one trial, 13 parkinsonian patients with L-DOPA-induced dyskinesia (LDD) and "on-off" fluctuations were included in a double-blind controlled trial progabide versus placebo. No change was observed during this trial in the severity of dyskinesia on progabide treatment but the drug significantly extended the "on" period as compared with placebo. In the second trial, 20 patients with neuroleptic-induced dyskinesia (TD) entered an open dose ranging trial with progabide. Fourteen of the 16 patients who completed the trial had a good-to-excellent therapeutic response. According to these results, progabide does not seem to have the same therapeutic benefit in LDD as TD. These data suggest that the hypothesis of a dopaminergic supersensitivity as a similar pathogenic substrate for both clinical conditions should be reconsidered. If this hypothesis remains the most consistent to explain the occurrence of LDD, the therapeutic effect of progabide in TD is an argument for an implication of the GABAergic system in the appearance of TD.

The literature data available on pethidine and norpethidine kinetics in women in labour and in their newborns is reviewed and compared with recent personal observations. In pregnant women the apparent blood half-life of pethidine is not different from that in healthy controls, however, apparent volume of distribution and total body clearance are reduced. Norpethidine blood levels are measurable after 10–20 min and tend to increase with time. The amount of drug transferred to the foetus is clearly linked to the dose administered to the mother, the dosing-delivery interval and to the metabolic capability of the mother. An equilibrium between maternal and umbilical venous blood is reached 2–3 h after dosing for pethidine and later for norpethidine. In the neonate, the apparent pethidine half-life is 2 to 7 times longer than in adults with values ranging from 7 to 32 h. Norpethidine is actively formed in the newborn with peak blood levels at 12–36 h and an apparent blood half-life of 20–36 h. At the doses usually recommended blood concentrations at birth are frequently higher than those required for analgesia and close to or within toxic ranges. An effort toward a more individualized dosage as well as toward a better understanding of the possible role of norpethidine with regard to adverse effects is needed.

Patients on long term valproate treatment exhibit unusual fluctuations in steady-state plasma levels of valproic acid. In order to delineate the underlying mechanisms of these fluctuations, 2 studies were undertaken. In the oral study, 6 epileptic patients received enteric-coated sodium valproate tablets (on a bid regimen for at least 1 month) and plasma levels were monitored on an hourly basis during 24 hours. In the intravenous study, 5 patients received first an intravenous bolus dose (800mg) of sodium valproate followed a week later by a combination intravenous loading dose/constant rate infusion for 36 hours. Plasma valproic acid concentrations were monitored hourly during the infusion study. In the oral study, valproic acid concentrations in all subjects continued to decay for 5 to 6 hours following the 8pm dose. The mean fluctuation in concentrations during 24 hours was 112.8 +/- 31.6%. Consecutive fasting levels were not reproducible. In the intravenous study, small but significant oscillations were present at steady-state; fluctuations ranged from 22 to 34%. However, no circadian rhythm was apparent. On the basis of these findings, it appears that the value of a single fasting sample during therapeutic monitoring of valproic acid is questionable. For an accurate evaluation of valproic acid plasma levels, an average concentration based upon several daily determinations should be performed.

Carbamazepine (CBZ) binding by human plasma proteins was studied by means of three different techniques : ultrafiltration, equilibrium dialysis and MSA (Microspheres of Serum Albumin). The validity of the new MSA procedure for determining binding parameters was confirmed. The effects of plasma dilution and of temperature were also investigated. The association constant for albumin was found to be relatively low : 1.35 × 10 3 l/mole with an n value of 1.06 sites/mole. The data suggest that other proteins may be implicated in CBZ binding by human plasma. For concentrations within the therapeutic range (5–30 μg/ml) the unbound fraction of CBZ was 24%.

In order to evaluate immediate recall and learning in epileptic patients, four tests were chosen: Wechsler's memory span for digits, graphic reproduction of geometric figures from the Wechsler Memory Scale, learning of a list of words from the Rey Memory Scale, and recognition of these words. These tests were performed on 200 epileptic patients over the age of 15 years, without defined cerebral lesions, and with a normal or subnormal social adjustment. Memory impairment was analyzed with respect to the following variables: seizure frequency, seizure type, duration of the disorder, and anticonvulsant medication. Patient data were compared with values obtained for a population of 100 normal subjects matched for age and level of education. Comparison between epileptics and controls clearly demonstrated a statistically significant memory impairment in the group of patients. However, the reasons for these poor performances are not clear, and none of the studied parameters (type of epilepsy, frequency of seizures, duration of the disease, and medication), if considered alone, accounts for this impairment.