Reducing cardiovascular risk in immune-mediated inflammatory diseases: Tumour necrosis factor inhibitors compared to conventional therapies-A systematic review and meta-analysis.

Immune-mediated inflammatory disease (IMID) patients including psoriasis, inflammatory arthritides and bowel diseases have a higher risk of developing cardiovascular (CV) diseases compared to the general population. The increased CV risk may be promoted by tumour necrosis factor (TNF)-α-mediated immunological processes, which are present both in the pathomechanism of IMIDs and atherosclerosis. Our objective was to comprehensively investigate the effect of TNF inhibitors (TNFi) on CV risk compared with conventional therapies in IMIDs. The systematic literature search was conducted in three databases (MEDLINE, EMBASE, Cochrane Library) on 14 November 2022. Randomized controlled trials, cohort and case-control studies were eligible for inclusion. Outcomes consisted of the incidence of CV events, with major adverse cardiovascular events (MACE) as a main endpoint. A random-effects meta-analysis was performed by pooling fully adjusted multivariate hazard ratios (HR) and incidence rate ratios (IRR) with a 95% confidence interval (CI) comparing TNFis with conventional systemic non-biologicals (CSNBs). Of a total of 8724 search results, 56 studies were included overall, of which 29 articles were eligible for the meta-analysis, and 27 were involved in the systematic review. Including all IMIDs, the TNFi group showed a significantly reduced risk of MACE compared with the CSNB group (HR = 0.74, 95% confidence interval (CI) 0.58-0.95, p = 0.025; IRR = 0.77, 95% CI 0.67-0.88, p < 0.001). Subgroup analysis of Pso, PsA patients by pooling IRRs also confirmed the significantly decreased risk of MACE in TNFi-treated patients compared with CSNB groups (IRR = 0.79, 95% CI 0.64-0.98). The observational nature of most included studies leading to high heterogeneity represents a limitation. Based on the results, TNFis may reduce the risk of CV events compared to CSNBs. Therefore, earlier use of TNFis compared to conventional systemic agents in the therapeutic sequence may benefit CV risk in IMID patients.

Design and rationale of the atrial fibrillation occurring transiently with stress (AFOTS) incidence study.

BACKGROUND: Atrial fibrillation (AF) is often detected for the first time in patients hospitalized for medical illness or non-cardiovascular surgery. AF occurring transiently with stress (AFOTS) describes this manifestation of AF, which may either be the result of a non-cardiac stressor, or existing paroxysmal AF that was not previously detected. Current estimates of AFOTS incidence are imprecise: ranging from 1 to 44%, owing to the marked heterogeneity in patient populations, identification and methods used to detect AFOTS. METHODS: The prospective, two-centre epidemiological AFOTS Incidence study will enroll 250 consecutive participants without a history of AF but with at increased risk of AF (Age ≥ 65 or >50 with one risk factor for AF) admitted to intensive care units (ICUs) for medical illness or non-cardiac surgery. Upon admission, participants will wear an ECG patch monitor that will remain in place for 14 days, or until discharge from hospital. Patients' consent to participation is deferred for up to 72 h after admission. The primary endpoint is the incidence of AF lasting ≥30 s. The study is powered to detect an AF incidence of 17% ±â€¯5%. RESULTS: We conducted a vanguard feasibility study, and 55 participants have completed participation. The median duration of monitoring was seven days. AF was detected by the clinical team in 8 participants (14%; 95% Confidence Interval 7-26%). CONCLUSIONS: The AFOTS Incidence study will employ a systematic and highly sensitive protocol for detecting AFOTS in medical illness and non-cardiac surgery ICU patients. This study is feasible and will provide a reliable estimate of the true incidence of AFOTS in this population.

Laparoscopic fellowship training can deliver a competent laparoscopic surgeon and trainer.

AIM: The study investigated whether experience gained during a UK laparoscopic colorectal fellowship enabled the fellow subsequently to train consultant colleagues in laparoscopic surgery. METHOD: In one unit a newly appointed post-laparoscopic fellowship consultant (PFC) mentored his other two colleagues. Prospectively collected data regarding surgical outcome were compared with those of the year preceding the PFC appointment. RESULTS: In the preceding year 18.5% of 260 resections were attempted laparoscopically. This increased to 92.6% (of 270) in the year after (P < 0.0001). Respective conversion rates were 4.2% and 8.4% (P = 0.5524). In the first 6 months after PFC appointment, mentored consultants performed 23 supervised cases. In the second 6 months they carried out 58 procedures independently and trainees performed 38 supervised cases. There was no significant difference in anastomotic leakage and readmission and 30-day mortality rates between the pre- and post-PFC periods. CONCLUSION: A laparoscopic fellowship enables the PFC to mentor consultant colleagues safely and effectively.

Genetically determined neuropathy (CMT 1A) accompanied by immune dysfunction: a case report.

Peripheral Myelin Protein 22 (PMP22) is mostly expressed in Schwann cells where it is essential in the compaction of myelin. The duplication of the PMP22 gene results in a hereditary demyelinating neuropathy of the Charcot-Marie-Tooth type 1A (CMT1A). So far there are only a few case reports suggesting that dysimmune mechanisms may take part in the pathophysiology of this disease. We describe three siblings carrying the duplication of the PMP22 gene, with a significant reduction of serum immunoglobulin G levels in all three cases and sural nerve vasculitis in the two women, which supports the proposition, that immune dysfunction may accompany this disease in some cases.

Novel mechanisms of growth hormone regulation: growth hormone-releasing peptides and ghrelin.

Growth hormone secretion is classically modulated by two hypothalamic hormones, growth hormone-releasing hormone and somatostatin. A third pathway was proposed in the last decade, which involves the growth hormone secretagogues. Ghrelin is a novel acylated peptide which is produced mainly by the stomach. It is also synthesized in the hypothalamus and is present in several other tissues. This endogenous growth hormone secretagogue was discovered by reverse pharmacology when a group of synthetic growth hormone-releasing compounds was initially produced, leading to the isolation of an orphan receptor and, finally, to its endogenous ligand. Ghrelin binds to an active receptor to increase growth hormone release and food intake. It is still not known how hypothalamic and circulating ghrelin is involved in the control of growth hormone release. Endogenous ghrelin might act to amplify the basic pattern of growth hormone secretion, optimizing somatotroph responsiveness to growth hormone-releasing hormone. It may activate multiple interdependent intracellular pathways at the somatotroph, involving protein kinase C, protein kinase A and extracellular calcium systems. However, since ghrelin has a greater ability to release growth hormone in vivo, its main site of action is the hypothalamus. In the current review we summarize the available data on the: a) discovery of this peptide, b) mechanisms of action of growth hormone secretagogues and ghrelin and possible physiological role on growth hormone modulation, and c) regulation of growth hormone release in man after intravenous administration of these peptides.

Age-related changes in acute central leptin effects on energy balance are promoted by obesity.

Leptin is a key catabolic regulator of food intake (FI) and energy expenditure. Both aging and obesity have been shown to induce leptin-resistance. The present study aimed to analyze age-related changes in the anorexigenic and hypermetabolic responsiveness to acute intracerebroventricular leptin administration in different age-groups of normally fed male Wistar rats (adult and old rats from 3 to 24months of age, NF3 to NF24, respectively). The expressions of the long form of the leptin receptor (Ob-Rb) and inhibitory SOCS3 genes were also assessed by quantitative RT-PCR in the arcuate nucleus (ARC). The influence of high-fat diet-induced obesity (HF) on the anorexigenic leptin effects were also tested in younger and older middle-aged groups (HF6 and HF12). Leptin-induced anorexia varied with age: leptin suppressed re-feeding FI (following 48-h fasting) strongly in young adult (NF3), but not in younger or older middle-aged (NF6 or NF12) or in aging (NF18) rats. However, anorexigenic leptin effects reached statistical significance again in old NF24 rats. Leptin-induced hypermetabolism, on the other hand, showed monotonous age-related decline and disappeared by old age. Ob-Rb expression declined until 12months of age followed by a partial recovery in NF18 and NF24 groups. On the other hand, SOCS3 expression was high in NF6 and NF18 and to some extent in NF24 rats. Age-related alterations of Ob-Rb and SOCS3 expression in the ARC may partly contribute to the explanation of age-related variations in anorexigenic but not hypermetabolic leptin effects. High-fat diet-induced obesity was associated with resistance to leptin-induced anorexia in HF6, similar to that seen in NF6. However, instead of the expected leptin-resistance in HF12, a strong leptin-induced suppression of re-feeding was detected in these obese middle-aged rats. Our results suggest that acute central effects of leptin on anorexia and hypermetabolism change in disparate ways during aging, implying separate mechanisms (e.g. signal transduction pathways) of different leptin actions. The age-related pattern shown by leptin-induced anorexia may contribute to the explanation of middle-aged obesity, and partly to that of aging anorexia. Our findings concerning obese rats are in accord with previous observations on anorexigenic effects of peripherally administered cholecystokinin: diet-induced obesity appeared to accelerate the development of age-related regulatory alterations. Similarly, our present data also raise the possibility that chronic diet-induced obesity promotes responsiveness to centrally applied leptin at least concerning anorexigenic effects.

Multiple copies of identical epitopes on the adenovirus hexon.

A double monoclonal antibody (MAb) sandwich enzyme-linked immunosorbent assay (double MAb ELISA), which uses the same MAb as solid-phase immunosorbent (capture MAb) and as detector MAb (peroxidase-labeled), was developed to quantify the specific epitopes of adenovirus hexon. Four MAbs directed against crystallized adenovirus type 1 (Ad h 1) hexon were tested by this assay with homologous and different heterologous hexons. The lowest reacting concn with the homologous and heterologous hexon types both in direct and double MAb ELISA was determined and compared. At least two copies of four different epitopes were identified by the MAbs. Evidence is presented that more than one copy of identical or closely related epitopes exist on the homologous as well as on the heterologous hexon molecules. However, their presence could be detected only in higher concn of hexon preparations of subgenera A, B and D.

Differentiation of adenovirus hexon epitopes with monoclonal antibodies by gel diffusion assays.

Nine monoclonal antibodies (MAbs) directed against crystallized human adenovirus type 1 (Ad h 1) hexon were tested with purified homologous and heterologous hexon preparations by gel diffusion. Six MAbs formed a single line with the homologous hexon in a 2-well pattern, and 3 MAbs formed lines only in biclonal combinations with an appropriate MAb. All of the 6 precipitating MAbs formed a continuous line of complete identity when tested simultaneously against homologous and different heterologous hexons. With Ad h 1 hexon a line of double partial identity (double spur) was formed when some pair combinations of 2 MAbs were placed in 2 juxtaposed wells. Other MAbs in the adjacent wells formed a line of identity. The MAbs could be divided into 2 antibody groups (groups A and B) based on this phenomenon. Members of antibody groups A and B apparently identified 2 sterically distinct epitopes: one of them is presumably the genus-specific epitope of the hexons (group A) and the other(s) should be intertype-specific epitope(s). Thus, the gel diffusion method can be used for selecting pairs of MAbs for their specificity to sterically independent epitopes. Mixtures of 2 MAbs belonging to the different antibody groups formed double lines with Ad h 1 hexons. Members of group A showed some helper effect to the members of group B for their precipitin line formation.

Mechanisms of calcitonin-induced growth hormone (GH) suppression: roles of somatostatin and GH-releasing factor.

Calcitonin (CT) binds to specific receptors in the hypothalamus and has been localized in the pituitary, suggesting a potential neuroendocrine role for this peptide. We and others have previously shown that CT given centrally markedly suppresses pulsatile GH secretion. However, the mechanism mediating this response remains to be elucidated. In the present study, we assessed the involvement of the two hypothalamic GH-regulatory peptides, somatostatin (SRIF) and GH-releasing factor (GRF), using a combination of in vivo and in vitro techniques. Six-hour GH secretory profiles were obtained from eight groups of freely moving rats bearing chronic intracerebroventricular (icv) and intraatrial cannulae. In four groups, salmon (s) CT (250 ng/10 microliters) was administered icv, whereas the remaining four groups received either normal saline (NS) icv or sCT iv. Central injection of sCT caused a severe suppression in amplitude of spontaneous GH pulses compared to NS icv-treated control rats, whereas the same dose of sCT iv had no significant effect. Passive immunization of sCT icv-injected rats with a specific antiserum to SRIF failed to restore the amplitude of GH pulses to normal values. In addition, in vitro basal and 50 mM K+-stimulated SRIF release from incubated hypothalamic fragments was not altered by sCT in doses ranging from 10(-10) to 10(-6) M. The iv administration of a bolus of rat GRF (1-29)NH2 (1 microgram) 1 h after sCT icv injection also failed to augment plasma GH levels compared to sCT iv-treated rats (16.6 +/- 10.0 vs. 326.6 +/- 63.6 ng/ml; P less than 0.001) and NS icv controls (407.2 +/- 145.4 ng/ml; P less than 0.01). Blood calcium levels decreased similarly 1 h after iv and icv sCT administration. These results demonstrate that: sCT inhibits pulsatile GH secretion via a central nervous system site of action, GH suppression induced by sCT is apparently not due solely to increased hypothalamic SRIF release, and centrally administered sCT produces an acute loss of responsiveness of somatotrophs to GRF, which can be dissociated from peripheral blood calcium levels.

Paradoxical enhancement of pituitary growth hormone (GH) responsiveness to GH-releasing factor in the face of high somatostatin tone.

Pituitary GH secretion is regulated by a delicate interplay between stimulatory (GRF) and inhibitory [somatostatin (SRIF)] hypothalamic hormones, although the nature of the GRF/SRIF interaction remains to be elucidated. In the present study, we documented a significant elevation of plasma SRIF-like immunoreactivity in 72-h fasted rats compared to that in fed controls (129.0 +/- 17.9 vs. 38.2 +/- 5.8 pg/ml; P less than 0.01) and used this model of high SRIF tone to further delineate the interrelation between GRF and SRIF in physiological regulation of pulsatile GH secretion. We examined pituitary GH responsiveness to GRF, both in vivo and in vitro, after 72-h exposure to nutritional deprivation and high SRIF secretion. In vivo, GRF-induced GH release was markedly enhanced in the face of high circulating SRIF; freely moving, starved rats released 4- to 8-fold more GH than fed controls in response to rat GRF iv. In vitro, both basal and human GRF-induced GH release were augmented 2- to 4-fold in perifused dispersed anterior pituitary cells of starved rats compared to those in fed controls, and this enhanced responsiveness persisted in the presence of 10(-9) M SRIF. These results demonstrate that SRIF not only inhibits GH secretion stimulated by GRF, but that under different temporal conditions SRIF may act in a paradoxically positive manner to sensitize pituitary GH responsiveness to GRF. Such a cooperative interaction of the two peptides may be necessary to optimize pulsatile GH release. Our findings provide support for the hypothesis that the temporal patterning of hypothalamic GRF/SRIF signals to pituitary somatotrophs may be the major determinant for pulsatile GH secretion and, ultimately, body growth.

Effects of short-term glucocorticoid deprivation on growth hormone (GH) response to GH-releasing peptide-6: studies in normal men and in patients with adrenal insufficiency.

There are no data in the literature about the effects of glucocorticoid deprivation on GH-releasing peptide-6 (GHRP-6)-induced GH release. The aims of this study were to evaluate GH responsiveness to GHRP-6 1) after metyrapone administration in normal men, and 2) in patients with chronic hypocortisolism after glucocorticoid withdrawal for 72 h. In normal subjects, metyrapone ingestion did not alter significantly GH responsiveness to GHRP-6 [n = 8; peak, 39.3 +/-7.1 microg/L; area under the curve (AUC), 1958.8 +/- 445.7 microg/min x L; mean +/- SE] compared to placebo (n = 8; peak, 21.9 +/- 4.5; AUC, 1131.0 +/- 229.6). In patients with chronic hypocortisolism (n = 8), GH responses to GHRP-6 were similar both during replacement therapy (peak, 11.8 +/- 3.9; AUC, 563.2 +/- 208.7) and after withdrawal of prednisone (peak, 14.4 +/- 4.5; AUC, 695.6 +/- 272.9) and did not differ from those in controls. Interestingly, after glucocorticoid withdrawal, GH responsiveness to GHRP-6 in patients with chronic hypocortisolism was significantly lower than that in normal subjects pretreated with metyrapone. Our data suggest that short term glucocorticoid deprivation does not have a major impact on GHRP-6-dependent GH-releasing mechanisms. However, in long standing hypocortisolism, subtle changes in GHRP-6 secretory pathways may be present.

Different growth hormone (GH) response to GH-releasing peptide and GH-releasing hormone in hyperthyroidism.

Altered GH responses to several pharmacological stimuli, including GHRH, have been found in hyperthyroidism. The mechanisms underlying these disturbances have not been fully elucidated. GH-releasing peptide-6 (GHRP-6) is a synthetic hexapeptide that specifically stimulates GH release both in vitro and in vivo. The mechanism of action of GHRP-6 is unknown, but it probably acts by inhibiting the effects of somatostatin on GH release. The aim of this study was to evaluate the effects of GHRP-6 on GH secretion in patients with hyperthyroidism (n = 9) and in control subjects (n = 9). Each subject received GHRP-6 (1 microg/kg, iv), GHRH (100 microg, iv), and GHRP-6 plus GHRH on 3 separate days. GH peak values (mean +/- SE; micrograms per L) were significantly lower in hyperthyroid patients compared to those in control subjects after GHRH alone (9.0 +/- 1.3 vs. 27.0 +/- 5.2) and GHRP-6 plus GHRH (22.5 +/- 3.5 vs. 83.7 +/- 15.2); a lack of the normal synergistic effect of the association of both peptides was observed in thyrotoxicosis. However, a similar GH response was seen in both groups after isolated GHRP-6 injection (31.9 +/- 5.7 vs. 23.2 +/- 3.9). In summary, we have shown that hyperthyroid patients have a normal GH response to GHRP-6 together with a blunted GH responsiveness to GHRH. Our data suggest that thyroid hormones modulate GH release induced by these two peptides in a differential way.

Dynamic evaluation of prolactin secretion in essential hypertension: evidence against hypothalamic-pituitary dopaminergic dysfunction.

Hyperprolactinemia has previously been noted in patients with essential hypertension and it has been suggested that the increased PRL levels in this condition may reflect reduced central dopaminergic activity. In the present study, PRL secretion was evaluated in 17 patients with essential hypertension and in 9 normal controls as an indirect index of hypothalamic-pituitary dopaminergic activity. PRL levels were measured basally, at night, and after TRH (200 micrograms, iv), metoclopramide (10 mg, orally), and L-dopa (500 mg, orally). Basal PRL levels were similar in both groups [essential hypertension, 301.2 +/- 176.2 microunits/ml; controls, 334.2 +/- 98.8 microunits/ml (mean +/- SD)]. No differences in PRL levels were found after TRH, L-dopa, and metoclopramide or during sleep between the 2 groups. When the patients were classified according to their PRA, no differences were noticed in either basal levels or the patterns of PRL response. It is concluded that PRL secretion is normal in patients with essential hypertension, which could be indirect evidence against reduced hypothalamic-pituitary dopaminergic activity in this disease. However, minor abnormalities not detected by PRL measurements could be involved in the pathogenesis of essential hypertension.

Taguchi optimisation of ELISA procedures.

We propose a new method in the field of ELISA optimization using an experimental design called the Taguchi method. This can be used to compare the net effects of different conditions which can be both qualitative and quantitative in nature. The method reduces the effects of the interactions of the optimized variables making it possible to access the optimum conditions even in cases where there are large interactions between the variables of the assay. Furthermore, the proposed special assignment of factors makes it possible to calculate the biochemical parameters of the ELISA procedure carried out under optimum conditions. Thus, the calibration curve, the sensitivity of the optimum assay, the intra-assay and inter-assay variability can be estimated. The method is fast, accessing the results in one step, compared to the traditional, time-consuming 'one-step-at-a-time' method. We exemplify the procedure with a method to optimize the detection of ScFv (single chain fragment of variable) phages by ELISA. All the necessary calculations can be carried out by a spreadsheet program without any special statistical knowledge.

Effects of dopamine and morphine on immunoreactive somatostatin and LH-releasing hormone secretion from hypothalamic fragments in vitro.

Dopamine and morphine modulate GH and LH release, probably at a hypothalamic locus. To investigate this in more detail, we studied the influence of these substances on somatostatin and LH-releasing hormone (LHRH) release from rat hypothalamic fragments in vitro. Hypothalamic fragments were incubated in Earle's medium. After 60 min of preincubation, medium from two 20-min incubations was collected and somatostatin and LHRH levels measured by radioimmunoassay. Dopamine (10 nmol/1-0.1 mmol/l) induced a progressive increase (r = 0.41; P less than 0.01) in basal somatostatin levels. K+ (30 mmol/l)-induced somatostatin release was also increased (r = 0.54; P less than 0.01) by increasing doses of dopamine. Metoclopramide (10 mumol/l) blocked the dopamine (1 mumol/l)-induced increase in somatostatin release. No significant relationship between dopamine and LHRH was found either basally or after K+ (30 mmol/l) stimulation. Basal somatostatin was negatively correlated (r = -0.63; P less than 0.01) with morphine concentrations. No significant correlation was found after K+ (30 mmol/l) depolarization. Basal LHRH release was not influenced by morphine, while K+ (30 mmol/l)-induced release was significantly lower than controls only at a concentration of 10 nmol/l. These results suggest that dopamine and morphine act at a hypothalamic level to modulate GH release through alterations in somatostatin secretion. Dopamine and morphine have no consistent effect on hypothalamic LHRH release.

H-Y antigen in 46,XY pure testicular dysgenesis.

Clinical, cytogenetic, pathologic, and histocompatibility-Y (H-Y) antigen studies were performed on a phenotype female with primary amenorrhea and streak gonads. Pathological examination of tissues removed at total hysterectomy and bilateral salpinog-gonadectomy showed gonadoblastoma and dysgerminoma of left streak. A single F-body (Y chromosome) was found in buccal smears. Analysis of blood cells and tumor fibroblasts showed a 46,XY chromosome constitution (Q-banding). The data were consistent with a diagnosis of 46,XY pure testicular dysgenesis. Positive results for H-Y antigen were found in this case.

Growth hormone (GH) response to GH-releasing peptide-6 in patients with insulin-dependent diabetes mellitus.

In insulin-dependent diabetes mellitus (IDDM), inappropriate growth hormone (GH) responses to several stimuli, including GH-releasing hormone (GHRH), have been described. A decreased hypothalamic somatostatinergic tone is one of the most likely explanations for these findings. His-DTrp-Ala-Trp-DPhe-Lys-NH2 [GH-releasing peptide-6 [GHRP-6]] is a synthetic hexapeptide that stimulates GH release in vitro and in vivo. The mechanism of action of GHRP-6 is unknown, but it probably does not inhibit hypothalamic somatostatin secretion. Also, GHRH and GHRP-6 apparently activate different intracellular pathways to release GH. The aim of this study was to evaluate whether there is a differential effect of IDDM on GHRP-6- and GHRH-induced GH secretion. Six patients with IDDM and seven control subjects were studied. Each subject received GHRP-6 (1 microgram/kg intravenously [IV]), GHRH (100 micrograms IV), and GHRP-6 + GHRH on 3 separate days. GH peak values (mean +/- SE in micrograms per liter) were similar in controls and diabetics after GHRH (22.5 +/- 7.8 v 24.0 +/- 9.7) and after GHRP-5 (20.5 +/- 5.3 v 24.4 +/- 6.3). The association of GHRP-6 and GHRH induced a significantly higher GH release than administration of the isolated peptides in both groups. The synergistic GH response to combined administration of GHRP-6 and GHRH was not different in controls (70.5 +/- 20.0) and diabetics (119.0 +/- 22.2). In summary, the effectiveness of GHRP-6 in IDDM could reinforce the evidence that this peptide probably does not release GH through a decrease in hypothalamic somatostatin secretion. Moreover, our data suggest that both GHRH and GHRP-6 releasing mechanisms are unaltered in IDDM.

Further analysis of the effects of cholecystokinin octapeptides on avoidance behaviour in rats.

Experiments were performed to examine the acute effects of cholecystokinin octapeptides and fragments on the active and passive avoidance behaviour of rats following peripheral and central administration. Both the sulphated (CCK-8-SE) and non-sulphated cholecystokinin octapeptide (CCK-8-NS) and also the COOH-terminal tetra-, penta-, hexa- and heptapeptides of cholecystokinin octapeptide facilitated the extinction of active avoidance behaviour and retention of passive avoidance behaviour. This latter effect of cholecystokinin octapeptides was reversed by anxiolytic chlordiazepoxide pretreatment, showing that in these test situations cholecystokinin octapeptides are able to modify fear-motivation or arousal of the animals; their effect is at least partly similar to that of the neuroleptic substance haloperidol. Subcutaneous treatment with CCK-8-SE or CCK-8-NS appeared to be 3-10 times more effective than intraperitoneal treatment. Following intracerebroventricular administration, 100-300 times lower doses were needed to cause a behavioural effect similar to that after subcutaneous injection. Microinjection of CCK-8-SE or CCK-8-NS in the fmol dose range into the nucleus accumbens facilitated the extinction of active avoidance behaviour and attenuated the retention of passive avoidance behaviour, while microinjection of these peptides into the central amygdaloid nucleus caused opposite effects on these behavioural tests. It seems that the neuroleptic-like effects of cholecystokinin octapeptides are mediated through the nucleus accumbens, and the opposite action (non neuroleptic-like) through the central amygdaloid nucleus.

Long-acting oral bromocriptine (Parlodel SRO) in the treatment of hyperprolactinemia.

OBJECTIVES: To compare the effect of Parlodel SRO (Sandoz, Basel, Switzerland), a long-acting oral bromocriptine, to Parlodel (Sandoz) and to study the chronic effects of Parlodel SRO. DESIGN: The study was twofold: (1) random, double-blind and (2) open. SETTING: Patients were studied in an academic environment. PATIENTS: Hyperprolactinemic patients were selected. Sixteen patients were treated during 1 month. Ten patients completed the 1-year follow-up. INTERVENTIONS: Parlodel SRO or Parlodel was administered during 1 month (first 15 days: 5 mg/d; afterwards: 10 mg/d). Parlodel SRO was given during 1 year in variable doses (maximal 20 mg/d). MAIN OUTCOME MEASURES: Prolactin (PRL) levels, clinical improvement, and side effects were evaluated. RESULTS: After 1 month, 63% of the patients in both groups had normal PRL and 43% had menses. Side effects were similar. After 1 year all patients except one had normal PRL levels, and 89% were ovulating. CONCLUSIONS: The efficacy, tolerability, and long duration of action of Parlodel SRO make it an excellent alternative for the treatment of hyperprolactinemic patients.

Long-acting injectable bromocriptine (Parlodel LAR) in the chronic treatment of prolactin-secreting macroadenomas.

OBJECTIVE: To evaluate the efficacy and tolerability of Parlodel LAR (Sandoz, Basel, Switzerland), a long-acting injectable bromocriptine, in PRL-secreting macroadenomas. DESIGN: Eleven patients with macroprolactinomas were studied in an academic environment in an open and prospective protocol. Ten patients were followed for 6 months and 8 for 1 year. Fifty to 200 mg IM of Parlodel LAR were administered every 28 days. RESULTS: At the end of the 1st month, 64% of the patients had PRL suppression of > 75% of baseline values. After 1 year, 88% of the cases had PRL suppression of > 90%. Persistent PRL normalization was seen in three cases. Tumor shrinkage was seen in 64% of the patients on day 5, in 73% on day 28, and in 90% after 6 months of treatment. Early visual field improvement was seen in 83% of the cases. All patients had improvement of clinical symptoms. CONCLUSION: Parlodel LAR is well tolerated and very effective in the long-term treatment of patients with PRL-secreting macroadenomas.