Antibody to epitope tag induces internalization of human muscarinic subtype 1 receptor

The degree to which a startle response to a loud noise is inhibited by a weak prestimulus is an operational measure of sensorimotor gating. Prepulse inhibition (PPI) can be measured across species and is reduced in schizophrenia patients and dopamine (DA)-activated rats. The ability of DA antagonists to restore PPI in apomorphine (APO)-treated rats correlates highly with their clinical antipsychotic potency. We compared the ability of systemic- vs. intracerebrally (i.c.)-administered haloperidol (HAL) to restore PPI in APO-treated rats. Consistent with previous studies, systemic administration of HAL completely restored PPI in rats treated with APO (0.5 mg/kg s.c.), with an ED50 of approximately 0.02 mg/kg. In an otherwise identical paradigm, HAL failed to fully restore PPI after infusion into either the nucleus accumbens (NACcore or NACshell), NACcore + caudate nucleus (CN), ventral subiculum (VS), medial prefrontal cortex (MPFC), or ventral tegmentum (VTA). A subtotal, but statistically significant restoration of PPI was achieved after HAL infusion into all regions, except the NACshell. Statistically significant effects of i.c. HAL tended to be observed at doses that were only approximately 5-10-fold lower than those at which significant effects were observed after systemic administration. The results suggest that systemically administered HAL may restore PPI in APO-treated rats through its action distributed throughout multiple levels of PPI-regulatory circuitry.     

Hyperalphalipoproteinemias and medical advise in primary care. Changes of the lipid pattern

OBJECTIVE: To analyse the modifications in the lipid pattern experienced in the observance of patients with Hyperalpha-lipoproteinaemia (HAL). DESIGN: A prospective follow-up study. SETTING: La Orden Primary Care Centre, Huelva. PATIENTS: 120 diagnosed with HAL (cHDL higher than the 90 percentile of their same age and sex group from a reference population with cLDL and Triglycerides less than 150 and 200 mg/dl, respectively) and observed for 2.5 +/- 1.5 years. MEASUREMENTS AND RESULTS: Blood pressure, weight, size, cholesterol, cHDL, cLDL, Triglycerides, Glucaemia and Uric acid were determined. The modifications in the diagnosis of HAL, and changes in averages and percentages of several variables, were calculated. Out of 95 people (79.1%) (Age: 42.6 +/- 16), HAL was confirmed in 42.1% (CI, 24.8-59.4) and Hypercholesterolaemia 11a in 20%. There was no lipid disorder in 37.9%. CONCLUSIONS: HAL at a high rate was not confirmed. After HAL is diagnosed, we must be cautious in our advice on cardiovascular protection, as it could be secondary or be modified over time.     

Neither dopamine nor dobutamine corrects mesenteric blood flow depression caused by positive end-expiratory pressure in a rat model of acute lung injury

OBJECTIVE: To determine if either dopamine or dobutamine would counteract the deleterious effect that positive end-expiratory pressure (PEEP) has on cardiac output and mesenteric blood flow in a rat model of acute lung injury. DESIGN: Prospective, randomized, controlled trial in a clinically relevant model of acute lung injury. SETTING: Microcirculation research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: The animals were anesthetized with pentobarbital (30 mg/kg) by intraperitoneal injection. They underwent tracheostomy, jugular and femoral vein cannulation, femoral artery cannulation, carotid artery thermistor placement, and bowel preparation for in vivo video microscopy. Acute lung injury was created by administering 0.1 N hydrochloric acid (1 mL/kg) via the tracheostomy. Dopamine or dobutamine (2.5 or 12.5 microg/kg/min), followed by two intravenous fluid boluses, was administered to rats ventilated with 5, 10, 15, and 20 cm H2O of PEEP. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure, thermodilution cardiac output, mesenteric arteriolar diameter, and red blood cell velocity were measured and mesenteric blood flow was calculated. Cardiac output was depressed in rats exposed to 20 cm H2O of PEEP by 32+/-2%. The corresponding values for cardiac output depression at 20 cm H2O of PEEP in rats receiving 2.5 and 12.5 microg/kg/min of dopamine and 2.5 and 12.5 microg/kg/min of dobutamine were 31+/-1%, 21+/-1%, 29+/-0%, and 24+/-2%, respectively. Mesenteric blood flow was depressed in rats ventilated with 20 cm H2O of PEEP by 74+/-3%, while the corresponding values in rats exposed to 20 cm H2O of PEEP and receiving 2.5 or 12.5 microg/kg/min of dopamine or 2.5 or 12.5 microg/kg/min of dobutamine were 86+/-3%, 77+/-3%, 73+/-3%, and 66+/-3%, respectively. Fluid boluses did not correct the deficits in cardiac output or mesenteric blood flow caused by the combination of acute lung injury and PEEP. CONCLUSIONS: The higher doses of dopamine and dobutamine partially, but insignificantly, corrected the cardiac output depression caused by PEEP in a model of acute lung injury. Neither dose of dopamine nor dobutamine was able to improve PEEP-induced mesenteric blood flow depression.     

Ribozymes. Their functions and strategies for their use

A 6-week acute phase of an international 1-year double-blind study was conducted comparing three dose ranges of olanzapine (5 +/- 2.5 mg/day, 10 +/- 2.5 mg/day, and 15 +/- 2.5 mg/day) with a fixed dose of olanzapine (1.0 mg/day) and with a dose range of haloperidol (15 +/- 5 mg/day) in the treatment of 431 patients with schizophrenia. The purpose was to determine whether olanzapine demonstrated a dose-related ability to decrease overall psychopathology with minimal associated extrapyramidal symptoms in patients with schizophrenia. The high-dose olanzapine group showed statistically significantly greater improvement in overall psychopathology based on mean change in the CGI Severity score and statistically significantly greater improvement in positive psychotic symptoms based on mean change in both the BPRS positive score and the PANSS positive score compared with the 1.0-mg/day olanzapine group. Analyses indicated that an increasing dose-response curve was observed across the range of all olanzapine dose groups. Acute extrapyramidal syndromes were reported less frequently among all olanzapine groups compared with the haloperidol group. Endpoint mean change on both the Simpson-Angus Scale and the Barnes Akathisia Scale reflected improvement for all olanzapine treatment groups compared with worsening for the haloperidol group. Olanzapine was associated with weight gain but did not appear to have any clinically meaningful effect on vital signs. Although olanzapine was associated with some increase in prolactin concentrations, increases were transient, occurred less often, and were of lesser magnitude than those observed with haloperidol.     

The role of endothelin-1 as a mediator of the pressure response after air embolism in blood perfused lungs

BACKGROUND: Irritable bowel syndrome is a common cause of abdominal pain and discomfort and may be related to disordered gastrointestinal motility. Our aim was to assess the effects of long-term treatment with a prokinetic agent, cisapride, on postprandial jejunal motility and symptoms in the irritable bowel syndrome (IBS). METHODS: Thirty-eight patients with IBS (constipation-predominant, n = 17; diarrhoea-predominant, n = 21) underwent 24-h ambulatory jejunal manometry before and after 12 week's treatment [cisapride, 5 mg three times daily (n = 19) or placebo (n = 19)]. RESULTS: In diarrhoea-predominant patients significant differences in contraction characteristics were observed between the cisapride and placebo groups. In cisapride-treated diarrhoea-predominant patients the mean contraction amplitude was higher (29.3 +/- 3.2 versus 24.9 +/- 2.6 mm Hg, cisapride versus placebo (P < 0.001); pretreatment, 25.7 +/- 6.0 mm Hg), the mean contraction duration longer (3.4 +/- 0.2 versus 3.0 +/- 0.2 sec, cisapride versus placebo (P < 0.001); pretreatment, 3.1 +/- 0.5 sec), and the mean contraction frequency lower (2.0 +/- 0.2 versus 2.5 +/- 0.4 cont./min, cisapride versus placebo (P < 0.001); pretreatment, 2.5 +/- 1.1 cont./min] than patients treated with placebo. No significant differences in jejunal motility were found in the constipation-predominant IBS group. Symptoms were assessed by using a visual analogue scale before and after treatment. Symptom scores relating to the severity of constipation were lower in cisapride-treated constipation-predominant IBS patients [score, 54 +/- 5 versus 67 +/- 14 mm, cisapride versus placebo (P < 0.05); pretreatment, 62 +/- 19 mm]. Diarrhoea-predominant IBS patients had a higher pain score after cisapride therapy [score, 55 +/- 15 versus 34 +/- 12 mm, cisapride versus placebo (P < 0.05); pretreatment, 67 +/- 19 mm]. CONCLUSION: Cisapride affects jejunal contraction characteristics and some symptoms in IBS.     

Actions of halothane and isoflurane on Purkinje fibers in the infarcted canine heart: conduction, regional refractoriness, and reentry

The actions of halothane (HAL) and isoflurane (ISO) on conduction and regional refractoriness were studied in infarcted canine hearts to compare their effects on reentry in vitro. In two anesthetic groups of 8 hearts, high and low dose effects were assessed using action potentials recorded from Purkinje fibers located in the nonischemic and ischemic regions. An extrastimulus technique was used to determine the relationship between delay of conduction of premature impulses into the more refractory ischemic region and induction of reentrant responses. At high doses (HAL 0.60 mM and ISO 0.64 mM, approximately 2.3 minimum alveolar anesthetic concentration [MAC]) both anesthetics decreased (P < or = 0.05) the effective refractory period for direct intracellular stimulation of nonischemic fibers (local ERP, initial control: 294 +/- 8 ms); the decrease with HAL (-29 +/- 6 ms) was smaller (P < or = 0.05) than with ISO (-50 +/- 7 ms). HAL and ISO also decreased (P < or = 0.05) the coupling interval of the earliest premature impulse which conducted into the infarct (system effective refractory period [SERP], control: 301 +/- 7 ms) by -31 +/- 11 and -44 +/- 8 ms, respectively. In contrast, the functional refractory period (FRP) in the ischemic region (control:354 +/- 4 ms) was increased by HAL (26 +/- 8 ms; P < or = 0.05) but decreased by ISO (-14 +/- 4 ms, P < or = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of administration and subsequent cessation of buserelin on cancellous bone of female rats

OBJECTIVE: Low-dose dopamine has been used in critically ill patients to minimize renal dysfunction without sufficient data to support its use. The aim of this study was to determine whether low-dose dopamine improves renal function, and whether dobutamine, a nondopaminergic inotrope, improves renal function. DESIGN: Prospective, randomized, double-blind trial. PATIENTS: Twenty-three patients at risk for renal dysfunction were entered into the study. Five patients were later withdrawn. Study data for the remaining 18 patients were: mean age 55 yrs; mean Acute Physiology and Chronic Health Evaluation (APACHE) II score of 18; mean weight 71 kg). The following conditions were present: mechanical ventilation (n = 17 [inverse-ratio ventilation, n = 6]); inotrope administration (n = 11); sepsis (n = 13); and adult respiratory distress syndrome or multiple organ failure syndrome (n = 9). INTERVENTIONS: The study patients were administered dopamine (200 micrograms/min), dobutamine (175 micrograms/min), and placebo (5% dextrose) over 5 hrs each in a randomized order. Ventilator settings, fluid management, and preexisting inotropic support were not altered during the study. MEASUREMENTS AND MAIN RESULTS: Systemic hemodynamic values and indices of renal function (4-hr urine volume, fractional excretion of sodium, and creatinine clearance) were measured during the last 4 hrs of each infusion. Dopamine produced a diuresis (145 +/- 148 mL/hr) compared with placebo (90 +/- 44 mL/hr; p < .01) without a change in creatinine clearance. Conversely, dobutamine caused a significant increase in creatinine clearance (97 +/- 54 mL/min) compared with placebo (79 +/- 38 mL/min; p < .01), without an increase in urine output. CONCLUSIONS: In stable critically ill patients, dopamine acted primarily as a diuretic and did not improve creatinine clearance. Dobutamine improved creatinine clearance without a significant change in urine output.     

Inhibition of proximal convoluted tubule transport by dopamine

BACKGROUND: Dopamine can produce a natriuresis and diuresis independent of changes in renal hemodynamics. However, previous studies have failed to demonstrate an inhibition of transport by dopamine in intact proximal convoluted tubules. METHODS: Rabbit proximal convoluted tubules were perfused in vitro with an ultrafiltrate-like solution and bathed in a serum-like albumin solution. RESULTS: In the present study, the addition of 10-5 M dopamine to the lumen or bath of proximal convoluted tubules perfused in vitro had no effect on transport. In proximal convoluted tubules, addition of 10-6 M bath norepinephrine increased the rate of volume absorption from 0.65 +/- 0.08 to 0.93 +/- 0.08 nl/mm. min (P < 0.01). Addition of 10-5 M luminal dopamine in the presence of bath norepinephrine inhibited the rate of volume absorption to 0.72 +/- 0.10 nl/mm. min (P = 0.01). The inhibition in the rate of volume absorption by luminal dopamine in the presence of bath norepinephrine was completely blocked by the DA1 antagonist, SCH 23390. The DA1 agonist luminal 10-5 M fenoldopam also inhibited volume absorption in the presence of bath norepinephrine, but the DA2 agonist luminal 10-5 M quinpirole was without effect. Bath 10-5 M dopamine had no effect on volume absorption in the presence of bath norepinephrine. CONCLUSION: Dopamine has no direct epithelial action on the proximal convoluted tubule. However, luminal dopamine antagonizes the stimulation in transport produced by norepinephrine. These studies suggest that luminal dopamine may play a role to modulate sodium transport in the presence of renal nerve activity.     

Follow-up of collagen and bone metabolism in patients with cement-free total hip endoprosthesis

Sixteen colts were premedicated with acepromazine and anaesthesia was induced with detomidine and ketamine. Ponies were randomly allocated to receive halothane (HAL) or infusion of detomidine, ketamine and guaiphenesin (DKG) to maintain anaesthesia. Heart and respiratory rate, ECG, mean arterial blood pressure (MABP), cardiac index (CI), blood gases and plasma cortisol, ketamine and guaiphenesin were measured. Surgical castration took place between 45 and 75 min and anaesthesia lasted 90 min. MABP with DKG was significantly higher than with HAL, and, with HAL, MABP increased from pre-surgery (64 +/- 6 mmHg) to mid-surgery (80 +/- 5 mmHg) but did not change with DKG. At 30 min, CI was similar in both groups (57 +/- 7 ml/kg bwt/min); it decreased during surgery with HAL and remained low, but it increased slightly with DKG, and was higher than with HAL at 60 and 90 min. Plasma cortisol decreased in both groups until 40 min then increased with HAL only during surgery. Ketamine concentration reached a plateau (1.3-1.8 microg/ml) between 20 and 90 min and guaiphenesin concentration between 60 and 90 min (99-101 microg/ml). Recovery was generally smooth in both groups. This study demonstrated that during HAL the increase in blood pressure associated with surgical stimulus is accompanied by decreased CI; this did not occur during DKG which is likely to lead to better tissue perfusion than HAL. The adrenocortical activity seen during HAL was absent during DKG which may result from pituitary depression, analgesic effects of total intravenous anaesthesia (TIVA) or better perfusion.     

Role of renal interstitial pressure on chronic control of arterial blood pressure

We examined the modulatory effect of serotonergic activities on haloperidol-induced up-regulation of dopamine D2 receptors in rat striatum. Chronic treatment with haloperidol (0.1, 0.5 mg/kg, i.p., 3 weeks) increased the number of dopamine D2 receptors, while no increase was observed with atypical antipsychotic drugs clozapine (10 mg/kg) and ORG 5222 (0.25 mg/kg). Chronic treatment with MK 212, a serotonin (5-HT)2A/2C receptor agonist (2.5 mg/kg), or with citalopram, a 5-HT reuptake inhibitor (10 mg/kg), potentiated the haloperidol (0.1 mg/kg)-induced up-regulation of dopamine D2 receptor, while that with (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a 5-HT1A receptor agonist (0.1 mg/kg), had no influence on the dopamine D2 receptor up-regulation. Co-administration of ritanserin (1 mg/kg), a 5-HT2A/2C receptor antagonist, with a low dose of haloperidol (0.1 mg/kg), but not with a high dose of the agent (0.5 mg/kg), attenuated the dopamine D2 receptor up-regulation. Drug occupation of 5-HT2A and dopamine D2 receptors in vivo examined with use of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was 69.8% and 45.1%, respectively, after the acute administration of haloperidol (0.1 mg/kg) plus ritanserin (1 mg/kg). This profile that 5-HT2A receptors were highly occupied compared with dopamine D2 receptors was similar to that of clozapine or ORG 5222. These results suggest that potent 5-HT2A receptor antagonism versus weak dopamine D2 receptor blockade may be involved in the absence of up-regulation of dopamine D2 receptors after chronic treatment with clozapine or ORG 5222.     

Characteristics of the NMDA receptor modulating hypoxia/hypoglycaemia-induced rat striatal dopamine release in vitro

We investigated the functional characteristics of the NMDA receptor that modulates hypoxia/hypoglycaemia-induced striatal dopamine release. Dopamine release was detected by fast cyclic voltammetry in rat neostriatal slices. Four variables were measured: T(on) -- time from initiation of hypoxia/hypoglycaemia to the onset of dopamine release, Tpk -- time from onset to maximum, deltaDA/delta(t) -- rate of dopamine release and DAmax -- maximum extracellular dopamine concentration. In controls, T(on) = 164.9 +/- 1.7 s, Tpk = 20.9 +/- 0.9 s, deltaDA/delta(t) = 5.31 +/- 0.44 microM/s and DAmax = 79.1 +/- 2.5 microM (means +/- S.E.M., n = 203). Cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS 19755, 20 microM) lengthened, while N-methyl-D-aspartate (NMDA) (100 microM) shortened T(on). (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,1 0-imine hydrogen maleate (MK 801, 1 and 10 microM) and dextromethorphan (10 and 100 microM) increased Tpk and decreased DAmax. Neither glycine (100 microM), 7-chlorokynurenic acid (50 microM) nor 5-nitro-6,7-dichloro-1,4-dihydroquinoxaline-2,3-dione (ACEA 1021, 100 microM) had any effect although 7-chlorokynurenic acid blocked the effect of NMDA. Increasing [Mg2+] from 1.3 to 3.7 mM, increased Tpk and decreased deltaDA/delta(t). Dithiothreitol (1 mM) accelerated T(on) while 5.5-dithio-bis-(2-nitrobenzoic acid) (1 mM) delayed T(on). Neither drug affected Tpk, DAmax or deltaDA/delta(t). Neither spermidine (100 microM) nor arcaine (100 microM) affected T(on), Tpk or deltaDA/delta(t) although arcaine decreased DAmax. In conclusion, hypoxia/hypoglycaemia-induced dopamine release was influenced by an NMDA receptor although modulation of the glycine recognition site of the receptor was ineffective, as were agents acting at polyamine modulatory zones. These findings highlight differences between recombinant and native NMDA receptors and suggest caution in extrapolating molecular biology to functional studies.     

Primary structure of apolipophorin-III from the greater wax moth, Galleria mellonella

BACKGROUND: Neurobiological research has implicated the dopamine and serotonin systems in the pathogenesis of autism. Open-label reports suggest that the serotonin2A-dopamine D2 antagonist risperidone may be safe and effective in reducing the interfering symptoms of patients with autism. METHODS: Thirty-one adults (age [mean+/-SD], 28.1+/-7.3 years) with autistic disorder (n=17) or pervasive developmental disorder not otherwise specified (n=14) participated in a 12-week double-blind, placebo-controlled trial of risperidone. Patients treated with placebo subsequently received a 12-week open-label trial of risperidone. RESULTS: For persons completing the study, 8 (57%) of 14 patients treated with risperidone were categorized as responders (daily dose [mean+/-SD], 2.9+/-1.4 mg) compared with none of 16 in the placebo group (P<.002). Risperidone was superior to placebo in reducing repetitive behavior (P<.001), aggression (P<.001), anxiety or nervousness (P<.02), depression (P<.03), irritability (P<.01), and the overall behavioral symptoms of autism (P<.02). Objective, measurable change in social behavior and language did not occur. Nine (60%) of 15 patients who received treatment with open-label risperidone following the double-blind placebo phase responded. Other than mild, transient sedation, risperidone was well tolerated, with no evidence of extrapyramidal effects, cardiac events, or seizures. CONCLUSION: Risperidone is more effective than placebo in the short-term treatment of symptoms of autism in adults.     

Electrochemical study of some 2-mercapto-5-R-ammino-1,3,4-thiadiazole derivatives using carbon paste electrodes

The electrochemical study of some 2-mercapto-5-R-ammino-1,3,4-thiadiazole derivatives was made by cyclic and linear sweep voltammetry using a carbon paste electrode (CPE, graphite/solid paraffin ratio 2:1) as working electrode and an Ag/AgCl reference electrode. The current-potential curves were recorded in anodic polarisation in -0.1 and +1.3 V range using aqueous solutions and different buffers (between pH 1.2 and 10.0), with 20 or 50 mV s(-1) sweep rate. The oxidation peak appears between +0.65 and +0.70 V due to disulphides formation. The 5-phenyl derivative has two oxidation peaks, the first at +0.45 +/- 0.03 V and the second at +0.65 +/- 0.03 V. The oxidation potentials are pH dependent, decreasing from 0.9 +/- 0.1 V at pH 1.2 to 0.6 +/- 0.1 V at a pH between 8.0 and 10.0. In some potential ranges depending on pKa of molecules the oxidation potential and oxidation current are pH independent. Simple, precise and accurate voltammetric methods for the determination of these compounds were developed and validated in 2.5 x 10(-6)-7.5 x 10(-4) mol l(-1) concentration ranges. The detection limits were 2.3 micromol l(-1) for 5-ammino-, 12.3 micromol l(-1) for 5-acetylammino-, 11.6 micromol l(-1) for 5-allylammino-, and 1.2 micromol l(-1) for 5-phenylammino-2-mercapto-1,3,4 thiadiazole derivatives.     

Ambulatory blood pressure, nocturnal blood pressure reduction and plasma catecholamines

OBJECTIVE AND DESIGN: Controversial data have been reported on plasma catecholamines in hypertensives. Aims of this study were to find whether 24-hour ambulatory blood pressure was correlated with circulating catecholamines and to investigate whether nocturnal blood pressure reduction was associated with baseline plasma catecholamines. Samples for catecholamine determination were obtained in 34 consecutive male subjects after a 30-minute rest and before ambulatory blood pressure monitoring. RESULTS: Hypertensive patients (n = 22; 24-hour blood pressure: 145 +/- 14/94 +/- 6 mm Hg) showed similar norepinephrine and epinephrine levels when compared with normotensives (n = 12; 24-hour blood pressure: 124 +/- 6/81 +/- 6 mm Hg), and higher dopamine values (hypertensives: 64.6 +/- 58; normotensives: 26.2 +/- 31 pg/ml; p < 0.05). A positive correlation was observed between dopamine and diastolic nocturnal blood pressure (p < 0.05) while a negative correlation was found between dopamine and nocturnal diastolic blood pressure reduction (p < 0.025). No significant relationship was observed between both norepinephrine and epinephrine, and 24-hour blood pressures. CONCLUSIONS: Since previous reports have documented malfunctioning of dopaminergic system in hypertension, the higher levels of circulating plasma dopamine found in hypertensive patients in the present study may account for a peripheral compensatory increase. The correlation between dopamine and nocturnal blood pressure fall seems to indicate that the impairment of dopaminergic system may influence the 24-hour blood pressure profile, affecting the nocturnal blood pressure reduction.     

The effect of cisapride on dysmotility-like functional dyspepsia: reduction of the fasting and postprandial area, but not of the postprandial antral expansion

OBJECTIVE: To test the effect of cisapride on symptom score and on fasting and postprandial antral area in patients with dysmotility-like functional dyspepsia compared with controls. METHODS: Nineteen consecutive patients with dysmotility-like functional dyspepsia (13 females, six males, aged 18-79 y) and 12 control subjects (six females, six males, aged 19-68 y) were investigated. A symptom score including six upper digestive symptoms rated from 0 to 3 was applied. The patients received in a randomized order cisapride 10 mg t.i.d. (n = 10), or placebo (n = 9) for 3 days. The controls also received cisapride (n = 6) or placebo (n = 6) in the same way. The antral area in fasting condition and immediately after a semiliquid test meal (250 ml, 342 kcal) was assessed by real-time ultrasonography in front of the aorta and mesenteric vein. The measurements were carried out before starting and after finishing the trials with cisapride and placebo. RESULTS: The symptom score (mean +/- SD) was 7.1 +/- 2.4 in dysmotility-like functional dyspepsia vs 0.5 +/- 0.2 in controls (P < 0.0001). The fasting antral area was 4.5 +/- 0.9 cm2 in dysmotility-like functional dyspepsia vs 2.2 +/- 0.2 cm2 in controls (P < 0.0001). Postprandial antral area was also larger in dysmotility-like dyspepsia than in controls (6.2 +/- 1.0 vs 3.0 +/- 0.3 cm2, Pb= 0.0001). Symptom score correlated with fasting antral area in dysmotility-like functional dyspepsia (rb= 0.38, Pb= 0.05). Cisapride decreased the symptom score to 4.5 +/- 2.5 (P = 0.0009) and placebo to 5.3 +/- 2.4 (P = 0.02). Cisapride significantly reduced the fasting antral area and the postprandial antral area in the dyspeptic group, but not in the control group. Postprandial antral expansion was not influenced by cisapride. Placebo did not change the sonographic parameters in both groups. CONCLUSIONS: In dysmotility-like functional dyspepsia, fasting and postprandial antral areas are wider than in controls. Despite a good placebo response, cisapride is effective in improving the symptoms in dysmotility-like functional dyspepsia, associated with the reduction of fasting and postprandial antral areas.     

Low dosages of felodipine ER once daily as monotherapy in elderly hypertensive patients: effect on ambulatory blood pressure and quality of life

OBJECTIVE: To establish the efficacy of 24-h ambulatory and casual blood pressure (BP) reduction, and the tolerability of once daily felodipine extended release (ER) 2.5 mg and felodipine ER 5 mg as monotherapy. DESIGN: Randomised, double-blind placebo controlled 6 weeks parallel study. SETTING: From 15 general practices centres (with 19 GPs) in the region of the University of Maastricht, The Netherlands. SUBJECTS: A total of 129 subjects aged 50-80 years with primary hypertension were screened; 27 men and 61 women with a casual diastolic BP of 100-115 mm Hg and/or a systolic BP of less than 200 mm Hg entered the study. MAIN OUTCOME MEASURES: Casual and 24-h ambulatory BP and a subjective symptom assessment (SSA) questionnaire after 6 weeks of therapy. RESULTS: After correlation for placebo response the mean casual systolic/diastolic BP (SBP/DBP) reduction was 10/5 mm Hg (NS) and 12/10 mm Hg (P < 0.05) for felodipine ER 2.5 and 5 mg, respectively. By using 24-h ambulatory BP measurements these reduction were 6/4 mm Hg (NS) and 13/8 mm Hg (P < 0.05), respectively. No significant difference for SBP and DBP was found during the night time between felodipine 2.5 and placebo (-1/0). Felodipine ER 5 mg lowered the BP load significantly during both daytime and night time but felodipine ER 2.5 mg only for DBP during the daytime. There was a significant difference for the number of responders between placebo (28%) vs felodipine ER 2.5 mg (55%) and ER 5.0 mg (59%). Both felodipine dosages and placebo were comparable in (a low) number of adverse events and results of the SSA. CONCLUSIONS: During daytime felodipine ER 2.5 mg and 5 mg are effective in BP lowering in elderly hypertensive patients. However, only felodipine ER mg is effective in reducing BP during night time (22.00-7.00). Only felodipine ER 5 mg has a significant reducing effect on BP load during day and night time. Both felodipine ER 2.5 and ER 5.0 have a significant effect on the responder rate. It appeared from this study that compared to placebo, and in contrast with felodipine ER 5 mg, the ER form of felodipine 2.5 mg has no BP lowering effect during night time in elderly patients. To assess the effectivity during night time of felodipine ER 2.5 mg in an individual patient it is recommendable to measure the BP at the end of the dose interval.     

Effects of estrogen replacement therapy on the lipoprotein profile in postmenopausal women with ESRD

BACKGROUND: Patients with ESRD have excessive cardiovascular morbidity and mortality. In postmenopausal women with normal renal function, estrogen replacement therapy decreases cardiovascular mortality by 50%, in part because of their beneficial effects on the lipoprotein profile. Because of similarities in the lipoprotein profile between healthy, postmenopausal women, and women with ESRD, we examined the effects of estrogen replacement on lipoproteins in 11 postmenopausal women with ESRD. METHODS: In a randomized, placebo-controlled crossover study (8 week treatment arms) using 2 mg daily of oral, micronized estradiol, 11 postmenopausal women with ESRD were treated. Neither baseline lipid nor lipoprotein abnormalities were used as entry criteria for study participation. RESULTS: Blood estradiol levels were 19 +/- 4 with placebo and 194 +/- 67 pg/ml (P = 0.024) with estradiol treatment. Total HDL cholesterol concentrations increased from 52 +/- 19 mg/dl to 61 +/- 20 mg/dl (16%), with placebo and estradiol treatments, respectively (P = 0.002). Apolipoprotein A1 increased by 24.6% (P = 0.0002) with estradiol intervention. HDL2 concentrations were 19 +/- 13 with placebo and 24 +/- 16 with estradiol treatment (P = 0.046). There were no differences in total or LDL cholesterol, other lipoprotein fractions including Lp(a), and triglycerides with 2 mg daily estradiol treatment. No significant side effects were observed. CONCLUSIONS: Therefore, using standard dosage regimens for estrogen replacement therapy in postmenopausal women with ESRD, HDL cholesterol is increased to an extent that would be expected to improve their cardiovascular risk profile. Further studies are needed to assess whether estrogen replacement therapy decreases the incidence or severity of cardiovascular disease in ESRD patients to a similar degree compared with other women.     

Effects of amlodipine on transient myocardial ischaemia in patients with a severe coronary condition treated with a beta-blocker. Amlor-Holter Study Investigators

The purpose of this trial was to study the additional anti-ischaemic effects of amlodipine in coronary patients with ambulant ischaemia despite beta-blocker therapy. Beta-blockers are the most effective drug therapy for reducing the frequency and duration of ambulatory ischaemic episodes. However, the therapeutic advantage of combined calcium antagonist-beta-blocker treatment remains questionable. Three hundred and thirteen patients with documented coronary artery disease, a positive exercise test within 6 months before entry and background beta-blocker therapy, were screened. Inclusion criteria (> or = 4 episodes of transient ST segment depression of > or = 1.0 mm and/or > or = 20 min of ischaemia) were demonstrated in a 48 h ECG during the placebo run-in period in 84 (25%) of the patients. Eighty-nine percent of the ischaemic episodes were silent. The eligible patients were then randomized in a 2-week, double-blind, parallel group study comparing placebo to amlodipine 10 mg daily added to the beta-blocker. The anti-ischaemic efficacy of the combination therapy was assessed by 48 h ECG monitoring and exercise tests. Compared to placebo, amlodipine did not significantly reduce either the frequency (3.7 +/- 4.3 vs 4 +/- 4.8 episodes in the amlodipine group) or the duration of ambulatory ischaemia (mean duration: 43.9 +/- 57.1 vs 39.6 +/- 65.7 min, total duration 3.1 +/- 6.7 vs 2.8 +/- 6.1 h). Exercise-induced ST segment depression tended to decrease with amlodipine (58% vs 73% in the placebo group) and the ischaemia-free workload capacity was increased (+1.7 stage vs 0.7 stage in the placebo group, P = 0.08). These results suggest that 2 weeks treatment with amlodipine may not provide any additional anti-ischaemic benefit in patients with ambulant ischaemia resistant to a beta-blocker therapy.     

The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance

OBJECTIVE: To study the effect of acarbose, an alpha-glucosidase inhibitor, on postprandial plasma glucose and insulin and insulin sensitivity in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Subjects with IGT were randomly treated in a double-blind fashion with placebo (n = 10) or acarbose (n = 8) at 100 mg t.i.d. for 4 months. All subjects were submitted before randomization and at the end of the study to a standardized breakfast and a 12-h daytime plasma glucose and plasma insulin profile, and insulin sensitivity was measured as steady-state plasma glucose (SSPG) using the insulin suppression test. RESULTS: While placebo had no effect on postprandial plasma glucose and plasma insulin incremental area under the curve (AUC) (3.03 +/- 0.5 vs. 3.76 +/- 0.6 mmol.h-1.l-1, P = NS; 1,488 +/- 229 vs. 1,609 +/- 253 pmol.h-1.l-1, P = NS), acarbose resulted in a significant reduction for both glucose (1.44 +/- 0.3 vs. 4.45 +/- 0.9 mmol.h-1.l-1, P = 0.002) and insulin (626.7 +/- 104.3 vs. 1,338.3 +/- 220.5 pmol.h-1.l-1, P = 0.003). The reduction in 12-h plasma glucose and insulin AUC on acarbose (11.2 +/- 2.1 mmol.h-1.l-1 and 7.5 +/- 0.7 nmol.h-1.l-1) was significantly greater than that on placebo (4.0 +/- 1.6 mmol.h-1.l-1 and 0.8 +/- 0.4 nmol.h-1.l-1) (P = 0.014 and 0.041). While SSPG was not affected by placebo (13.9 +/- 0.4 vs. 13.8 +/- 0.3 mmol/l; P = NS), it was significantly improved by acarbose (10.9 +/- 1.4 vs. 13.1 +/- 1.5 mmol/l, P < 0.004) and was also significantly different from placebo at 4 months (P < 0.02). CONCLUSIONS: It is concluded that in subjects with IGT, acarbose treatment decreases postprandial plasma glucose and insulin and improves insulin sensitivity. Acarbose may therefore be potentially useful to prevent the progression of IGT to NIDDM.     

The effect on bone mass and bone markers of different doses of ibandronate: a new bisphosphonate for prevention and treatment of postmenopausal osteoporosis: a 1-year, randomized, double-blind, placebo-controlled dose-finding study

The present article describes the results from a phase II dose finding study of the effect of ibandronate, a new, third generation bisphosphonate, in postmenopausal osteoporosis. One hundred and eighty postmenopausal, white women, at least 10 years past a natural menopause, with osteopenia defined as a bone mineral density (BMD) in the distal forearm at least 1.5 SD below the premenopausal mean, entered and 141 (78%) completed a 12 months randomized, double-blind, placebo-controlled study. The women received 0.25, 0.5, 1.0, 2.5, or 5.0 mg ibandronate daily or placebo. All women received a daily calcium supplementation of 1000 mg Ca2+. Bone mass and biochemical markers of bone turnover were measured every 3 months throughout the study period. The average changes in bone mass showed positive outcome in all regions in the groups receiving ibandronate 2.5 and 5.0 mg. The responses in the two groups were not significantly different, although there was a tendency toward a higher response in bone mass in the group receiving ibandronate 2.5 mg, where the increase in BMD was 4.6 +/- 3.1% (SD) in the spine (p < 0.001), 1.3 +/- 3.0% (SD) to 3.5 +/- 5.3% (SD) in the different regions of the proximal femur (p < 0.03 to p < 0.002), and 2.0 +/- 1.9% (SD) in total body bone mineral content (BMC) (p < 0.001). There was no significant changes in bone mass in the group receiving calcium (placebo) and ibandronate 0.25 mg. Dose-related responses were found in all biochemical markers of bone turnover. In average, serum osteocalcin decreased 13 +/- 14% (SD) (placebo) and 35 +/- 14% (SD) (5.0 mg). Urinary excretions of breakdown products of type I collagen decreased 35 +/- 21% (SD) (placebo) and 78 +/- 28% (SD) (5.0 mg), p < 0.001 in all groups. In conclusion, the results suggest that ibandronate treatment increases bone mass in all skeletal regions in a dose dependent manner with 2.5 mg being the most effective dose. Ibandronate treatment reduces bone turnover to premenopausal levels and is well tolerated.