bluuebunny/crossref_metadata_2025 huggingface dataset:
Progesterone, oestradiol and oxytocin and their in vitro effect on maintaining the number of gap junction plaques in human myometrium at term
Authors: KILARSKI W. M. , FU X. , BÄCKSTRÖM T. , ROOMANS G. M. , ULMSTEN U.
Published: October 2003

Previous studies by electron microscopy and laser confocal microscopy of immuno‐histochemically stained sections have shown that during pregnancy the extent of gap junction formation in human myometrium is low, but that an increase occurs in the active stages of labour despite a high concentration of progesterone in maternal blood. The present investigation focused on the effect of in vitro exposure of isolated myometrical tissue to progesterone, oestradiol and oxytocin, on the number of gap junction plaques in human myometrium at term. Myometrial biopsies were obtained at term from 13 pregnant women who had an elective caesarean section in the 37th or 40th week of pregnancy. The biopsies were immersed immediately in Hepes buffer and buffer containing 0.5, 5.0 μg mL‐1 of progesterone, and 0.1 μg mL‐1 of oestradiol. The muscle biopsies were trimmed under a stereo microscope into strips along the bundles of smooth muscle cells and mounted in tissue baths, superfused with Hepes buffer supplemented with glucose (0.01 mm); subsequently the strips were exposed to buffer containing different concentrations of progesterone, oestradiol and oxytocin. Incubation of the muscle strips for 180 min resulted in a significant decrease of the number of gap junctions (P <0.01). Neither oestradiol or oxytocin, alone or in combination, had a significant effect on the maintenance of the number of gap junctions. The progesterone concentration of 5.0 μg mL‐1, combined with oxytocin, and with or without oestradiol had a significantly positive effect on the number of gap junction plaques in strips of human myometrium at term (P<0.05 vs. buffer alone). The high concentration of progesterone in the superfusion medium during in vitro experiments may be responsible for the maintenance of high numbers of gap junction complexes in term human myometrium. This finding is of interest in the light of findings of persisting high progesterone levels in maternal blood during labour.
Electrical restitution in rat ventricular muscle
Authors: NANASI P. P. , PANKUCSI C. , BANYASZ T. , SZIGLIGETI P. , PAPP J. Gy. , VARRO A.
Published: October 2003

The mechanism of electrical restitution was studied in isolated rat ventricular muscle using drugs that inhibit specific ion currents. The effect of transient changes in cytosolic Ca concentration and Na/Ca exchange in relation to the restitution process was also studied in single ventricular cardiomyocytes. Conventional microelectrode techniques were applied to record action potentials having gradually increasing coupling intervals, each evoked following a train of stimuli with a frequency of 1 Hz. Ion currents were recorded from enzymatically isolated cells using the whole cell patch clamp technique. Ca transients were monitored in myocytes loaded with the fluorescent dye, indo‐1. The electrical restitution process in multicellular rat ventricular preparations at 37 °C was described as a sum of three exponential components: an early positive component, a subsequent fast negative component and a late negative component, having time constants of 21.9±1.9, 73.1±6.0 and 1053±61 ms, respectively (n=9). Inhibition of the transient outward K current, the delayed rectifier K current, or the chloride current did not substantially alter these time constants. The early positive and fast negative components were fully abolished by nifedipine or MnCl2. In the presence of caffeine, the fast negative component was absent, while the time constant of the early positive component increased to 39.5±5.8 ms (n=5). In single myocytes loaded with indo‐1, the Ca transients decayed with a time constant of 151±12 ms at room temperature (n=5). These Ca transients were accompanied by inward current tails, identified as a Na/Ca exchange current, having a decay time constant of 140±4.5 ms. It is concluded that electrical restitution in rat ventricular muscle is relatively little affected by recovery from voltage‐dependent inactivation of ion channels, it is rather governed by transient changes in cytosolic Ca concentration possible via Ca‐dependent inactivation of the L‐type Ca current and activation of the Na/Ca exchange current.
Characterization of bumetanide‐sensitive Na+ and K+ transport in rat skeletal muscle
Authors: DØRUP I. , CLAUSEN T.
Published: October 2003

In isolated rat soleus muscle an average of 23% of the total 22Na influx was found to be suppressible by bumetanide (K0.5=0.1 mm) and furosemide (K0.5=1 mm), whereas the influx and efflux of 42K were not affected. In extensor digitorum longus muscle, around 25% of the total 22Na influx was suppressible by bumetanide (1 mm). In the presence of ouabain, both diuretics decreased net intracellular accumulation of Na+, but caused no change in K+ content. In extensor digitorum longus (but not in soleus), bumetanide‐suppressible 22Na influx was stimulated by increasing extracellular osmolarity with the bumetanide having no effect on 42K influx. Bumetanide‐suppressible Na+ influx was almost abolished in Cl‐‐free buffer, but was unaffected by the omission of K+. In rat soleus, the inhibitory effects of bumetanide, amiloride and tetrodotoxin on 22Na influx were found to be additive. The results indicate that a NaCl cotransport system is present in both fast‐ and slow‐twitch skeletal muscles, and may participate in volume regulation. Due to the large pool of muscle cells, activation of NaKCl2 cotransport is likely to entail the hazards of hypokalemia. The advantage of exerting volume control via NaCl cotransport is that this risk can be avoided.
The preference for warm drinking water induces hyperhydration in heat‐stressed lactating goats
Authors: OLSSON K. , HYDBRING E.
Published: October 2003

The aim of this study was to determine whether lactating goats regulate their water intake when given a choice between warm (35 °C) and cold (15 °C) water. Six lactating goats were kept individually in pens. At 07.00 h one bucket was filled with warm water and another with cold water. Water consumption was measured at intervals until 18.00 h. Water temperature was not controlled at night. Two experiments were made, one at normal room temperature (18–19 °C) and the other at 39–40 °C from 10.45 to 17.00 h. At normal room temperature the goats drank 6.0±1.4 L of the warm water but only 1.7±1.3 L of the cold water (P<0.001). The total water consumption, including the following night, was 9.2±1.6 L. This differed from control days, when only cold water was available (5.9±0.4 L; P<0.05). Neither the plasma Na concentration nor the osmolality changed, which indicate that the goats regulated their fluid balance. In the experiments involving heat stress the goats drank 11.5±1.7 L of the warm water but only 2.0±1.0 L of the cold water (P<0.001). In total, including the following night, they drank 16.2±2.6 L (P<0.001 vs. control days). Goats drank repeatedly despite falling plasma Na and osmolality, proving that their thirst was not induced by water losses. Their abdomens became distended, indicating that water was stored in the reticulo‐rumen and explaining why their body weights increased. The goats appeared distressed. It is concluded that goats prefer to drink warm water. Nevertheless, our results suggest that, if possible, warm drinking water should not be given to lactating goats under hot ambient conditions.
Capillary geometry in the soleus muscle of rats cold‐acclimatized for 68 generations
Authors: SUZUKI J. , GAO M. , YAHATA T. , KUROSHIMA A. , KOYAMA T.
Published: October 2003

The effects of chronic cold exposure on soleus muscle capillarity were examined, particularly in terms of the distribution of arteriolar and venular capillaries and their capillary domain area (CDA) in adult rats exposed to cold for 68 generations (CG; n = 6). These parameters were compared with those obtained from control rats (CON; n = 5) and deacclimatized rats (DCG; n = 4), reared in thermoneutral temperature after being reared for 11 generations in cold. Morphometric data were obtained from muscle cross sections exposed to a double‐staining method that stained the arteriolar and venular portions of capillaries blue and red, respectively. In CG, the capillary densities of arteriolar and venular capillaries were significantly greater than that of both CON and DCG (P < 0.05). The CDA of arteriolar, intermediate and venular portions in CG was significantly smaller by 15, 14 and 13%, respectively, than those of respective portions in CON (P < 0.05). Although CDA of arteriolar and venular capillary portions was also smaller in DCG than in CON, the degree of reduction was less in DCG than in CG. The succinate dehydrogenase activity of soleus muscle was significantly greater in CG than in both CON and DCG (P < 0.05). These results suggest that adaptive changes in the oxygen transport system, identified as an increase in the number of arteriolar capillaries and a reduction in the diffusion distance for oxygen, were observed in the soleus muscle after chronic cold exposure. These changes may improve the effective oxygen supply to muscle tissues and enable muscle tissues to promote thermogenesis in the cold atmosphere.
Central and peripheral components of diaphragmatic fatigue during inspiratory resistive load in cats
Authors: ALEKSANDROVA N. P. , ISAEV G.G.
Published: October 2003

The development of fatigue was investigated in the diaphragm of anaesthetized, tracheostomized, spontaneously breathing cats during restricted air flow. Ventilation, transdiaphragmatic pressure (Pdi), integrated electrical activity of diaphragm (Edi) and phrenic nerve (Eph) were measured simultaneously and expressed as a percentage of values at unloaded breathing. Inspiratory loads were 60, 70 and 80% of Pdi max. The Pdi max was measured by airway occlusion at functional residual capacity. The duration of loads was 40–60 min. The diaphragmatic fatigue developed only during heavy inspiratory loading (80% Pdi max). During the first 10 min of heavy load Pdi, Edi and Eph increased to 905 ± 60%, 248 ± 20% and 229 ± 24%, respectively (P < 0.01), and then began to fall gradually. Ventilation declined to 39 ± 3% after 60 min of heavy load (P < 0.01), resulting in acute hypercapnia and hypoxia. Initial fatigue appeared as a decrease in Pdi (to 781 ± 63%) and parallel decline in Edi (to 233 ± 21%) after 30 min of load (P < 0.05). Phrenic nerve activity did not change during this stage. These data suggest a peripheral basis of diaphragmatic fatigue, related to disorders in neuromuscular transmission. After 60 min of heavy load, Pdi fell to 675 ± 49%, Edi declined to 209 ± 28% and Eph decreased to 189 ± 25%. We interpret the decrease in phrenic nerve activity as a weakening of central inspiratory drive and development of the central component of diaphragmatic fatigue in the last stage.
Spinal expression of mRNA for immediate early genes in a model of chronic pain
Authors: DELANDER G. E. , SCHÖTT E. , BRODIN E. , FREDHOLM B. B.
Published: October 2003

We have used a partial nerve ligation model of chronic pain to investigate if there are changes in the expression of mRNA for several immediate early genes (IEG) that correlate in time with the initial adaptive behavioural changes and with development of allodynia in this model. The animals were inspected for typical changes in posture, and mechanical allodynia was evaluated using von Frey filaments. Expression of three of the immediate early genes examined, c‐fos, NGFI‐A and jun B, was transiently increased in the ipsilateral dorsal horn of the spinal cord following the partial ligation of the sciatic nerve. The time course and extent of these changes were similar to those reported for acute noxious stimuli. c‐jun mRNA expression was significantly enhanced, after a delay of more than 12 h, and then remained elevated over the entire studied period of 4 weeks. These changes occurred only in the ventral horn, particularly in lamina IX. Except for c‐jun mRNA, all changes were transient despite behavioural evidence for continuing allodynia. These results from the partial nerve ligation model, when compared with results obtained using other models of acute or chronic nerve injury, suggest that the immediate early genes we have examined are not sufficient to explain the transition to chronic pain states. The results also show that in this model of chronic pain there are prolonged adaptive changes in motor neurons and that these changes are temporally associated with the development of chronic pain and allodynia.
Role of increased insulin demand in the adaptation of the endocrine pancreas to pregnancy
Authors: NIEUWENHUIZEN A. G. , SCHUILING G. A. , MOES H. , KOITER T. R.
Published: October 2003

Nieuwenhuizen, A. G., Schuiling, G. A., Moes, H. & Koiter, T. R. 1997. Role of increased insulin demand in the adaptation of the endocrine pancreas to pregnancy. Acta Physiol Scand 159, 303–312. Received 8 July 1996, accepted 24 October 1996. ISSN 0001–6772. Department of Obstetrics and Gynaecology, University of Groningen, Groningen, the Netherlands.

During gestation the demand for insulin increases due to a decrease in insulin sensitivity of the maternal tissues. Simultaneously, pancreatic islet‐cell proliferation, as well as insulin production and secretion increase. Both phenomena appear to be caused by the actions of pregnancy hormones. We studied the relationship between the two phenomena by investigating whether the supply of exogenous insulin affects the secretion of pregnancy hormones and islet function during gestation. For that purpose rats were treated with high doses of insulin (4.8 IU day−1 by sub‐cutaneous osmotic mini pumps) so that the endogenous demand for insulin was fully satisfied from day 8–14 of gestation. Euglycaemia (5.0 mm) was maintained by intra venous infusion of glucose. The treatment suppressed insulin synthesis, as measured by in situ hybridization, in both pregnant and cyclic rats. In addition, in pregnant rats the increments in insulin secretion and in islet‐cell proliferation were partly prevented. Furthermore, the data also suggest that in pregnant rats the treatment partly prevented the decrease in insulin sensitivity. Finally, the treatment did not affect the plasma concentrations of progesterone, prolactin and placental lactogen, but prevented the rise in growth hormone concentrations in pregnant rats. The present data suggest that, next to direct effects of pregnancy hormones and growth hormone on the pancreatic islets, a decreased insulin sensitivity in the maternal tissues, induced by actions of the same hormones, is involved in the regulation of islet function during gestation.
Circadian variation of sweating responses to passive heat stress
Authors: AOKI K. , KONDO N. , SHIBASAKI M. , TAKANO S. , TOMINAGA H. , KATSUURA T.
Published: October 2003

The aim of present study was to examine whether sweating responses to passive heat stress change with the circadian rhythm of internal temperature. Six men had their legs immersed in water at 42 °C for 60 min in an ambient temperature of 28 °C on four separate days. Experiments were conducted at four different times [ 06.00 h (morning), 12.00 h (daytime), 18.00 h (evening) and 24.00 h (night)]. We measured oesophageal temperature (Toes), mean body temperature T¯b, local sweating rate m˙sw on the forehead, back, forearm and thigh, the densities of activated sweat gland (ASG) on the back, forearm and thigh, and the frequency of sweat expulsion per minute (Fsw) which has been suggested to represent central sudomotor activity. Sweat gland output (SGO) on each site was calculated by dividing m˙sw by ASG. ASG was significantly higher on the forearm than on the back and thigh, and SGO was significantly lower on the forearm than on the back and thigh. However, ASG and SGO did not significantly change over the day. T¯b and Toes thresholds for the onset of sweating showed a significant change with both the temperature rhythms at rest prior to each procedure, while the slopes of the relationships Fsw– T¯b and m˙sw–Fsw showed no significant difference over the day. We suggest that the circadian variation of sweating response to passive heat stress is regulated by a central sudomotor mechanism rather than by sweat gland function.
Reinfection versus recrudescence in Helicobacter pylori infection
Authors: VAN DER ENDE A. , VAN DER HULST R. W. M. , DANKERT J. , TYTGAT G. N. J.
Published: October 2003

Antimicrobial treatment of Helicobacter pylori is the proper management strategy in patients with ulcers. A high rate of H. pylori reinfection after successful eradication therapy however, may give rise to ulcer recurrence. The risk of reinfection, depending on the prevalence and the rate of acquisition of H. pylori infection, varies with socioeconomic status, age and geographical location. The rate of reinfection may vary in a similar way. The available data in the literature reveal that reinfection by H. pylori is low or absent in developed countries and may be lower than the initial rate of acquisition. In addition, reported cases of H. pylori reinfection are often cases of recrudescent H. pylori infection. Acquisition rate in developing countries is high, so the reinfection rate is expected to be higher than in developed countries. However, studies discriminating reinfection from recrudescence are lacking and therefore more data from developing regions are needed to settle if ‘cured once, cured forever’ holds true.
The actions of bismuth in the treatment of Helicobacter pylori infection
Authors: LAMBERT J. R. , MIDOLO P.
Published: October 2003

Bismuth salts have been used in medicine for over three centuries, particularly in the treatment of dyspepsia. Commonly used agents include colloidal bismuth subcitrate (CBS), bismuth subsalicylate (BSS) and the newer ranitidine bismuth citrate (RBC). These are safe drugs which exert local effects on the gastro‐duodenal mucosa. Gastric mucosal levels of bismuth exceed the concentrations required to kill Helicobacter pylori in vitro. The mechanisms of actions of bismuth on gastrointestinal pathogens including H. pylori are complex and include inhibition of protein and cell wall synthesis, membrane function and ATP synthesis. Adherence of H. pylori to surface epithelial cells is also impaired. Bismuth monotherapy is effective in vivo to suppress H. pylori but cure rates are low. CBS, BSS and RBC have synergistic activity with one or two antibiotics and are effective in eradicating H. pylori. CBS and RBC also exert other effects on the mucosa including cytoprotective and ulcer healing properties. In addition, RBC is effective in inhibiting gastric acid secretion.
The role of Helicobacter pylori infection in non‐ulcer dyspepsia
Authors: VELDHUYZEN VAN ZANTEN S. J. O.
Published: October 2003

It is currently unclear whether Helicobacter pylori (H. pylori) infection plays a role in patients who fulfil the criteria for non‐ulcer dyspepsia. This paper reviews evidence for H. pylori‐induced changes in gastric emptying, gastrointestinal motility, gastric acid secretion, and gastric perception in patients with non‐ulcer dyspepsia. Problems in study design and execution of non‐ulcer dyspepsia treatment trials are discussed. The results of non‐ulcer dyspepsia treatment trials which have been performed in H. pylori‐positive patients are reviewed. To date none of them has convincingly shown that cure of the H. pylori infection leads to a sustained improvement in symptoms.
Endoscopic methods for the diagnosis of Helicobacter pylori
Authors: COHEN H. , LAINE L.
Published: October 2003

This article reviews endoscopic methods for the diagnosis of Helicobacter pylori. At the time of endoscopy certain findings (gastroduodenal ulceration and/or antral nodularity) may be highly suggestive of H. pylori infection. Endoscopic acquisition of gastric biopsies, however, leads to a definitive diagnosis of infection on the basis of both direct and indirect tests.

Direct tests include culture and histological detection (considered the gold standard). There are a variety of stains available for the detection of H. pylori; their choice is influenced by local expertise and the clinical situation. If at least three biopsies are obtained from non‐adjacent gastric sites, incorrect assessment of H. pylori status should be rare.

Indirect methods utilize the detection of urease. The three biopsy rapid urease tests commercially available in the USA have similar performance characteristics, except that two are gel tests requiring up to 24 h to read, while one is a strip test which is read up to 1 h. Specificity is excellent for these tests, while sensitivity is more variable. Rapid urease tests are the endoscopic tests of choice for initial evaluation due to their low cost.
Essential fatty acid supplementation in chronic hepatitis B
Authors: JENKINS A. P. , GREEN A. T. , THOMPSON R. P. H.
Published: October 2003

Background: Dietary supplementation with essential fatty acids and polyunsaturated lecithin may improve biochemical and histological parameters in liver disease.

Methods: Ten patients with serological and histological evidence of chronic hepatitis B received capsules of the polyunsaturated fatty acid‐rich evening primrose oil in a dose of 4 g daily for 12 months, while a matched group received liquid paraffin capsules as a placebo.

Results: Compared to the placebo group, the patients receiving evening primrose oil showed no improvement in either biochemical or histological indices of liver damage, or in the rate of loss of circulating e antigen.

Conclusions: Dietary supplementation with this dose of essential fatty acids is unlikely to be of benefit in chronic hepatitis B.
Influence of loperamide on lactose handling and oral–caecal transit time
Authors: SZILAGYI A. , SALOMON R. , SEIDMAN E.
Published: October 2003

Background: The influence of pharmacologically prolonged oral caecal transit time on lactose handling is examined in the wake of finding improved lactose handling during naturally occurring prolonged oral– caecal transit time.

Methods: Sixteen normal male volunteers with lactose maldigestion were pretreated with 8 and 12 mg loperamide on different days and lactose handling was compared by measuring areas under the curve during lactose breath H2 testing (3 h). The oral–caecal transit time was similarly measured using lactulose and exhaled breath H2. Symptom scores were recorded and, in three subjects, blood sugar was simultaneously measured.

Results: The mean±S.E.M. baseline oral–caecal transit time was 56.9±5.9 min. Loperamide significantly prolonged oral–caecal transit time (90.3±11.1 and 82.1±13.9 min for 12 and 8 mg loperamide, respectively; P<0.05). The lactose breath H2 area under the curve with 12 mg loperamide was significantly less than at baseline (7685±985.6 vs. 10243.1±1607, respectively; P<0.05). Significantly fewer symptoms were recorded with both doses of loperamide during the 3 h test but with 12 mg loperamide only on follow‐up. There was no significant rise in blood sugar at any time in the three subjects studied.

Conclusions: Loperamide‐induced graded prolongation of oral–caecal transit time is associated with significantly improved lactose handling as measured by a reduction of the area under the curve. Symptoms of lactose intolerance may also be improved with loperamide. Prolongation of oral–caecal transit time with loperamide may be useful as adjunctive or primary therapy of carbohydrate intolerance in patients with rapid transit.
In vitro dissolution profiles of enteric‐coated microsphere/microtablet pancreatin preparations at different pH values
Authors: GAN K.‐H. , GEUS W. P. , BAKKER W. , LAMERS C. B. H. W. , HEIJERMAN H. G. M.
Published: October 2003

Objectives: Enteric‐coated microsphere/microtablet pancreatin should stay intact in the stomach and dissolve promptly on entering the duodenum. Post‐prandial intraluminal pH in the distal duodenum is 5.75 and is lower in exocrine pancreatic insufficiency. The aim of the study was to measure in vitro dissolution times in buffer solutions with pH 4.0–6.0 for five currently available enteric‐coated microsphere/microtablet pancreatin preparations.

Methods: The following preparations were tested: Creon, Creon Forte, Pancrease, Pancrease HL and Panzytrat. Two capsules were placed in the buffer solution at 37 °C in a USP dissolution testing apparatus. Buffer solutions with pH between 4.0 and 6.0 were used. Solutions were stirred at 125 r.p.m. and the rate of dissolution was monitored by taking 2‐mL samples at regular intervals and measuring extinction at 280 nm. Measurements were repeated six times.

Results: All preparations failed to dissolve at pH 4.0. At pH 5.0 Pancrease HL showed 43% dissolution within 30 min, all other preparations 15% or less. Panzytrat and Pancrease HL showed more than 50% dissolution within 30 min at pH 5.2. Panzytrat, Pancrease HL and Creon Forte had more than 90% dissolution within 30 min at pH 5.6, and all preparations more than 90% dissolution within 30 min at pH 5.8 and higher.

Conclusions: For the treatment of exocrine panceatic insufficiency conventional strength enteric‐coated microsphere/microtablet pancreatin preparations do not have an optimal dissolution profile. The newer, high lipase preparations such as Pancrease HL perform better, although still not optimally, at pH 5.4 and lower.
Rapid symptom relief in reflux oesophagitis: a comparison of lansoprazole and omeprazole
Authors: MEE A. S. , ROWLEY J. L. ,   THE LANSOPRAZOLE CLINICAL RESEARCH GROUP
Published: October 2003

Background: Lansoprazole, a substituted benzimidazole, is a proton pump inhibitor which is highly effective in the control of 24‐h intragastric acidity. The aim of this multicentre, randomized, double‐blind study was to compare lansoprazole 30 mg once daily and omeprazole 20 mg once daily in the symptom relief and healing of patients with reflux oesophagitis.

Methods: Six hundred and four patients with endoscopically proven oesophagitis and a recent history of heartburn were randomly assigned to receive lansoprazole 30 mg or omeprazole 20 mg daily for 4–8 weeks. Daily assessment of symptoms was made by the patient using a 100‐mm Visual Analogue Scale. Clinical symptoms were evaluated at weeks 0, 1, 4 and 8. Endoscopic assessment of healing, defined by normalization of the oesophageal mucosal appearance, was made at weeks 4 and 8.

Results: Two hundred and eighty‐two patients in the lansoprazole group and 283 patients in the omeprazole group were eligible for inclusion in the per protocol analysis. At 3 days, there was a significant improvement in daytime symptoms of heartburn for patients in the lansoprazole group compared with the omeprazole group (P=0.05). A similar but non‐significant trend was seen at 7 days (P=0.18). Clinical assessment at 7 days demonstrated significant improvement in daytime epigastric pain in the lansoprazole group compared with the omeprazole group (P=0.03), with a similar but non‐significant trend in night‐time epigastric pain (P=0.07). Healing rates of oesophagitis at 4 and 8 weeks were 70 and 87%, respectively, with lansoprazole, and 63 and 82%, respectively, with omeprazole. Logistic regression analysis of the cumulative healing rates, which included baseline factors affecting outcome, resulted in an odds ratio of 1.46 (95% CI=0.87–2.45), suggesting a higher chance of being healed with lansoprazole treatment compared with omeprazole treatment. A total of 615 adverse events were reported by 308 (51%) patients during the study period. The majority of events were mild in nature and the incidence was similar in both treatment groups. The most frequently reported events were headache, diarrhoea and nausea.

Conclusion: Lansoprazole provides greater symptom relief compared with omeprazole during the first week of treatment. Both treatments were effective in healing oesophagitis.
Clinical economics review: cost‐effectiveness of treatment alternatives for gastro‐oesophageal reflux disease
Authors: SRIDHAR S. , HUANG J. , O'BRIEN B. J. , HUNT R. H.
Published: October 2003

Gastro‐oesophageal reflux disease is a chronic recurring disorder, which is widespread, especially in Western societies. Faced with increasing health costs and finite resources, an increasingly important part of evaluating new treatments is economic appraisal. In this paper, we review critically the published economic studies of the cost‐effectiveness of treatments for gastro‐oesophageal reflux disease. Proton pump inhibitors are considered the best choice for the management of grades II–IV oesophagitis and are more cost‐effective than H2‐receptor antagonists because of their fast healing of oesophagitis, early relief of symptoms, and prevention of recurrent oesophagitis and development of complications.
A prospective follow‐up study of 5669 users of lansoprazole in daily practice
Authors: LEUFKENS H. , CLAESSENS A. , HEERDINK E. , VAN EIJK J. , LAMERS C. B. H. W.
Published: October 2003

Background:

Immediately after the introduction of the proton pump inhibitor lansoprazole, a 2‐year follow‐up study was started to evaluate patterns of use, safety and effectiveness of this drug in naturally occurring groups of patients in the Netherlands. Medical data were recorded by participating physicians while medication listings were provided by pharmacists.

Methods:

The study was designed according to the Safety Assessment of Marketed Medicines guidelines. The only inclusion criterion was the use of lansoprazole prior to entry into the study.

Results:

A total of 5669 lansoprazole users was included by 374 general practitioners and 117 specialists. Lansoprazole was mostly prescribed in patients with reflux oesophagitis (55.1%), `gastritis' (26.8%) and duodenal ulcers (11.4%), sometimes as part of a Helicobacter pylori eradication therapy (8.5%). For their complaints most patients (91.1%) had previously used acid‐related drugs. Improvement or disappearance of complaints was achieved in 88.9% and 90.5% of patients after 4 and 8 weeks of treatment, respectively. Diarrhoea (4.1%), headache (2.9%) and nausea (2.6%) were the most frequently reported adverse events.

Conclusion:

The patterns of use of lansoprazole in daily practice deviated from the recommendations in the information leaflet. Nevertheless, lansoprazole was found to be safe in this naturally occurring group of users. Effectiveness appeared to be comparable to results found in clinical trials of the registered indications for lansoprazole.
Twice a day quadruple therapy (bismuth subsalicylate, tetracycline, metronidazole plus lansoprazole) for treatment of Helicobacter pylori infection
Authors: GRAHAM D. Y. , HOFFMAN J. , EL‐ZIMAITY H. M. T. , GRAHAM D. P. , OSATO M.
Published: October 2003

Background:

Quadruple therapy (bismuth, metronidazole and tetracycline (BMT) + proton pump inhibitor) is touted as being >95% effective, regardless of metronidazole resistance. We tested a 10‐day b.d. quadruple therapy for treatment of H. pylori infection.

Methods:

Anti‐H. pylori therapy consisted of lansoprazole 15 mg b.d. plus tetracycline 500 mg b.d., metronidazole 500 mg b.d., and swallowable Pepto‐Bismol caplets (2 b.d.) for 10 days. H. pylori status was evaluated by culture and histology before and 4 or more weeks after therapy.

Results:

The cure rate for intention‐to‐treat was 70%. Treatment success was calculated overall and separately in relation to antimicrobial resistance patterns. The cure rate among the metronidazole‐sensitive isolates was 89.7% (26 of 29) vs. 41.2% (7 of 17) of the metronidazole‐resistant isolates (P < 0.005). Moderate (n = 1) or severe (n = 3) side‐effects were experienced in four patients with only one withdrawing because of side‐effects.

Conclusion:

Twice a day quadruple therapy is effective for metronidazole‐sensitive strains but its usefulness is markedly reduced by the presence of pre‐treatment metronidazole resistance. Twice a day quadruple therapy can be recommended in locations where background metronidazole resistance is uncommon. Possibly, 14‐day therapy or a higher dosage of metronidazole provide better results with metronidazole‐resistant H. pylori.
Lack of dose–response with Pancrease MT for the treatment of exocrine pancreatic insufficiency in adults
Authors: OPEKUN Jr A. R. , SUTTON Jr F. M. , GRAHAM D. Y.
Published: October 2003

Background

Choosing the optimum pancreatic enzyme replacement therapy for patients with exocrine insufficiency remains a problem. An enteric coated enzyme microsphere pancreatic enzyme preparation (Pancrease) has been marketed with several levels of lipase activity, implying that there is a dose–response relationship between dose and effectiveness such that the high potency form appears to be the most cost effective.

Methods

In a randomized, single‐blind, cross‐over study, we evaluated the effectiveness of a commercial enzyme preparation with different amounts of lipase per dosage unit in adults with exocrine pancreatic insufficiency. Patients received a diet comprising 100 g fat each day for 6 days. With each meal (three per day) they received two capsules of either Pancrease MT4 (8000 unit lipase), Pancrease MT10 (20 000 units lipase), Pancrease MT16 (32 000 units lipase) or placebo. A 72‐h quantitative faecal collection was carried out for the last 3 days of the 6‐day period.

Results

There was a reduction in faecal fat excretion with each of the preparations compared to placebo. The difference failed to reach significance with the 8000 units lipase preparation (P>0.05) but was significant (P=0.02) with the 20 000 units lipase and the 32 000 units lipase preparations (faecal fat excretion: placebo=42.1±29 g, lipase 8000 =22.1 ± 7.3 g, lipase 20 000 =10.2±4.5 g and lipase 32 000 = 15.8±12.5 g, P < for 20 000 units and 32 000 units lipase compared to placebo).

Conclusion

A dose–response relationship between the amount of lipase administered with each meal and a reduction in faecal fat was not evident. The most potent preparation did not provide additional benefits compared to the less expensive lower potency dosage form.
Prognostic factors for relapse of reflux oesophagitis and symptoms during 12 months of therapy with lansoprazole
Authors: HATLEBAKK J. G. , BERSTAD A.
Published: October 2003

Background:

Symptom relief and endoscopic healing are both important treatment goals in patients with reflux oesophagitis. Knowledge of predictive factors for treatment success could facilitate choice of treatment in individual patients.

Aim:

To assess the value of clinical data and data from baseline ancillary investigations in predicting the outcome of maintenance therapy with a proton pump inhibitor.

Methods:

After healing and symptom relief had been obtained on open therapy with lansoprazole 30 mg daily, 103 patients with reflux oesophagitis grade 1 or 2 were randomized to maintenance therapy with lansoprazole 15 or 30 mg daily, and time until recurrence of symptoms and/or endoscopic changes was recorded. The predictive value of the following variables was assessed by Cox regression analysis: dose of lansoprazole, symptom severity, grade of reflux oesophagitis, Helicobacter pylori infection status, lower oesophageal sphincter resting tone, percentage of 24 h with an oesophageal pH of <4.0, and median 24 h intragastric pH before start of treatment.

Results:

Dose of lansoprazole (P = 0.01) and symptom severity (P < 0.05) both significantly predicted time to relapse. Grade of reflux oesophagitis had only a borderline predictive value (P = 0.09), while H. pylori infection status and data from manometry and intraoesophageal 24‐hour pH‐metry did not predict relapse.

Conclusions:

Symptom severity before starting therapy is a significant predictive factor for treatment success during potent antisecretory therapy with lansoprazole, more so than endoscopic grade of reflux oesophagitis. In a group of patients with uncomplicated reflux oesophagitis being considered for maintenance therapy with lansoprazole, ancillary investigations with endoscopy, manometry and 24‐hour pH‐metry gave very limited prognostic information. H. pylori infected patients relapsed as early as patients who were not infected.
YF476 is a new potent and selective gastrin/cholecystokinin‐B receptor antagonist in vitro and in vivo
Authors: TAKINAMI Y. , YUKI H. , NISHIDA A. , AKUZAWA S. , UCHIDA A. , TAKEMOTO Y. , OHTA M. , SATOH M. , SEMPLE G. , MIYATA K.
Published: October 2003

Background: We newly synthesized YF476 ((R)‐1‐[2,3‐dihydro‐2‐oxo‐1‐pivaloylmethyl‐5‐(2′‐pyridyl)‐1H‐1,4‐benzodiazepin‐3‐yl]‐3‐(3‐methylamino‐phenyl)urea) as a gastrin/cholecystokinin‐B (CCK‐B) receptor antagonist. We investigated the pharmacological profile of YF476 in vitro and in vivo.

Methods: We examined the binding properties of YF476 to the rat brain, cloned canine and cloned human gastrin/CCK‐B receptors, and the effect of YF476 on secretagogue‐induced gastric acid secretion in rats and Heidenhain pouch dogs.

Results: YF476 replaced the specific binding of [125I]CCK‐8 to the rat brain, cloned canine and cloned human gastrin/CCK‐B receptors, with Ki values of 0.068, 0.62 and 0.19 nM, respectively. The affinity of YF476 for rat brain gastrin/CCK‐B receptor was 4100‐fold higher than that for rat pancreatic CCK‐A receptor. In anaesthetized rats, intravenous YF476 inhibited pentagastrin‐induced acid secretion with an ED50 value of 0.0086 μmol/kg, but did not affect histamine‐ and bethanechol‐induced acid secretion at a dose of 10 μmol/kg. In Heidenhain pouch dogs, intravenous and oral YF476 inhibited pentagastrin‐stimulated gastric acid secretion in a dose‐dependent manner with ED50 values of 0.018 and 0.020 μmol/kg, respectively, but did not affect histamine‐induced acid secretion.

Conclusion: These results suggest that YF476 is an extremely potent and highly selective gastrin/CCK‐B receptor antagonist, and that the gastrin/CCK‐B receptor is not involved in histamine‐ or bethanechol‐induced gastric acid secretion in dogs or rats.
Suppression of intestinal mucosal natural killer cells by corticosteroids
Authors: VAN IERSSEL A. J. H. M. , MIEREMET‐OOMS M. A. C. , VAN DER ZON J. M. , VAN HOGEZAND R. A. , GRIFFIOEN G. , LAMERS C. B. H. W. , VERSPAGET H. W.
Published: October 2003

Background: Corticosteroid therapy of patients with inflammatory bowel disease can give rise to systemic side‐effects. Budesonide is a topically acting corticosteroid with low systemic bioavailability and is efficacious in the treatment of inflammatory bowel disease. Natural killer cells were previously found to be altered, both systemically and locally, in patients with inflammatory bowel disease. Modulatory effects of budesonide, prednisolone, dexamethasone, and cortisol on peripheral blood NK cells have already been described, but have never been assessed on mucosal NK cells from the intestine.

Methods: The effect of the synthetic corticosteroids prednisolone and budesonide, the endogenous corticosteroid cortisol, and adrenocorticotropic hormone was analysed on NK cells isolated from the lamina propria of human intestinal resection specimens.

Results: The three corticosteroids suppressed intestinal NK cell activity, not only during the cytotoxicity assay, but also after pre‐incubation of the lamina propria mononuclear cells. ACTH, however, did not affect the activity of intestinal NK cells. We previously showed that corticosteroid‐suppressed peripheral blood NK cell activity could be restored in vivo, but not in vitro, by the administration of ACTH. In the present study, the in vitro incubation of budesonide‐ or prednisolone‐suppressed mucosal NK cells with cortisol, alone or combined with ACTH, did not revert the suppressed NK cell activity. These findings are similar to our previous observations with peripheral blood NK cells.

Conclusions: Intestinal mucosal NK cells can be suppressed by systemically as well as locally acting corticosteroids. This suppression in NK cell activity is not reversed by incubation with cortisol and/or ACTH.
Effects of recombinant human thrombopoietin on megakaryocyte colony formation and megakaryocyte ploidy by human CD34+ cells in a serum‐free system
Authors: Angchaisuksiri Pantep , Carlson Patricia , Dessypris Emmanuel
Published: October 2003

In serum‐free cultures of human CD34 cells, recombinant human thrombopoietin (TPO) induced megakaryocyte colony formation in a dose‐dependent fashion that was further enhanced by the presence of interleukin‐3 (IL‐3) and stem cell factor (SCF), but not by IL‐6, IL‐11 or erythropoietin. TPO gave rise to much smaller colonies and at an earlier time than IL‐3, indicating that TPO affects predominantly more mature megakaryocytic progenitors. In liquid cultures, TPO increased the percentage and the absolute number of ≥8N megakaryocytes, but it did not shift their modal ploidy from 2N. TPO‐induced endomitosis was totally inhibited by the presence of, or previous exposure of cells to, IL‐3 and/or SCF. The mechanism by which TPO overcomes in vivo the negative effects of IL‐3 and SCF on megakaryocyte ploidy remains unknown.
A phase II trial of partially incompatible bone marrow transplantation for high‐risk acute lymphoblastic leukaemia in children: prevention of graft rejection with anti‐LFA‐1 and anti‐CD2 antibodies
Authors: CAVAZZANA‐CALVO M. , BORDIGONI P. , MICHEL G. , ESPEROU H. , SOUILLET G. , LEBLANC T. , STEPHAN J. L. , VANNIER J. P. , MECHINAUD F. , REIFFERS J. , VILMER E. , LANDMAN‐PARKER J. , BENKERROU M. , BARUCHEL A. , PICO J. , Bernaudin F. , Bergeron C. , PLOUVIER E. , THOMAS C. , WIJDENES J. , LACOUR B. , BLANCHE S. , FISCHER A.
Published: October 2003

Bone marrow transplantation (BMT) from matched sibling donors has been useful for the treatment of acute lymphoblastic leukaemia in children with a poor prognosis but is not available to more than two‐thirds of patients who do not have a matched allogeneic donor. This study was undertaken to assess one strategy of marrow graft rejection prevention when alternative marrow sources such as HLA‐phenoidentical unrelated volunteers and HLA‐partially incompatible relatives were used. Results have been compared with two matched groups of children with the same risks factors and disease status who underwent HLA‐genoidentical or autologous BMT. The conditioning regimen was the same for the three groups of patients; in the study group anti‐LFA‐1 and anti‐CD2 monoclonal antibodies combined with T‐cell depletion of the marrow was added to prevent graft rejection and graft‐versus‐host disease.  Nineteen patients were included and followed for a median of 25 months (14 months to 3 years). Bone marrow engraftment occurred in 83% of the evaluable patients. Post‐transplantation infectious diseases were the most frequent causes of death in the study group, occurring in 31% of patients. No fatal infections occurred in the two control groups. Post‐transplantation relapse of leukaemia occurred in 26% of study group's patients, in 58% of autologous BMT control group's patients and in 5% of HLA‐genoidentical allogeneic group's patients. The event‐free survival was 83% in the HLA‐genoidentical control group, and 30% and 24% in the study group and in the autologous control group, respectively.  In conclusion, a high rate of engraftment was achieved by the use of anti‐LFA‐1 and anti‐CD2 antibodies. Occurrence of a long‐lasting immunodeficiency, however, led to a high incidence of lethal infections and relapses. Combined approaches are therefore to be investigated accelerating immune reconstitution after transplantations of T‐depleted HLA partially incompatible marrow.
The release of nitric oxide and superoxide anion by neutrophils and mononuclear cells from patients with sickle cell anaemia
Authors: Dias‐Da‐Motta Péricles M. , Arruda Valder R. , Muscará Marcelo N. , Saad Sara T. O. , De Nucci Gilberto , Costa Fernando F. , Condino‐Neto Antonio
Published: October 2003

The aim of this work was to investigate the release of nitric oxide and superoxide by neutrophils and mononuclear cells from patients with sickle cell anaemia. Nitric oxide release was assayed by the ability of leucocytes to inhibit thrombin‐induced washed platelet aggregation. Superoxide release was assessed by a cytochrome c reduction assay. Neutrophils from sickle cell anaemia patients released nitric oxide in a similar manner to those from healthy controls, because inhibition of platelet aggregation by neutrophils from sickle cell anaemia or from healthy controls was blocked by the inhibitor of nitric oxide synthesis N ω‐nitro‐l‐arginine methyl ester (300 μm), but not by N ω‐nitro‐d‐arginine methyl ester (300 μm) and was reversed by l‐arginine (1 mm). Additionally, a similar number of neutrophils from sickle cell anaemia patients and from healthy controls was required to inhibit platelet aggregation. Mononuclear cells from sickle cell anaemia patients inhibited platelet aggregation only in the presence of superoxide dismutase (60 U ml−1). Phorbol 12‐myristate 13‐acetate (PMA, 30 nm)‐ or zymosan (100 particles/cell)‐induced release of superoxide by mononuclear cells from sickle cell anaemia patients was significantly higher than that observed in mononuclear cells from healthy controls (P < 0.001 and P < 0.01 respectively, Mann‐Whitney test). The levels of superoxide released by neutrophils from sickle cell anaemia patients were similar to those from healthy controls. We conclude that mononuclear cells from sickle cell anaemia patients release more superoxide than those from healthy controls, when stimulated with PMA or zymosan in vitro. Considering that superoxide inactivates nitric oxide, that nitric oxide is an important endogenous vasodilator, and that superoxide produces oxidant damage, this greater production of superoxide by mononuclear cells from sickle cell anaemia patients may represent an additional risk factor for the obstruction of the microcirculation and tissue damage in these patients.
Effects of desmopressin on circulating P‐selectin
Authors: Jilma Bernd , Eichler Hans‐Georg , Vondrovec Barbara , Breiteneder Helene , Kyrle Paul A. , Kitzweger Elvira , Kapiotis Stylianos , Speiser Wolfgang
Published: October 2003

Von Willebrand factor (VWF) and P‐selectin share an identical intracellular storage compartment and transport to the cell surface. We induced degranulation of the Weibel‐Palade bodies and measured circulating (c)P‐selectin in plasma to test whether soluble P‐selectin is present in the Weibel‐Palade bodies, or if P‐selectin bound to the cell membrane of endothelial cells (EC) is rapidly proteolytically cleaved in vivo.  A dose of 0.3 μg/kg of desmopressin (DDAVP) or placebo was infused over 30 min to eight healthy men in a double‐blind cross‐over study. Plasma levels of cP‐selectin and VWF‐Ag were followed for 24 h. Despite a twofold increase in VWF‐Ag levels immediately after and 2 h after infusion of DDAVP, no significant change in plasma concentrations of cP‐selectin were observed.  In summary, degranulation of the Weibel‐Palade bodies is an unlikely source of cP‐selectin. Thus cP‐selectin in healthy subjects is conceivably attributable to other mechanisms, such as minor degrees of platelet activation or transcription induction of an alternatively spliced P‐selectin.