bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacotherapy Of The Ion Transport Defect In Cystic Fibrosis
Authors: Kunzelmann Karl , Mall Marcus 
Published: March 2003

SUMMARY1. More than 1300 different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF), a disease characterized by deficient epithelial Cl– secretion and enhanced Na+ absorption. The clinical course of the disease is determined by the progressive lung disease. Thus, novel approaches in pharmacotherapy are based primarily on correction of the ion transport defect in the airways.2. The current therapeutic strategies try to counteract the deficiency in Cl– secretion and the enhanced Na+ absorption. A number of compounds have been identified, such as genistein and xanthine derivatives, which directly activate mutant CFTR. Other compounds may activate alternative Ca2+‐activated Cl– channels or basolateral K+ channels, which supply the driving force for Cl– secretion. Apart from that, Na+ channel blockers, such as phenamil and benzamil, are being explored, which counteract the hyperabsorption of NaCl in CF airways.3. Clinical trials are under way using purinergic compounds such as the P2Y2 receptor agonist INS365. Activation of P2Y2 receptors has been found to both activate Cl– secretion and inhibit Na+ absorption.4. The ultimate goal is to recover Cl– channel activity of mutant CFTR by either enhancing synthesis and expression of the protein or by activating silent CFTR Cl– channels. Strategies combining these drugs with compounds facilitating Cl– secretion and inhibiting Na+ absorption in vivo may have the best chance to counteract the ion transport defect in cystic fibrosis.
Angiotensin I‐Converting Enzyme And Metabolism Of The Haematological Peptide N‐Acetyl‐Seryl‐Aspartyl‐Lysyl‐Proline
Authors: Azizi Michel , Junot Christophe , Ezan Eric , Ménard Joël 
Published: March 2003

SUMMARY1. Angiotensin I‐converting enzyme (ACE) has two homologous active N‐ and C‐terminal domains and displays activity towards a broad range of substrates. The tetrapeptide N‐acetyl‐seryl‐aspartyl‐lysyl‐proline (AcSDKP) has been shown to be hydrolysed in vitro by ACE and to be a preferential substrate for its N‐terminal active site. This peptide reversibly prevents the recruitment of pluripotent haematopoietic stem cells and normal early progenitors into the S‐phase.2. Angiotensin I‐converting enzyme inhibitors, given as a single dose to normal subjects or during long‐term treatment in hypertensive patients, result in plasma AcSDKP levels five‐ to six‐fold higher and urine concentrations 40‐fold higher than those of control subjects and/or patients. Thus, AcSDKP is a natural peptide hydrolysed by the N‐terminal domain of ACE in vivo. In addition, ACE may be implicated in the process of haematopoietic stem cell regulation by permanently degrading this natural circulating inhibitor of cell entry into the S‐phase.3. Besides hydrolysis by ACE, the second very effective mechanism by which AcSDKP is cleared from plasma is glomerular filtration. Because of its high sensitivity and specificity, the measurement of AcSDKP in plasma and urine provides a valuable tool in screening specific inhibitors of the N‐terminal domain of ACE and in monitoring ACE inhibition during chronic treatment.4. The long‐term consequences of AcSDKP accumulation are not known. During chronic ACE inhibition in rats, AcSDKP levels slightly increase in organs with high ACE content (kidneys, lungs). To significantly increase its concentration in target haematopoietic organs (the extracellular fraction of bone marrow), AcSDKP has to be infused on top of a captopril‐based treatment.5. A selective inhibitor of the N‐domain of ACE in vitro and in vivo has been identified recently. The phosphinic peptide RXP 407 does not interfere with blood pressure regulation, but does increase, dose dependently, plasma concentrations of AcSDKP in mice, in contrast with lisinopril, which affects the metabolism of both AcSDKP and angiotensin I. N‐Terminal‐selective ACE inhibitors may be used to selectively control AcSDKP metabolism in target haematopoietic organs. This new therapeutic strategy may be of value for protecting haematopoietic cells from the toxicity of cancer chemotherapy.
Molecular Diversity Of Vascular Potassium Channel Isoforms
Authors: Korovkina Victoria P , England Sarah K 
Published: March 2003

SUMMARY1. One essential role for potassium channels in vascular smooth muscle is to buffer cell excitation and counteract vasoconstrictive influences. Several molecular mechanisms regulate potassium channel function. The interaction of these mechanisms may be one method for fine‐tuning potassium channel activity in response to various physiological and pathological challenges.2. The most prevalent K+ channels in vascular smooth muscle are large‐conductance
calcium‐ and voltage‐sensitive channels (maxi‐K channels) and voltage‐gated channels
(Kv channels). Both channel types are complex molecular structures consisting of
a pore‐forming α‐subunit and an ancillary β‐subunit. The
maxi‐K and Kv channel α‐subunits assemble as tetramers and have S4 transmembrane
domains that represent the putative voltage sensor. While most vascular smooth muscle
cells identified to date contain both maxi‐K and Kv channels, the expression of individual
α‐subunit isoforms and β‐subunit association occurs in a tissue‐specific manner, thereby providing functional specificity.3. The maxi‐K channel α‐subunit derives its molecular diversity by
alternative splicing of a single‐gene transcript to yield multiple isoforms that
differ in their sensitivity to intracellular Ca2+ and voltage, cell surface
expression and post‐ translational modification. The ability of this channel to assemble
as a homo‐ or heterotetramer allows for fine‐tuning control to intracellular regulators.
Another level of diversity for this channel is in its association with accessory
β‐subunits. Multiple β‐subunits have been identified that
can arise either from separate genes or alternative splicing of a β‐subunit
gene. The maxi‐K channel β‐subunits modulate the channel’s Ca2+ and voltage sensitivity and kinetic and pharmacological properties.4. The Kv channel α‐subunit derives its diverse nature by the expression
of several genes. Similar to the maxi‐K channel, this channel has been shown to assemble
as a homo‐ and heterotetramer, which can significantly change the Kv current phenotype
in a given cell type. Association with a number of the ancillary β‐subunits affects Kv channel function in several ways. Beta‐subunits can induce inactivating properties and act as chaperones, thereby regulating channel cell‐surface expression and current kinetics.
Transcriptional Activation Of Energy Metabolic Switches In The Developing And Hypertrophied Heart
Authors: Lehman John J , Kelly Daniel P 
Published: March 2003

SUMMARY1. The present review focuses on the gene regulatory mechanisms involved in the control of cardiac mitochondrial energy production in the developing heart and following the onset of pathological cardiac hypertrophy. Particular emphasis has been given to the mitochondrial fatty acid oxidation (FAO) pathway and its control by members of the nuclear receptor transcription factor superfamily.2. During perinatal cardiac development, the heart undergoes a switch in energy substrate preference from glucose in the fetal period to fatty acids following birth. This energy metabolic switch is paralleled by changes in the expression of the enzymes and protein involved in the respective pathways.3. The postnatal activation of the mitochondrial energy production pathway involves the induced expression of nuclear genes encoding FAO enzymes, as well as other proteins important in mitochondrial energy transduction/production pathways. Recent evidence indicates that this postnatal gene regulatory effect involves the actions of the nuclear receptor peroxisome proliferator‐activated receptor α (PPARα)
and its coactivator the PPARγ coactivator 1 (PGC‐1).4. The PGC‐1 not only activates PPARα to induce FAO pathway enzymes in the postnatal heart, but it also plays a pivotal role in the control of cardiac mitochondrial number and function. Thus, PGC‐1 plays a master regulatory role in the high‐capacity mitochondrial energy production system in the adult mammalian heart.5. During the development of pathological forms of cardiac hypertrophy, such as that due to pressure overload, the myocardial energy substrate preference shifts back towards the fetal pattern, with a corresponding reduction in the expression of FAO enzyme genes. This metabolic shift is due to the deactivation of the PPARα/PGC‐1 complex.6. The deactivation of PPARα and PGC‐1 during the development of cardiac hypertrophy involves regulation at several levels, including a reduction in the expression of these genes, as well as post‐translational effects due to the mitogen‐activated protein kinase pathway. Future studies aim at defining whether this transcriptional ‘switch’ and its effects on myocardial metabolism are adaptive or maladaptive in the hypertrophied heart.
Altered Mitogen‐Activated Protein Kinase Activation In Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats
Authors: Kubo Takao , Ibusuki Takahiro , Chiba Satoshi , Kambe Toshie , Fukumori Ryuji 
Published: March 2003

SUMMARY1. We previously reported that activation function of mitogen‐activated protein kinases (MAPK) is enhanced in aorta strips from both prehypertensive and hypertensive spontaneously hypertensive rats (SHR) and that this enhancement of MAPK activation results from enhanced MAPK activation reactivity to angiotensin (Ang) II in SHR aorta strips.2. The purpose of the present study was to examine whether the enhanced function of the vascular angiotensin system observed in SHR aorta strips results from genetic alterations of vascular smooth muscle cells from SHR.3. Basal MAPK activity was within normal limits in cells from 4‐week‐old SHR, whereas enzyme activity was enhanced in 9‐week‐old SHR compared with age‐matched Wistar‐Kyoto (WKY) rats.4. Mitogen‐activated protein kinase activation reactivity to AngII and endothelin‐1 was enhanced in 9‐week‐old SHR cells but not in 4‐week‐old SHR cells. The enhancement of basal MAPK activity in 9‐week‐old SHR cells was abolished by a combination of the angiotensin AT1 receptor antagonist losartan and the endothelin receptor antagonist BQ123.5. These findings suggest that MAPK activation function in 4‐week‐old SHR cells is not enhanced. Thus, it appears that factors outside vascular smooth muscle cells are needed for the enhanced MAPK activation observed in 4‐week‐old SHR aorta strips. In 9‐week‐old SHR, MAPK activation function is enhanced in cells themselves and this function may, at least in part, contribute to the enhanced MAPK activation observed in SHR aorta strips.
In vitro neuromuscular activity of snake venoms
Authors: Hodgson Wayne C , Wickramaratna Janith C 
Published: March 2003

Summary1. Snake venoms consist of a multitude of pharmacologically active components used for the capture of prey. Neurotoxins are particularly important in this regard, producing paralysis of skeletal muscles. These neurotoxins can be classified according to their site of action (i.e. pre‐ or post‐synaptic).2. Presynaptic neurotoxins, which display varying phospholipase A2 activities, have been identified in the venoms of the four major families of venomous snakes (i.e. Crotalidae, Elapidae, Hydrophiidae and Viperidae). The blockade of transmission produced by these toxins is usually characterized by a triphasic effect on acetylcholine release. Considerable work has been directed at identifying the binding site(s) on the presynaptic nerve terminal for these toxins, although their mechanism of action remains unclear.3. Post‐synaptic neurotoxins are antagonists of the nicotinic receptor on the skeletal muscle. Depending on their sequence, post‐synaptic toxins are subdivided into short‐ and long‐chain toxins. These toxins display different binding kinetics and different affinity for subtypes of nicotinic receptors. Post‐synaptic neurotoxins have only been identified in venoms from the families Elapidae and Hydrophiidae.4. Due to the high cost of developing new antivenoms and the reluctance of many companies to engage in this area of research, new methodologies are required to test the efficacy of existing antivenoms to ensure their optimal use. While chicken eggs have proven useful for the examination of haemorrhagic venoms, this procedure is not suited to venoms that primarily display neurotoxic activity. The chick biventer cervicis muscle has proven useful for this procedure, enabling the rapid screening of antivenoms against a range of venoms.5. Historically, the lethality of snake venoms has been based on murine LD50 studies. Due to ethical reasons, these studies are being superseded by in vitro studies. Instead, the time taken to produce 90% inhibition of nerve‐mediated twitches (i.e. t90) in skeletal muscle preparations can be determined. However, these two procedures result in different rank orders because they are measuring two different parameters. While murine LD50 determinations are based on ‘quantity’, t90 values are based on how ‘quick’ a venom acts. Therefore, knowledge of both parameters is still desirable.6. In vitro neuromuscular preparations have proven to be invaluable tools in the examination of snake venoms and isolated neurotoxins. They will continue to play a role in further elucidating the mechanism of action of these highly potent toxins. Further study of these toxins may provide more highly specific research tools or lead compounds for pharmaceutical agents.
Abnormality in fibre type distribution of soleus and plantaris muscles in non‐obese diabetic Goto‐Kakizaki rats
Authors: Yasuda Koichiro , Nishikawa Waka , Iwanaka Nobumasa , Nakamura Eitaro , Seino Yutaka , Tsuda Kinsuke , Ishihara Akihiko 
Published: March 2003

Summary1. Fibre type distributions of the slow soleus and fast plantaris muscles were investigated in 5‐, 9‐ and 20‐week‐old male Goto‐Kakizaki (GK) rats, as an animal model of non‐obese diabetes, and were compared with those of age‐matched non‐diabetic Wistar rats.2. Bodyweight and both soleus and plantaris muscle weights were lower in GK rats than in Wistar rats, regardless of age. In addition, both relative soleus and plantaris muscle weights per bodyweight were lower in GK rats than in Wistar rats, regardless of age.3. In the soleus muscle, a higher percentage of type I fibres and a lower percentage of type IIA fibres were observed in 5‐ and 9‐week‐old GK rats. In addition, there were no type IIA fibres in 20‐week‐old GK rats.4. In the plantaris muscle, there were no differences in fibre type distribution of 5‐week‐old GK rats. However, a higher percentage of type IIB fibres and a lower percentage of type I and type IIA fibres were observed in 9‐ and 20‐week‐old GK rats. In addition, there were no type I fibres in 20‐week‐old GK rats.5. These results indicate that the decreased percentage of high‐oxidative fibres (e.g. type IIA fibres in the soleus muscle and type I and type IIA fibres in the plantaris muscle) of the diabetic animals is concerned with an impairment in insulin sensitivity and glucose metabolism and is not related to bodyweight.
Roles and regulation of glutamate transporters in the central nervous system
Authors: O'Shea RD 
Published: March 2003

Summary1. Glutamate transporters (also known as excitatory amino acid transporters or EAAT) are solely responsible for the removal of the excitatory neurotransmitter l‐glutamate (Glu) from the extracellular space and, thus, permit normal transmission, as well as preventing cell death due to the excessive activation of Glu receptors.2. Five subtypes of glutamate transporter (EAAT1–5) exist, possessing distinct pharmacology, cellular localization and modulatory mechanisms.3. Experimental inhibition of EAAT activity in vitro and in vivo results in increased extracellular concentrations of Glu and in neuronal death via excitotoxicity, highlighting the importance of EAAT in normal excitatory neurotransmission.4. Dysfunction of EAAT may contribute to the pathology of both acute neuronal injury and chronic neurodegenerative conditions, so correction of EAAT function under these conditions may provide a valuable therapeutic strategy.5. The present review describes basic pharmacological studies that allow new insights into EAAT function and suggest possible strategies for the therapeutic modulation of EAAT.
Effects of the angiotensin‐converting enzyme inhibitor alacepril on exercise capacity and neurohormonal factors in patients with mild‐to‐moderate heart failure
Authors: Kinugawa Toru , Osaki Shuichi , Kato Masahiko , Ogino Kazuhide , Shimoyama Masaki , Tomikura Yoko , Igawa Osamu , Hisatome Ichiro , Shigemasa Chiaki 
Published: March 2003

Summary1. Alacepril is a long‐acting, sulphydryl‐containing angiotensin‐converting enzyme inhibitor. Data are limited regarding the effects of alacepril on exercise tolerance in patients with chronic heart failure (CHF). The aim of the present study was to determine the effects of chronic alacepril treatment on exercise capacity and neurohormones in patients with CHF.2. The effects of 12 weeks treatment with alacepril on clinical, echocardiographic and cardiopulmonary exercise variables were studied in 18 CHF patients (mean age: 63 ± 2 years; New York Heart Association (NYHA) class I n = 6, class II n = 10, class III n = 2) in a cross‐over fashion. Resting levels of plasma noradrenaline, renin–angiotensin system activity and natriuretic peptides were evaluated.3. Treatment with alacepril significantly improved NYHA functional class and decreased cardiothoracic ratio (60.1 ± 2.0 vs 58.1 ± 1.9% for baseline vs alacepril, respectively; P < 0.01). Cardiac dimensions by echocardiogram were decreased after alacepril therapy. Peak Vo2 (17.7 ± 1.2 vs 19.5 ± 1.3 mL/min per kg; P < 0.01) and anaerobic threshold (11.7 ± 0.6 vs 13.2 ± 0.9 mL/min per kg; P < 0.01) increased with alacepril treatment. Plasma noradrenaline and plasma angiotensin II levels were not altered, but plasma aldosterone (77.7 ± 13.5 vs 51.7 ± 9.7 pg/mL; P < 0.01), atrial natriuretic peptide (ANP; 86.5 ± 20.3 vs 43.6 ± 7.6 pg/mL; P < 0.05) and brain natriuretic peptide (BNP; 222.7 ± 59.3 vs 117.7 ± 34.3 pg/mL; P < 0.05) levels decreased after alacepril treatment.4. These results suggest that treatment with alacepril improves functional status and exercise capacity in patients with mild‐to‐moderate CHF. Neurohormones were favourably influenced by alacepril therapy, with significant decreases in plasma aldosterone, ANP and BNP levels.
Antihyperglycaemic effect of Cassia auriculata in experimental diabetes and its effects on key metabolic enzymes involved in carbohydrate metabolism
Authors: Latha Muniappan , Pari Leelavinothan 
Published: March 2003

Summary1. In experimental diabetes, enzymes of glucose and fatty acid metabolism are markedly altered. Persistent hyperglycaemia is a major contributor to such metabolic alterations, which lead to the pathogenesis of diabetic complications. To our knowledge, there are no available reports on the enzymes of hepatic glucose metabolism of Cassia auriculata flower against diabetes. The present study was designed to study the effect of Cassia auriculata flower extract (CFEt) on hepatic glycolytic and gluconeogenic enzymes.2. Streptozotocin diabetic rats were given CFEt (0.15, 0.30 and 0.45 g/kg) or 600 µg/kg glibenclamide for 30 days. At the end of 30 days, blood glucose, plasma insulin, haemoglobin, glycosylated haemoglobin, glycolytic and gluconeogenic enzymes were assessed.3. Administration of CFEt at 0.45 g/kg significantly decreased blood glucose, glycosylated haemoglobin and gluconeogenic enzymes and increased plasma insulin, haemoglobin and hexokinase activity. Similarly, administration of glibenclamide showed a significant effect; however, CFEt at 0.15 and 0.30 g/kg did not show any significant effect.4. In conclusion, the observations show that the aqueous extract of CFEt possesses an antihyperglycaemic effect and suggest that enhanced gluconeogenesis during diabetes is shifted towards normal and that the extract enhances the utilization of glucose through increased glycolysis. The effect of CFEt was more prominent than that of glibenclamide.
Evaluation of antidotes for poisoning by organophosphorus pesticides
Authors: Johnson Martin K , Jacobsen Dag , Meredith Tim J , Eyer Peter , Heath Andrew J , Ligtenstein David A , Marrs Tim C , Szinicz Ladislaus , Vale J Allister , Haines John A 
Published: March 2003

AbstractPoisoning by organophosphorus pesticides results from inhibition of acetylcholinesterase. The outcome and optimum treatment depend on properties which differ among individual compounds. Treatment consists of supportive care, especially aimed at respiratory complications, and specific antidotal treatment. Treatment with atropine and diazepam is well established, but there is controversy concerning treatment with oximes capable of forcing reactivation of inhibited acetylcholinesterase. Although all parameters have not been fully established, initial bolus doses followed by continuous intravenous infusion to achieve plasma concentrations of 85–170 μmol/L of pralidoxime or 10–20 μmol/L of obidoxime have been recommended. These are well above concentrations that were likely to have been achieved by many of the ineffective regimens reported in the literature. Several independent reasons for failure of attempts at oxime therapy are discussed in this overview. If nothing else, it is likely that maintenance of adequate levels of oxime will shorten the period that a patient requires assisted ventilation with its associated risks. Topics for further laboratory and clinical research are listed. It is important to seek further understanding and the introduction of better practice because death rates from this type of poisoning remain significant.
Using the Toomey syringe as an oesophagal detector device
Authors: Marillier Eleanor , Bailey Paul , Rogers Ian R 
Published: March 2003

AbstractIn this report we describe the negative‐pressure or ‘Wee’ test for detection of inadvertent oesophageal intubation with reference to the published data on its reliability and potential problems. We also raise the possibility of using the readily available, low‐cost 50 mL catheter‐tipped (Toomey) syringe as an oesophageal‐detector device and present the results of a pilot study into the feasibility of this variation. Given the high sensitivity and specificity of these techniques, their widespread use is encouraged.
Impact of a toxicology service on a metropolitan teaching hospital
Authors: Lee Victor , Kerr J Fergus , Braitberg George , Louis William J , O'Callaghan Chris J , Frauman Albert G , Mashford M Laurence 
Published: March 2003

AbstractObjective:To evaluate the impact of a toxicology service on a major metropolitan teaching hospital.Method:A descriptive comparative study of all patients presenting with poisoning or suspected poisoning 12 months before and after the commencement of a toxicology service. Data on length of stay in the emergency department, disposition, length of stay of admitted patients and substance(s) involved were examined.Results:A total of 1316 poisoned patients were studied. There was a statistically significant increase in self‐poisonings from 612 to 704 (P= 0.002) and in the number of admissions from 113 to 192 (P < 0.05). There was no significant change in emergency department length of stay. The average length of stay for patients admitted under the care of the toxicology service decreased, especially for complicated patients.Conclusion:In the first 12 months of operation the toxicology service treated more patients than the 12‐month period prior to commencement, achieving a decrease in average length of stay for those patients admitted to the service. The emergency department length of stay was not altered. We surmise that by decreasing average length of stay for the patients under the care of the toxicology service, the net increase in the general pool of unoccupied beds improves bed access for all emergency department patients.