bluuebunny/crossref_metadata_2025_split huggingface dataset:
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: PHARMACOKINETIC/CYTOKINETIC PRINCIPLES IN THE CHEMOTHERAPY OF SOLID TUMOURS
Authors: Baguley Bruce C. , Finlay Graeme J. 
Published: June 2007

SUMMARY1. The solid tumour has various properties which tend to minimize the effects of a cytotoxic agent; the low vascular density of tumours, in particular, limits the diffusion of many anti‐tumour drugs.2. This applies particularly to two general classes of anti‐cancer drugs which already play an important role in chemotherapy: mitotic poisons and topoisomerase poisons. Such compounds bind strongly to proteins and/or DNA, and their diffusion from the bloodstream into solid tumours is slow, as is their clearance from tumour tissue.3. The specific question posed here is whether anti‐cancer compounds of these types are more cytotoxic when administered at a low concentration for a long time (mimicking conditions in solid tumours) than at a correspondingly high concentration for a short time (mimicking conditions in host tissue). Two possible principles may be involved, the first baaed on cytokinetic considerations and the second on self‐inhibition of drug cytotoxicity.4. Using cultured human cancer cells we have shown that taxol, which acts on mitotic cells and camptothecin, which acts on S‐phase cells, are examples of the first principle. Exposures to high drug concentrations for short times are much less cytotoxic than exposure to correspondingly lower drug concentrations for a longer time (with the same concentration × time of exposure). We also show that the drug DACA (N‐[2‐(dimethylamino)ethyl]acridine‐4‐carboxamide), developed in this laboratory and currently undergoing clinical trial, achieves the same result through the principle of self‐inhibition of cytotoxicity.5. Matching of the cytokinetic or self‐inhibitory profile of a drug's action with the pharmacokinetics of drug in tumours may provide new drugs with increased anti‐tumour effects.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: NEW DRUGS IN THE TREATMENT OF HEART FAILURE
Authors: Brown Lindsay 
Published: June 2007

SUMMARY1. Current therapy of heart failure relies on diuretics, positive inotropic compounds and vasodilators. The short‐term haemo‐dynamic benefits, especially of the cAMP generators, may be compromised by long‐term limitations leading to an increased mortality. In contrast, some vasodilators, especially angiotensin converting enzyme inhibitors, improve survival even in severe heart failure.2. Modulation of Na+‐ or K+‐channels and calcium sensitization are positive inotropic mechanisms whose promise in treatment of heart failure needs to be fully explored.3. The introduction of vasodilator therapy has been a significant advance. Newer compounds act to inhibit the endogenous vasoconstrictors angiotensin II and endothelin, or to potentiate the endogenous vasodilators atrial natriuretic factor and nitric oxide. The full potential of these compounds is yet to be realised.
OPIOIDS: A PHARMACOLOGIST'S DELIGHT!
Authors: Mather Laurence E. 
Published: June 2007

SUMMARY1. Opioids, in one form or another, have been used for their pain‐relieving properties from prehistoric times: they are still the first line medication for the treatment of severe nociceptive pain and are likely to remain so for the foreseeable future.2. The therapeutic index of opioids used for pain management is low: opioid side effects are essentially extensions of therapeutic effects and no available agent has a marked advantage over the others. When used for opioid ‘anaesthesia’, differences in therapeutic index are more obvious due to differences in non‐opioid effects.3. Opioid receptors in brain and spinal cord periphery are the main ‘therapeutic targets’ and clinical dosage strategies have been derived using a variety of systemic (indirect or blood‐borne) methods as well as intraspinal and intracerebro‐ventricular (direct) methods: no method, however, is without potential side effects. Peripheral opioid effects are now being exploited with intra‐articular injection.4. Opioid pharmacokinetics and pharmacodynamics are characterized by high inter‐subject variability: accordingly, patient‐controlled dosage strategies are found to be more successful for pain control than deterministic recipes.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: A NEW VIEW OF THE ROLE OF DOPAMINE RECEPTORS IN THE REGULATION OF MUSCLE TONE
Authors: Crocker A. D. 
Published: June 2007

SUMMARY1. Clinical and exptrimental studies support the view that nigrostriatal dopaminergic neurons are involved in the maintenance of muscle tone.2. The effects of inactivating dopamine receptors in the rat substantia nigra on muscle tone, assessed as tonic electro‐myographic (EMG) activity, was investigated.3. Dopamine receptors were inactivated by injections of the irreversible dopamine receptor antagonist, N‐ethoxycarbonyl‐2‐ethoxy‐l,2‐dihydroquinoline (EEDQ) into the pars reticulata of the substantia nigra.4. Significant increases in EMG activity were observed from 2 to 24 h after EEDQ injection and were associated with a loss of nigral dopamine receptors.5. Increases in EMG activity were found only when both D1 and D2 receptors were inactivated.6. Inactivation of α‐adrenoceptors, 5HT2c and muscarinic receptors had no effect on EMG activity.7. Injections of apomorphine did not reduce the increased EMG activity associated with nigral dopamine receptor loss.8. The results are consistent with the hypothesis that dopamine receptors in the substantia nigra of the rat play an important role in the regulation of muscle tone.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: THE ALLOMETRIC APPROACH FOR INTERSPECIES SCALING OF PHARMACOKINETICS AND TOXICITY OF ANTI‐CANCER DRUGS
Authors: Paxton James W. 
Published: June 2007

SUMMARY1. The rationale for extrapolation or ‘scaling’ across animal species is based on their underlying anatomical, physiological and biochemical similarities.2. Research carried out in the 19th and early 20th century resulted in Benedict's famous ‘mouse‐to‐elephant’ graph which showed that the log of the basal metabolic rate plotted against the log of body weight (W) produced a straight line with a slope of 0.76. Since then it has become apparent that a number of other physiological variables (Y) exhibit a similar relationship which can be represented by the general allometric equation, Y =αWβ; where β is the slope of the log‐log plot and α is the intercept on the y axis.3. The major pharmacokinetic parameters such as clearance and volume of distribution of many drugs are also related to W in a similar manner.4. This empirical approach does not require a strong mathematical background and offers a relatively simple method of predicting the kinetics of anti‐cancer drugs in patients from pre‐clinical animal data.5. The occurrence of major qualitative and quantitative differences in the metabolism of drugs between species is probably the single greatest complicating factor in the use of animals as predictors of drug toxicity and kinetics in patients.6. Despite this, the allometric approach is useful for allowing the estimation of a more appropriate starting dose for some drugs in a Phase I trial, which might result in potential savings in escalation steps and maximize the chance that the dose which an individual receives has the potential for therapeutic value.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: HYPOXIA‐ACTIVATED PRODRUGS AS ANTITUMOUR AGENTS: STRATEGIES FOR MAXIMIZING TUMOUR CELL KILLING
Authors: Wilson William R. , Pruijn Frederik B. 
Published: June 2007

SUMMARY1. Hypoxia arises in solid tumour because of inefficient blood supply. While hypoxic cells are resistant to radiotherapy and probably to many chemotherapeutic drugs they can, in principle, be turned to advantage through the development of hypoxia‐activated cytotoxic drugs (bioreductive drugs).2. Three general approaches to exploiting tumour hypoxia are discussed. The first relies on fluctuating blood flow in tumours and the consequent cycling of cells through the hypoxic compartment. The second incorporates a prodrug approach in which drug activation gives rise to cytotoxic metabolites which diffuse out of hypoxic zones. The third utilizes selective inhibitors of tumour blood flow to induce additional hypoxia and thus enhance bioreductive drug activation.3. The latter two approaches are illustrated by recent studies with the dinitrobenzamide nitrogen mustard class of bioreductive drugs and their combination with the tumour blood flow inhibitor 5,6‐dimethylxanthenone‐4‐acetie acid.
RELATIVE CONTRIBUTIONS OF VOLUNTARY APNOEA, EXPOSURE TO COLD AND FACE IMMERSION IN WATER TO DIVING BRADYCARDIA IN HUMANS
Authors: Marsh Neville , Askew Debra , Beer Kelli , Gerke Michelle , Muller Diane , Reichman Coral 
Published: June 2007

SUMMARY1. Diving or face immersion bradycardia is a well recognized but incompletely understood reflex which occurs in man and other mammals.2. In order to investigate the contributions made by voluntary apnoea, face immersion in water and cold exposure, 18 normal subjects were exposed to these challenges separately and in various combinations.3. Tested individually, cold and apnoea caused significant reductions in heart rate (P<0.01 and 0.002, respectively). Face immersion in thermoneutral water had no effect on heart rate.4. The bradycardic effect of apnoea at maximal inspiration may be due to stimulation of pulmonary stretch receptors.5. Cold exposure and voluntary apnoea applied simultaneously caused a summative effect but when tested with face immersion in water there was a synergistic response greater than the sum of individual responses.6. The results confirm the bradycardic effect of apnoea and cold exposure, whereas immersion in thermoneutral water had little effect, a finding which has been disputed in the literature.
DIRECT EFFECTS OF ANGIOTENSIN I, ANGIOTENSIN II, AN ACE INHIBITOR AND A SERINE PROTEINASE INHIBITOR ON CULTURED HEART CELLS FROM SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Kuzuo Hiroshi , Honda Masaaki , Tanaka Koichi , Kuramochi Takehiko , Morioka Shigefumi , Takabatake Toshikazu , Yamori Yukio 
Published: June 2007

SUMMARY1. The purpose of the present study was to investigate how angiotensin 1 (AI), angiotensin II (AII), an angiotensin converting enzyme inhibitor (ACE inhibitor; ACE‐I) and a serine proteinase inhibitor contribute to the protein metabolism of cultured newborn spontaneously hypertensive rats (SHR) heart cells. We examined the uptake of [3H]‐uridine and [3H]‐proline into cultured cardiac myocytes and fibroblasts, respectively.2. Both AI and AII increased the uptake of [3H]‐uridine into myocytes in a concentration‐dependent manner. However, the effect of AI was denied in the presence of the ACE‐I with the concentration of 10−6 g/mL. Both AI and AII increased the uptake of [3H]proline into cardiac fibroblasts in a concentration‐dependent manner. However, this effect was only partially abolished in the presence of 10−6 g/mL of the ACE‐I, which was the maximal concentration that did not exert any effect on the [3H]‐proline uptake. In the presence of AII receptor antagonist, [Sar1, Led8]‐ AII, the uptake of [3H]. proline into cardiac fibroblasts was completely inhibited. Moreover, the stimulatory effects of AI on the uptake of [3H]‐proline into cardiac fibroblasts were completely inhibited in the presence of a serine proteinase inhibitor in addition to the ACE‐I.3. These results suggest that an ACE‐I has different effects on protein metabolism in the heart and also suggest the presence of serine proteinase in cultured cardiac fibroblasts from SHR.
DELETERIOUS EFFECTS OF SALT INTAKE OTHER THAN EFFECTS ON BLOOD PRESSURE
Authors: Antonios Tarek F. T. , MacGregor Graham A. 
Published: June 2007

SUMMARY1. Salt intake is not only known to play an important role in determining blood pressure (BP) but has been shown to have other deleterious effects independent of BP.2. Epidemiological and animal studies have provided evidence that salt intake may have an adverse effect on stroke mortality independent of BP.3. Significant correlation between sodium excretion (as a measure of salt intake) and left ventricular (LV) hypertrophy has been shown in many clinical studies. Salt restriction has also been found to produce a significant reduction in LV mass.4. In animal studies, salt restriction in uninephrectomized spontaneously hypertensive rats retarded renal glomerular injury and suppressed compensatory growth independent of hypertension. Moreover, a high sodium diet accelerated cerebral arterial disease even when no increases in BP could be detected.5. Epidemiological data have shown an association between asthma mortality and regional purchases of table salt. Furthermore, dietary salt restriction in asthmatic patients results in improvement of symptomatology with lower consumption of bronchodilators.6. Patients with essential hypertension are known to have increased urinary calcium excretion, and hypertension may be one factor that may increase the likelihood of osteoporosis. High salt intake is also associated with increased hydroxyproline excretion indicating increased resorption of bone. Sodium restriction reduces calcium excretion and may reduce bone demineralization and hip fractures in a similar manner to that seen with diuretics.
ALCOHOL AND HYPERTENSION
Authors: Beilin L. J. 
Published: June 2007

SUMMARY1. Regular alcohol consumption is a significant contributor to the prevalence of hypertension in drinking communities.2. The effect is additive to that of obesity and is partly reversible over 2–4 weeks with moderation of ethanol intake.3. In heavy drinkers acute alcohol withdrawal may lead to more blood pressure elevation following an initial depressor response.4. Heavy drinking is also associated with an increased risk of haemorrhagic stroke and cardiomyopatby.5. Lighter drinking habits appear to offer significant protection against ischaemic heart deaths and ischaemic strokes.6. Antihypertensive drug treatment for alcohol related hypertension may mask some of the adverse cardiovascular effects of alcohol.7. Arguments as to whether alcohol is a cause of essential hypertension are tautological, given the many reversible lifestyle factors now known to contribute to the rise in blood pressure with ageing.
NEW WORLD SYNDROME IN WESTERN AUSTRALIAN ABORIGINES
Authors: Gracey Michael 
Published: June 2007

SUMMARY1. It has become clear over the past 25 years that Aborigines in Western Australia (WA) now experience very high rates of type 2 diabetes mellitus and its complications as well as hypertension and cardiovascular disease; these disorders are often associated with obesity and abnormalities of plasma lipids.2. This experience is similar to that of Aboriginal people in other parts of Australia and to other previously traditional societies now in transition to an ubanized, Westernized existence; this is widely attributed to lifestyle factors and genetic susceptibility.3. This so‐called ‘New World Syndrome’ is responsible for disproportionately high levels of morbidity and mortality in the Aboriginal population of WA; prevention and improved methods of screening, detection and management are needed to reduce this problem.
USE OF PRIMARY CULTURES AND CONTINUOUS CELL LINES TO STUDY EFFECTS ON ASTROCYTIC REGULATORY FUNCTIONS
Authors: Walum Erik , Eriksson Gun , Peterson Anders , Holme Elisabeth , Larsson Nils‐Göran , Eriksson Charlotta , El‐Shamy Wael 
Published: June 2007

SUMMARY1. Current opinions on the mechanisms for glutamate‐mediated neurotoxicity are reviewed. The protective role of astrocytic high‐affinity glutamate transport is also discussed.2. Low‐density seeding of primary astrocytes from rat hemispheres was found to result in the development of reactive‐like astrocytes. Typical glial signs of amyotrophic lateral sclerosis (ALS) could not be induced in astrocyte cultures by serum from ALS‐patients.3. Glutamate (100 μmol/L) was found to induce an increase in respiratory activity in primary cultures of astrocytes. This stimulation appeared to be related to the co‐transport of Na2+ with glutamate and a resulting activation of Na2+/K+‐ATPase. Both basal respiration and glutamate‐stimulated oxygen consumption was inhibited by organic solvents.4. Preliminary results show that heavy metals cause an increase in the mitochondrial DNA content at concentrations that have no effect on growth rate or morphology in a glial cell line. This increase was accompanied by an inhibition of oxygen consumption and an increased production of lactate at unaltered ATP levels.
NEUROPHARMACOLOGY OF NICOTINE: EFFECTS ON THE AUTOREGULATION OF ACETYLCHOLINE RELEASE BY SUBSTANCE P AND METHIONINE ENKEPHALIN IN RODENT CEREBRAL SLICES AND TOXICOLOGICAL IMPLICATIONS
Authors: Sastry B. V. Rama 
Published: June 2007

SUMMARY1. The neuronal release of acetylcholine (ACh) and its autoregulation by neuromodulators, substance P (SP) and methionine enkephalin (MEK), have been studied using super‐fused rodent cerebral slices. Nicotine exerts significant effects on autoregulation of ACh release, which may have toxicological implications.2. Positive and negative feedback systems have been postulated for autoregulation of ACh release. The components of the positive feedback system include a muscarinic (Ms) receptor, SP, and activation of Ca2+ influx. Low levels of ACh in the biophase of the cholinergic synaptic gap may trigger the positive feedback system, and high levels of ACh may trigger the negative feedback system.3. There are also neuronal pathways for direct reciprocal regulations of SP and MEK.4. Low concentrations of nicotine triggers the release of ACh followed by MEK and SP. Release of SP causes neurogenic inflammation.5. Nicotine and its metabolite, cotinine, activate platelet activating factor (PAF)‐hydrolase and thereby enhance the turnover rate of PAF. This effect may contribute to tobacco‐induced arterial thrombosis in peripheral and central nervous systems.
NEUROPROTECTION IN VITRO AND IN VIVO BY CELL MEMBRANE‐PERMEANT Ca2+ CHELATORS
Authors: Tymianski Michael 
Published: June 2007

SUMMARY1. A method of attenuating excitotoxic and hypoxic/ ischaemic neurodegeneration in vitro and in vivo using cell‐permeant Ca2+‐chelating agents is described.2. The mechanism of neuroprotection may depend on both pre‐ and post‐synaptic effects on intracellular Ca2+ dynamics.3. This method is unique, because it targets Ca2+ ions, the presumed triggers of neurodegeneration, rather than a specific cellular receptor.
APOPTOTIC AN IN AN IN VITRO MODEL OF NEURONAL OXIDATIVE STRESS
Authors: Ratan Rajiv R. , Baraban Jay M. 
Published: June 2007

SUMMARY1. Oxidative stress is believed to be an important mediator of neuronal cell death but the precise mechanism by which this accurs is unknown.2. We have developed an in vitro model of neuronal oxidative stress to study the pathways by which free radicals kill neurones.3. We have shown that oxidative stress, cystine deprivation and glutathione depletion results in cell death with the morphological and biochemical features of apoptosis.4. Neuronal apoptosis induced by oxidative stress can be inhibited by macromolecular synthesis inhibitors.5. This in vitro model will be a valuable tool for defining the molecular targets of toxic free radicals in neurones and, in turn, in designing rational new therapies for free radical mediated diseases.
NITRIC OXIDE INHIBITION DOES NOT PREVENT THE HYPOTENSIVE RESPONSE TO INCREASED RENAL PERFUSION IN RABBITS
Authors: Thomas C. J. , Anderson W. P. , Woods R. L. 
Published: June 2007

SUMMARY1. The involvement of nitric oxide (NO) and platelet activating factor (PAF) in the systemic depressor responses to increased renal perfusion pressure (RPP) were investigated.2. In anaesthetized rabbits, the left kidney was perfused via an extracorporeal circuit which allowed RPP to be increased from 65 mmHg to 125 mmHg. The response of systemic blood pressure (SBP) to increasing RPP was measured in the same rabbits.3. One group of rabbits (n = 5) was treated with NG‐nitro‐L‐arginine (NOLA) to inhibit NO synthase activity (20 mg/kg i.v. bolus). Another group (n= 5), received 250mmol/L NaHCO3 (4mL/kg bolus) as vehicle treatment.4. Following an increase in RPP to 125 mmHg, SBP fell at a rate of 0.43 ± 0.06 mmHg/min in the vehicle treated rabbits. After NO synthase inhibition the rate of fall in SBP of 0.34 ± 0.07 mmHg/min was not significantly different from that in the vehicle group (P= 0.3).5. Blockade of NO synthesis did not alter the renal blood flow, renal vascular resistance changes and pressure‐related natriuresis and diuresis responses to increased RPP to 125 mmHg.6. PAF receptor blockade, using WEB 2086 (0.5 mg/kg plus 0.5 mg/kg/h), did not alter the systemic, renal haemodynamic or urinary responses to increasing renal perfusion pressure to 125 mmHg.7. These findings indicate that neither NO nor PAF play an important role in the blood pressure lowering activity, intrarenal haemodynamics and urinary excretory responses observed when RPP was increased to a level within the physiological range.
ANALYSIS OF THE STEADY‐STATE DYNAMICS OF ORGANELLE MOTION IN CULTURED NEURITES: PUTATIVE INDICATOR OF NEUROTOXIC EFFECT
Authors: Chute Stewart K. , Flint Oliver P. , Durham Stephen K. 
Published: June 2007

SUMMARY1. The objective of this study was to develop a physiologically based method to evaluate the neurotoxic potential of drug candidates in vitro. Rat embryo midbrain cells were grown in micromass culture, and the movement of mitochondria labelled with the fluorescent dye rhodamine 123 was quantified in fasciculated neurites, using a laser cytometer.2. The rhodamine 123 signal in a defined region of fascicle was quantified and photobleached with the laser. A series of post‐photobleach scans revealed the movement of fluorescent‐labelled mitochondria into the bleached region from adjacent unbleached regions. Recovery of fluorescence is a measure of the size of the mobile pool of mitochondria relative to the total (moving plus stationary) pool.3. The steady‐state levels of fluorescence recovery was dependent on intracellular calcium and magnesium concentrations, energy status (ATP), and microtubule integrity (post taxol or vinblastine treatment).4. This technique may be a useful indicator of neurotoxic effect.
SUBUNIT‐DEPENDENT ACTION OF LEAD ON NEURONAL NICOTINIC ACETYLCHOLINE RECEPTORS EXPRESSED IN XENOPUS OOCYTES
Authors: Oortgiesen Marga , Zwart Ruud , van Kleef Regina G. D. M. , Vijverberg Henk P. M. 
Published: June 2007

SUMMARY1. Pb2+ affects neuronal nicotinic acetylcholine receptors (nAChR) in NIE‐115 neuroblastoma cells in a dual manner. At nanomolar concentrations a blockade is observed, while at submillimolar concentrations this blocking effect is reversed.2. The Xenopus oocyte expression system was used to examine whether the dual effect of Pb2+ is related to a differential action on nAChR subtypes. Effects of Pb2+ were investigated in oocytes expressing nAChR after co‐injection of a3 and β2 or α3 and β4 cDNA.3. At 1–250 μmol/L, Pb2+ causes a 10–1000% increase of the response mediated by the α3β2 nAChR.4. Pb2+ blocks ACh‐induced inward currents mediated by α3β4 nAChR. The inhibitory potency of Pb2+ greatly varies between cells. In 50% of the cells concentrations ≤μmol/L Pb2+ blocked the nicotinic response by 31–93%. In the other cells even at higher concentrations Pb2+ caused only 0–65% inhibition.5. These results show that Pb2+ may both potentiate and block nAChR, depending on the type of nAChR subunit expressed.