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Pharmacological Interventions (pharmacological + intervention)
Selected AbstractsRates of adherence to pharmacological treatment among children and adolescents with attention deficit hyperactivity disorderHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 5 2002El Sheikh R. Ibrahim Abstract Pharmacological intervention, mainly with psychostimulants, alone or with psychotherapy or behavioural modification, was found to be effective in increasing sustained attention span, improving concentration, reducing hyperactive behaviour and improving areas of academic deficits in children and adolescents with the diagnosis of attention deficit-hyperactivity disorder (ADHD). Despite their proven efficacy, noncompliance of the children and adolescents to the prescribed medication presents serious problems to patients and health care providers alike. Objective To investigate the rate of adherence to prescribed medication in a clinically referred sample of children and adolescents diagnosed as having ADHD. In addition, the stability of reports of adherence over a 3 month period was explored. Method Fifty-one children and adolescents (males: n,=,42; females: n,=,9) between the age of 7 years and 16.6 years diagnosed with ADHD and their parents were administered a children behaviour checklist, a teacher report form scale and a compliance with treatement opinion and attitude scale. Results There were very high reports of adherence by children to prescribed medications for ADHD with rates of compliance greater than 70%. Correlation between the children and adolescents' reports and the parents' reports revealed high agreement both at the end of week 1 and at the end of the study (week 12). There were also findings of stability of adherence reports over a 3 month period. Conclusion The results of this study documented high rates of adherence to medication prescribed for symptoms of attention deficit hyperactivity disorder in a sample of children and adolescents. Their reports of adherence were well correlated with parents' reports. Several factors were found to be related to the high level of adherence. Copyright © 2002 John Wiley & Sons, Ltd. [source] Effect of ,-adrenoceptor antagonists on autonomic control of ciliary smooth muscleOPHTHALMIC AND PHYSIOLOGICAL OPTICS, Issue 5 2002Barry Winn Abstract Purpose: Pharmacological intervention with peripheral sympathetic transmission at ciliary smooth muscle neuro-receptor junctions has been used against a background of controlled parasympathetic activity to investigate the characteristics of autonomic control of ocular accommodation. Methods: A continuously recording infra-red optometer was used to measure accommodation on a group of five visually normal emmetropic subjects under open- and closed-loop conditions. A double-blind protocol between saline, timolol and betaxolol was used to differentiate between the localised action on ciliary smooth muscle and effects induced by changes in stimulus conditions. Data were collected before and 45 min following the instillation of saline, timolol or betaxolol. Open-loop post-task decay was investigated following 3 min sustained near fixation of a stimulus placed 3 D above the subject's pre-task tonic accommodation level. Closed-loop dynamic responses were recorded for each treatment condition while subjects viewed sinusoidally (0.05,0.6 Hz) or stepwise vergence-modulated targets over a 2 D range (2,4 D). Results: Open-loop data demonstrate a rapid post-task regression to pre-task tonic accommodation levels for saline and betaxolol control conditions. A slow positive post-task shift was induced by timolol indicating that sympathetic inhibition contributes to accommodative adaptation during sustained near vision. Closed-loop accommodation responses to temporally modulated sinusoidal stimuli showed characteristic features for both saline and betaxolol control conditions. Timolol induced a reduced gain for low- and mid-temporal frequencies (< 0.3 Hz) but did not affect the response at higher temporal frequencies. Response times to stepwise stimuli increased following the instillation of timolol for the near-to-far fixation condition compared with the controls and was related to the period of sustained prior fixation. Conclusions: Modulation of accommodation under open- and closed-loop conditions by a non-selective ,-blocker is consistent with the temporal and inhibitory features of sympathetic innervation to ciliary smooth muscle. Although parasympathetic innervation predominates there is evidence to support a role for sympathetic innervation in the control of ocular accommodation. [source] Dynamics of Ca2+ and Na+ in the dendrites of mouse cerebellar Purkinje cells evoked by parallel fibre stimulationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2003Akinori Kuruma Abstract Ca2+ and Na+ play important roles in neurons, such as in synaptic plasticity. Their concentrations in neurons change dynamically in response to synaptic inputs, but their kinetics have not been compared directly. Here, we show the mechanisms and dynamics of Ca2+ and Na+ transients by simultaneous monitoring in Purkinje cell dendrites in mouse cerebellar slices. High frequency parallel fibre stimulation (50 Hz, 3,50-times) depolarized Purkinje cells, and Ca2+ transients were observed at the anatomically expected sites. The magnitude of the Ca2+ transients increased linearly with increasing numbers of parallel fibre inputs. With 50 stimuli, Ca2+ transients lasted for seconds, and the peak [Ca2+] reached ,100 µm, which was much higher than that reported previously, although it was still confined to a part of the dendrite. In contrast, Na+ transients were sustained for tens of seconds and diffused away from the stimulated site. Pharmacological interventions revealed that Na+ influx through ,-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and Ca2+ influx through P-type Ca channels were essential players, that AMPA receptors did not operate as a Ca2+ influx pathway and that Ca2+ release from intracellular stores through inositol trisphosphate receptors or ryanodine receptors did not contribute greatly to the large Ca2+ transients. [source] Pharmacological interventions in aging and age-associated disordersGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 2 2007Kenichi Kitani In the present study, past attempts using different pharmaceuticals and chemicals which were reported to prolong lifespans of animals are critically reviewed. Despite a large number of trials in animals and humans, the validity of supplementation of antioxidant vitamins such as vitamins A, E and C for improving human health remains unresolved at present. A recent approach using antioxidant mimetics called the EUK series which, despite an initial enthusiastically reported success in prolonging the lifespan of nematodes, remains again unsettled because of the failure in reproducing the initial success by follow-up studies. ,-Phenyl- tert -butylnitrone and related nitrones were initially introduced as radical scavengers. Some of these (e.g. disodium 2,4-disulfophenyl-N- tert -butylnitrone) are at phase 3 clinical trials as an agent to treat cerebral stroke. This effect, however, appears at least in part to be related to signal transduction which makes these agents effective against cerebral stroke even when they are administered later than its onset. (,)Deprenyl is a monoamine oxidase-B inhibitor and has some neuroprotective and anti-apoptotic effects. The drug has also been shown to prolong the lifespans of at least four different animal species. The drug upregulates superoxide dismutase and catalase activities in selective brain regions of dopaminergic nature. These effects on antioxidant enzyme activities are suspected to be causally related to its effect on lifespans of animals. Future trials using these and other drugs are expected to open new doors for interventions in aging and age-associated disorders in humans. [source] Efficacy of pharmacological treatment of dystonia: evidence-based review including meta-analysis of the effect of botulinum toxin and other cure optionsEUROPEAN JOURNAL OF NEUROLOGY, Issue 6 2004Y. Balash The treatment of both generalized and focal dystonia is symptomatic. There is no evidence-based information about the efficacy of the different methods of the pharmacological therapeutic options currently being applied in dystonia. The specific questions addressed by this study were which treatments for dystonia have proven efficacy and which of them have unproven results. Following evidence-based principles, a literature review based on MEDLINE and the Cochrane Library, augmented by manual search of the most important journals was performed to identify the relevant publications issued between 1973 and 2003. All articles appearing in the professional English literature, including case reports, were considered. In the presence of comparable studies the meta-analysis was performed to obtain pooled information and make a reasonable inference. Based on this review, we conclude: (i) botulinum toxin has obvious benefit (level A, class I,II evidence) for the treatment of cervical dystonia and blepharospasm; (ii) trihexyphenidyl in high dosages is effective for the treatment of segmental and generalized dystonia in young patients (level A, class I,II evidence); (iii) all other methods of pharmacological intervention for generalized or focal dystonia, including botulinum toxin injections, have not been confirmed as being effective according to accepted evidence-based criteria (level U, class IV studies). [source] Epigenetic dysregulation in cognitive disordersEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2009Johannes Gräff Abstract Epigenetic mechanisms are not only essential for biological functions requiring stable molecular changes such as the establishment of cell identity and tissue formation, they also constitute dynamic intracellular processes for translating environmental stimuli into modifications in gene expression. Over the past decade it has become increasingly clear that both aspects of epigenetic mechanisms play a pivotal role in complex brain functions. Evidence from patients with neurodegenerative and neurodevelopmental disorders such as Alzheimer's disease and Rett syndrome indicated that epigenetic mechanisms and chromatin remodeling need to be tightly controlled for proper cognitive functions, and their dysregulation can have devastating consequences. However, because they are dynamic, epigenetic mechanisms are also potentially reversible and may provide powerful means for pharmacological intervention. This review outlines major cognitive disorders known to be associated with epigenetic dysregulation, and discusses the potential of ,epigenetic medicine' as a promising cure. [source] Differential involvement of the prelimbic cortex and striatum in conditioned heroin and sucrose seeking following long-term extinctionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2005E. Donné Schmidt Abstract Relapse to drug taking is triggered by stimuli previously associated with consumption of drugs of misuse (cues) and involves brain systems controlling motivated behaviour towards natural reinforcers. In this study, we aimed to identify and compare neuronal pathways in corticostriatal systems that control conditioned heroin or natural reward (sucrose) seeking. To that end, rats were trained to self-administer heroin or sucrose in association with an identical compound cue. After more than 3 weeks of abstinence during extinction training, cue exposure robustly reinstated heroin and sucrose seeking, but induced distinct and even opposing changes in the expression of the neuronal activation marker zif268 in the prelimbic cortex and striatal complex, respectively. Because in the prelimbic area zif268 expression was enhanced during cue-induced heroin seeking but unaffected during sucrose seeking, a pharmacological intervention was aimed at this prefrontal region. Injection of a GABA agonist mixture within the prelimbic area enhanced conditioned heroin seeking, but had no effect on conditioned sucrose seeking. Our findings suggest a differential role of the prelimbic area and the striatum in the persistence of heroin vs. sucrose seeking following long-term extinction. [source] Contractility of the myometrium; the rationale for pharmacological intervention in preterm labourEXPERIMENTAL PHYSIOLOGY, Issue 6 2001Mats Åkerlund No abstract is available for this article. [source] Differential involvement of the dorsal hippocampus in passive avoidance in C57bl/6J and DBA/2J miceHIPPOCAMPUS, Issue 1 2008Petra J.J. Baarendse Abstract The inferior performance of DBA/2 mice when compared to C57BL/6 mice in hippocampus-dependent behavioral tasks including contextual fear conditioning has been attributed to impaired hippocampal function. However, DBA/2J mice have been reported to perform similarly or even better than C57BL/6J mice in the passive avoidance (PA) task that most likely also depends on hippocampal function. The apparent discrepancy in PA versus fear conditioning performance in these two strains of mice was investigated using an automated PA system. The aim was to determine whether these two mouse strains utilize different strategies involving a different contribution of hippocampal mechanisms to encode PA. C57BL/6J mice exhibited significantly longer retention latencies than DBA/2J mice when tested 24 h after training irrespective of the circadian cycle. Dorsohippocampal NMDA receptor inhibition by local injection of the selective antagonist DL -2-amino-5-phosphonovaleric acid (AP5, 3.2 ,g/mouse) before training resulted in impaired PA retention in C57BL/6J but not in DBA/2J mice. Furthermore, nonreinforced pre-exposure to the PA system before training caused a latent inhibition-like reduction of retention latencies in C57BL/6J, whereas it improved PA retention in DBA/2J mice. These pre-exposure experiments facilitated the discrimination of hippocampal involvement without local pharmacological intervention. The results indicate differences in PA learning between these two strains based on a different NMDA receptor involvement in the dorsal hippocampus in this emotional learning task. We hypothesize that mouse strains can differ in their PA learning performance based on their relative ability to form associations on the basis of unisensory versus multisensory contextual/spatial cues that involve hippocampal processing. © 2007 Wiley-Liss, Inc. [source] A comparison of donepezil and galantamine in the treatment of cognitive symptoms of Alzheimer's disease: a meta-analysisHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 3 2005Robin D. J. Harry Abstract This review was conducted in order to determine the efficacy of donepezil and galantamine in the treatment of cognitive symptoms of Alzheimer's disease, and also to determine whether galantamine was a superior pharmacological intervention. Meta-analytic methods were used to analyse the data from eight empirical studies which met the inclusion criteria specified. By finding the mean effect sizes of the treatment on the outcome measures of cognition, it was determined that neither drug was greatly efficacious. However, this result does not necessarily diminish the practical value of the drug. It was also found that galantamine was no better than donepezil at treating cognitive decline in AD. Copyright © 2005 John Wiley & Sons, Ltd. [source] Novel Mechanisms for Feedback Regulation of Phospholipase C-, ActivityIUBMB LIFE, Issue 5 2002Irene Litosch Abstract The receptor-regulated phospholipase C- ,(PLC- ,) signaling pathway is an important component in a network of signaling cascades that regulate cell function. PLC- ,signaling has been implicated in the regulation of cardiovascular function and neuronal plasticity. The G q family of G proteins mediate receptor stimulation of PLC- ,activity at the plasma membrane. Mitogens stimulate the activity of a nuclear pool of PLC- ,. Stimulation of PLC- ,activity results in the rapid hydrolysis of phosphatidylinositol-4,5-bisphosphate, with production of inositol-1,4,5-trisphosphate and diacylglycerol, intracellular mediators that increase intracellular Ca 2+ levels and activate protein kinase C activity, respectively. Diacylglycerol kinase converts diacylglycerol to phosphatidic acid, a newly emerging intracellular mediator of hormone action that targets a number of signaling proteins. Activation of the G q linked PLC- ,signaling pathway can also generate additional signaling lipids, including phosphatidylinositol-3-phosphate and phosphatidylinositol-3,4,5-trisphosphate, which regulate the activity and/or localization of a number of proteins. Novel feedback mechanisms, directed at the level of G q and PLC- ,, have been identified. PLC- ,and regulators of G protein signaling (RGS) function as GTPase-activating proteins on G q to control the amplitude and duration of stimulation. Protein kinases phosphorylate and regulate the activation of specific PLC- ,isoforms. Phosphatidic acid regulates PLC- ,1 activity and stimulation of PLC- ,1 activity by G proteins. These feedback mechanisms coordinate receptor signaling and cell activation. Feedback mechanisms constitute possible targets for pharmacological intervention in the treatment of disease. [source] Vasomotion dynamics following calcium spiking depend on both cell signalling and limited constriction velocity in rat mesenteric small arteriesJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2008Ed VanBavel Abstract Vascular smooth muscle cell contraction depends on intracellular calcium. However, calcium-contraction coupling involves a complex array of intracellular processes. Quantitating the dynamical relation between calcium perturbations and resulting changes in tone may help identifying these processes. We hypothesized that in small arteries accurate quantitation can be achieved during rhythmic vasomotion, and questioned whether these dynamics depend on intracellular signalling or physical vasoconstriction. We studied calcium-constriction dynamics in cannulated and pressurized rat mesenteric small arteries (,300 ,m in diameter). Combined application of tetra-ethyl ammonium (TEA) and BayK8644 induced rhythmicity, consisting of regular and irregular calcium spiking and superposition of spikes. Calcium spikes induced delayed vasomotion cycles. Their dynamic relation could be fitted by a linear second-order model. The dirac impulse response of this model had an amplitude that was strongly reduced with increasing perfusion pressure between 17 and 98 mmHg, while time to peak and relaxation time were the largest at an intermediate pressure (57 mmHg: respectively 0.9 and 2.3 sec). To address to what extent these dynamics reside in intracellular signalling or vasoconstriction, we applied rhythmic increases in pressure counteracting the vasoconstriction. This revealed that calcium-activation coupling became faster when vasoconstriction was counteracted. During such compensation, a calcium impulse response remained that lasted 0.5 sec to peak activation, followed by a 1.0 sec relaxation time, attributable to signalling dynamics. In conclusion, this study demonstrates the feasibility of quantitating calcium-activation dynamics in vasomoting small arteries. These dynamics relate to both intracellular sig-nalling and actual vasoconstriction. Performing such analyses during pharmacological intervention and in genetic models provides a tool for unravelling calcium-contraction coupling in small arteries. [source] Kisspeptin and the Preovulatory Gonadotrophin-Releasing Hormone/Luteinising Hormone Surge in the Ewe: Basic Aspects and Potential Applications in the Control of OvulationJOURNAL OF NEUROENDOCRINOLOGY, Issue 7 2010A. Caraty The identification of the neural mechanisms controlling ovulation in mammals has long been a ,holy grail' over recent decades, although the recent discovery of the kisspeptin systems has totally changed our views on this subject. Kisspeptin cells are the major link between gonadal steroids and gonadotrophin-releasing hormone (GnRH) neurones. In the female rodent, kisspeptin cells of the preoptic area are involved in the positive-feedback action of oestrogen on GnRH secretion, although the picture appears more complicated in the ewe. As in rodents, activation of preoptic kisspeptin neurones accompanies the GnRH surge in the ewe but an active role for arcuate kisspeptin neurones has also been proposed. Experimentally, kisspeptin is able to restore reproductive function when the hypothalamic-hypophyseal ovarian axis is quiescent. For example, i.v. infusion of a low dose of peptide in anoestrous ewes induces an immediate and sustained release of gonadotrophin, which subsides and then provokes a luteinising hormone (LH) surge a few hours later. This pharmacological intervention induces the same hormonal changes normally observed during the follicular phase of the oestrous cycle, including the secretion of oestrogen and its negative- and positive-feedback actions on the secretion of LH and follicle-stimulating hormone. Accordingly, a high percentage of kisspeptin-infused animals ovulated. Although the multiple facets of how the kisspeptin systems modulate GnRH secretion are not totally understood, the demonstration that exogenous kisspeptin administration can induce ovulation in anovulatory animals paves the way for future therapeutic applications aiming to control reproduction. [source] Temporal and spatial profiles of cell loss after spinal cord injury: Reduction by a metalloporphyrinJOURNAL OF NEUROSCIENCE RESEARCH, Issue 10 2007Xiang Ling Abstract This study presents quantitative temporal and spatial profiles of neuronal loss and apoptosis following a contusion spinal cord injury (50 g · cm). The profiles were evaluated by counting the cresol violet,stained surviving cells and the total number of TUNEL-positive cells and of TUNEL-positive neurons in sections 0, 4 mm from the epicenter and 1, 6, 12, 24, 48, and 72 hr and 1 week postinjury. We demonstrated that neurons continue to disappear over 1 week postinjury and that neuronal loss shifts to areas longer distances from the epicenter over time. TUNEL-positive cells in both gray and white matter appeared after 6 hr, gradually increased to a peak level after 48 hr, and declined by 72 hr postinjury. TUNEL-positive neurons peaked earlier and were present for 1 week, although the total number of neurons was reduced significantly by the end of the week. The neuronal loss and apoptosis were partially prevented by a metalloporphyrin [Mn(III) tetrakis (4-benzoic acid) porphyrin (MnTBAP)]. We demonstrated that MnTBAP (10 and 50 mg/kg, given intraperitoneally) significantly reduced neuronal death in the sections 1,2.5 mm rostral and 1 mm caudal from the epicenter compared with that in the vehicle-treated group, suggesting MnTBAP is more effective in the sections rostral than in those caudal to the epicenter. MnTBAP (10 mg/kg) significantly reduced the number of TUNEL-positive neurons in the sections 1 mm caudal from the epicenter. Our profiles provide a database for pharmacological intervention, and our results on MnTBAP treatment support an important role for antioxidant therapy in spinal cord injury. © 2007 Wiley-Liss, Inc. [source] Potential roles of melatonin and chronotherapy among the new trends in hypertension treatmentJOURNAL OF PINEAL RESEARCH, Issue 2 2009Fedor Simko Abstract:, The number of well-controlled hypertensives is unacceptably low worldwide. Respecting the circadian variation of blood pressure, nontraditional antihypertensives, and treatment in early stages of hypertension are potential ways to improve hypertension therapy. First, prominent variations in circadian rhythm are characteristic for blood pressure. The revolutionary MAPEC (Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study, in 3000 adult hypertensives investigates, whether chronotherapy influences the cardiovascular prognosis beyond blood pressure reduction per se. Second, melatonin, statins and aliskiren are hopeful drugs for hypertension treatment. Melatonin, through its scavenging and antioxidant effects, preservation of NO availability, sympatholytic effect or specific melatonin receptor activation exerts antihypertensive and anti-remodeling effects and may be useful especially in patients with nondipping nighttime blood pressure pattern or with nocturnal hypertension and in hypertensives with left ventricular hypertrophy (LVH). Owing to its multifunctional physiological actions, this indolamine may offer cardiovascular protection far beyond its hemodynamic benefit. Statins exert several pleiotropic effects through inhibition of small guanosine triphosphate-binding proteins such as Ras and Rho. Remarkably, statins reduce blood pressure in hypertensive patients and more importantly they attenuate LVH. Addition of statins should be considered for high-risk hypertensives, for hypertensives with LVH, and possibly for high-risk prehypertensive patients. The direct renin inhibitor, aliskiren, inhibits catalytic activity of renin molecules in circulation and in the kidney, thus lowering angiotensin II levels. Furthermore, aliskiren by modifying the prorenin conformation may prevent prorenin activation. At present, aliskiren should be considered in hypertensive patients not sufficiently controlled or intolerant to other inhibitors of renin,angiotensin system. Third, TROPHY (Trial of Preventing Hypertension) is the first pharmacological intervention for prehypertensive patients revealing that treatment with angiotensin II type 1 receptor blocker attenuates hypertension development and thus decreases the risk of cardiovascular events. [source] Therapeutic potential of melatonin in traumatic central nervous system injuryJOURNAL OF PINEAL RESEARCH, Issue 2 2009Supriti Samantaray Abstract:, A vast literature extolling the benefits of melatonin has accumulated during the past four decades. Melatonin was previously considered of importance to seasonal reproduction and circadian rhythmicity. Currently, it appears to be a versatile anti-oxidative and anti-nitrosative agent, a molecule with immunomodulatory actions and profound oncostatic activity, and also to play a role as a potent neuroprotectant. Nowadays, melatonin is sold as a dietary supplement with differential availability as an over-the-counter aid in different countries. There is a widespread agreement that melatonin is nontoxic and safe considering its frequent, long-term usage by humans at both physiological and pharmacological doses with no reported side effects. Endeavors toward a designated drug status for melatonin may be enormously rewarding in clinics for treatment of several forms of neurotrauma where effective pharmacological intervention has not yet been attained. This mini review consolidates the data regarding the efficacy of melatonin as an unique neuroprotective agent in traumatic central nervous system (CNS) injuries. Well-documented actions of melatonin in combating traumatic CNS damage are compiled from various clinical and experimental studies. Research on traumatic brain injury and ischemia/reperfusion are briefly outlined here as they have been recently reviewed elsewhere, whereas the studies on different animal models of the experimental spinal cord injury have been extensively covered in this mini review for the first time. [source] Adherence to Oral Therapy for Type 2 Diabetes: Opportunities for Enhancing Glycemic ControlJOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS, Issue 1 2004CDEArticle first published online: 24 MAY 200, David Bartels PharmD Purpose Although diet and exercise are important parts of type 2 diabetes treatment, most patients require pharmacological intervention with multiple agents to maintain adequate glycemic control. This article addresses the numerous patient-related, disease-related, and demographic variables affecting medication adherence in this patient population. Data Sources Extensive review of scientific literature, clinical practice guidelines, and Internet sources. Conclusions Studies have demonstrated that treatments including multiple medications or frequent dosing had a negative impact on adherence. Practitioners have used several approaches in an effort to improve adherence to oral antidiabetic medical therapy, including increased communication between health care providers and patients, implementation of multidisciplinary programs, and use of treatment regimens with easier dosing (i.e., reduced number of drugs or doses taken per day). Implications for Practice Options for type 2 diabetes treatments that combine effective medications into a simpler oral-dosage form may motivate and improve patient adherence. Ultimately, simplifying dosing may lead to better glycemic control, thereby reducing the risks associated with long-term consequences of the disease. [source] Review article: anorexia and cachexia in gastrointestinal cancerALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2005J. OCKENGA Summary In patients with gastrointestinal malignancies, i.e. cancers of the stomach, colon, liver, biliary tract or pancreas, progressive undernutrition can be regularly observed during the course of illness. Undernutrition significantly affects the patients' quality of life, morbidity and survival. Pathogenetically, two different causes are relevant in the development of undernutrition in patients with gastrointestinal cancer. One cause is reduced nutritional intake. This condition is referred to as anorexia and can be worsened by the side effects of cancer therapy. The other cause is the release of endogenous transmitters and/or other products of the tumour leading to the cachexia syndrome, which is characterized by loss of body weight, negative nitrogen balance and fatigue. Cancer anorexia and cancer cachexia may have synergistic negative effects in affecting the patients' status. In this review, current nutritional support strategies with respect to different clinically relevant situations are described. An algorithm of the treatment strategies, including dietetic counselling, oral supplements, enteral and parenteral nutritional support is given. One focus is the approach of nutrition-focused patient care, which shows promising results. In addition, the possibilities of pharmacological intervention are discussed. [source] Anti-angiogenic drugs: from bench to clinical trialsMEDICINAL RESEARCH REVIEWS, Issue 4 2006Ana R. Quesada Abstract Angiogenesis, the generation of new capillaries through a process of pre-existing microvessel sprouting, is under stringent control and normally occurs only during embryonic and post-embryonic development, reproductive cycle, and wound repair. However, in many pathological conditions (solid tumor progression, metastasis, diabetic retinopathy, hemangioma, arthritis, psoriasis and atherosclerosis among others), the disease appears to be associated with persistent upregulated angiogenesis. The development of specific anti-angiogenic agents arises as an attractive therapeutic approach for the treatment of cancer and other angiogenesis-dependent diseases. The formation of new blood vessels is a complex multi-step process. Endothelial cells resting in the parent vessels are activated by an angiogenic signal and stimulated to synthesize and release degradative enzymes allowing endothelial cells to migrate, proliferate and finally differentiate to give rise to capillary tubules. Any of these steps may be a potential target for pharmacological intervention. In spite of the disappointing results obtained initially in clinical trials with anti-angiogenic drugs, recent reports with positive results in phases II and III trials encourage expectations in their therapeutic potential. This review discusses the current approaches for the discovery of new compounds that inhibit angiogenesis, with emphasis on the clinical developmental status of anti-angiogenic drugs. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 4, 483,530, 2006 [source] New and active role of the interstitium in control of interstitial fluid pressure: potential therapeutic consequencesACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 2 2003H. Wiig Here we present recent data indicating that the present view of the interstitium as a passive fluid reservoir has to be revised. The connective tissue cells and extracellular matrix have a role in the control of Pif and a fundamental role in the rapid development of edema in burns and in the initial swelling in inflammation by generating a lowering of interstitial fluid pressure. In this process, the ,1 -integrin system seems to provide a common pathway by which the cells can lower as well as raise Pif. Inflammatory swelling can be reversed by endo- and exogenous substances, thereby suggesting that the connective tissue can serve as a novel target for pharmacological intervention. Furthermore, the new knowledge in interstitial physiology on means to reduce interstitial fluid pressure may be of importance for drug delivery into solid tumors, where a high Pif limits the uptake of therapeutic agents. [source] A comparison of manual and automated methods of measuring conjunctival vessel widths from photographic and digital imagesOPHTHALMIC AND PHYSIOLOGICAL OPTICS, Issue 2 2004Christopher G. Owen Abstract We investigated the application of a fully automated computer algorithm for identifying vessels of the conjunctiva from their scleral surround, and compared measures of vessel width with established methods. Vessel widths at 101 locations (ranging from 20 to 140 ,m), from 12 patients, were measured from film and digital images, using a variety of methods, and compared. Widths were measured manually, by semi-automated methods using grey level (densitometric) profiles taken from digital images, and by automated techniques set at different operating levels. Good intra-session repeatibility was obtained using the automated method with an operating sigma value of 3 pixels (16 ,m) (mean difference 0.5 ,m, 95% CI ,8.5 to 9.4 ,m) and manual calliper measurements from digitally created photographic slides (mean difference 0.4 ,m, ,9.3 to 10.1 ,m). For comparison with other measures of width, the latter was used as the gold standard. Widths measured from film were slightly larger than those measured directly from digital images, although this effect was small (5 ,m) for most vessels. Overall widths measured using the automated method, with a sigma value of 3 pixels, agreed best with the gold standard (inter-method repeatibility; mean difference 1.4 ,m, ,32.5 to 35.2 ,m) although the automated method overestimated small widths (<40 ,m) and underestimated larger vessel widths (>40 ,m). Automated detection of vessels of the conjunctiva from digital images avoids manual and operator involved measures which are time consuming, and which preclude large patient studies. The resulting data may help in monitoring the vascular response of the conjunctiva to surgical or pharmacological intervention, and in describing vascular changes in response to ocular or systemic disease. The application of this algorithm to the study of retinal vessels is yet to be realised. [source] Methodology of QT-Interval Measurement in the Modular ECG Analysis System (MEANS)ANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 2009Jan A. Kors Ph.D. Background: QT prolongation as can be induced by drugs, signals the risk of life-threatening arrhythmias. The methodology of QT measurement in the modular ECG analysis system (MEANS) is described. Methods: In the simultaneously recorded leads of the standard 12-lead electrocardiogram (ECG), the QRS complexes are detected by a spatial velocity function. They are typed as dominant or nondominant, and a representative complex per lead is obtained by averaging over the dominant complexes. QRS onset and T end are determined by a template technique, and QT is measured. MEANS performance was evaluated on the 125 ECGs of the common standards for quantitative electrocardiography (CSE) multilead database, of which the waveform boundaries have been released. Results: MEANS detected correctly all 1445 complexes of the CSE library, with one false-positive detection due to a sudden baseline jump. All dominant complexes were correctly typed. The average of the differences between MEANS and reference was less than 2 ms (=1 sample) for both QRS onset and T end, and 2.1 ms for QT duration. The standard deviation of the differences was 3.8, 8.4, and 10.4 ms, respectively. Conclusions: A standard deviation of 10.4 ms for QT measurement seems large when related to the regulatory requirement that a prolongation as small as 5 ms should be detected. However, QT variabilities as encountered in different individuals will be larger than when measured in one individual during pharmacological intervention. Finally, if the U wave is part of the total repolarization, then T and U form a continuum and the end of T becomes questionable. [source] Myogenic bladder decompensation in boys with a history of posterior urethral valves is caused by secondary bladder neck obstruction?BJU INTERNATIONAL, Issue 1 2005Philippos A. Androulakakis OBJECTIVE To investigate whether myogenic bladder decompensation in patients treated for congenital posterior urethral valves (PUV, the most serious cause of infravesical obstruction in male neonates and infants) may be secondary to bladder neck obstruction, as despite prompt ablation of PUV these patients can have dysfunctional voiding during later childhood or adolescence, the so-called ,valve bladder syndrome'. PATIENTS AND METHODS The study comprised 18 boys (mean age 14 years, range 6.2,18.5) who had had successful transurethral ablation of PUV between 1982 and 1996, and had completed a follow-up which included serial assessment of serum creatinine, completion of a standard voiding diary, ultrasonography with measurement of urine before and after voiding, a urodynamic examination with simultaneous multichannel recording of pressure, volume and flow relationships during the filling and voiding phases, coupled with video-cystoscopy at least twice. The mean (range) follow-up was 9.3 (6,17) years. RESULTS Urodynamic investigation showed myogenic failure with inadequate bladder emptying in 10 patients; five with myogenic failure also had unstable bladder contractions. On video-cystoscopy the posterior bladder neck lip appeared elevated in all patients but in those with myogenic failure it was strongly suggestive of hypertrophy, with evidence of obstruction. At the last follow-up one patient with myogenic failure who had had bladder neck incision and four others who were being treated with ,-adrenergic antagonists had a significant reduction of their postvoid residual urine. CONCLUSION Despite early valve ablation, a large proportion of boys treated for PUV have gradual detrusor decompensation, which may be caused by secondary bladder neck obstruction leading to obstructive voiding and finally detrusor failure. Surgical or pharmacological intervention to improve bladder neck obstruction may possibly avert this course, but further studies are needed to validate this hypothesis. [source] The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMCBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2009NJ Liptrott Mandarin translation of abstract Background and purpose:, The function of transporters in peripheral blood mononuclear cells (PBMC) has been characterized, but less is known about cytochrome P450 (CYP) enzyme function in these cells. Given that cytokines are dysregulated in many diseases, the purpose of this work was to assess the impact of cytokines on the expression of CYPs, transporters and chemokine receptors in PBMC. Experimental approach:, Human PBMC were incubated with cytokines for 48 h. ATP-binding cassette (ABC)B1, ABCC1, ABCC2, CYP2B6, CYP3A4, CXCR4 and CCR5 expression were measured by quantitative polymerase chain reaction and flow cytometry at 0, 4, 8, 24 and 48 h. Enzyme activity was assessed using fluorescent probes. Key results:, We show here functional activity of CYP3A4 and CYP2B6 in PBMC. Furthermore, cytokines had a significant impact on the mRNA and protein expression of all proteins. For example, interleukin-2 (IL-2) had a marked impact on ABCB1 mRNA (% control 4745 ± 11961) and protein (% control 200 ± 57). Increases in drug efflux transporter expression, in response to cytokines, resulted in reduced cellular accumulation of digoxin [decrease of 17% and 26% for IL-2 and interferon-, (IFN,) respectively] and saquinavir (decrease of 28% and 30% for IL-2 and IFN, respectively). The degree to which drug transporter and chemokine receptor expression changed in response to cytokines was positively correlated (e.g. ABCB1 and CXCR4, r2 = 0.545). Conclusions and implications:, These data have important implications for diseases in which cytokines are dysregulated and for which pharmacological intervention targets immune cells. Mandarin translation of abstract [source] Experimental study of a type 3 phosphodiesterase inhibitor on liver graft functionBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 1 2001T. Ikegami Background: The number of liver transplant recipients is increasing but donor organ shortages have become more severe. The effect of milrinone, a type 3 phosphodiesterase inhibitor (PDEI), on non-heart-beating donor grafts was evaluated using an orthotopic liver transplantation model in rats. Methods: Type 3 PDEI or normal saline (control group) was given intravenously to the donor animals for 60 min continuously (50 µg kg,1 min,1 ) before 60 min of warm ischaemia followed by cold preservation and subsequent transplantation. Survival, serum chemistry, bile output, histopathological findings and tissue cyclic 3,,5,-adenosine monophosphate (cAMP) concentrations were then compared. Results: Five of seven animals in the PDEI group were alive at 7 days, compared with only one of seven rats in the control group (P < 0·01). Serum levels of alanine aminotransferase 2 and 6 h after reperfusion, and hyaluronic acid levels 6 h after reperfusion, were significantly lower in the PDEI group than in the control group. Bile output from the transplanted graft was significantly greater in the PDEI group than in controls 2 h after reperfusion (P < 0·01). The mean necrotic area 6 h after reperfusion was also reduced in the PDEI-treated grafts (P < 0·01). cAMP levels in liver tissue at the end of both warm and cold ischaemia, and 2 and 6 h after reperfusion, were significantly higher in the PDEI group compared with those in the control group. Conclusion: Type 3 PDEI attenuated the graft injury caused by warm and cold ischaemia and subsequent reperfusion injury via an increase in intracellular cAMP levels. This treatment may be a novel pharmacological intervention for safe and efficient usage of liver grafts from non-heart-beating donors. © 2001 British Journal of Surgery Society Ltd [source] Wnt signaling inside the nucleusCANCER SCIENCE, Issue 4 2008Miki Shitashige Accumulation of the ,-catenin protein and transactivation of a certain set of T-cell factor (TCF)-4 target genes by accumulated ,-catenin have been considered crucial in colorectal carcinogenesis. In the present review, we summarize nuclear proteins that interact with, and regulate, the ,-catenin and TCF and lymphoid enhancer factor (LEF) transcriptional complexes. Our recent series of proteomic studies has also revealed that various classes of nuclear proteins participate in the ,-catenin,TCF-4 complex and modulate its transcriptional activity. Furthermore, the protein composition of the TCF-4-containing nuclear complex is not fixed, but is regulated dynamically by endogenous programs associated with intestinal epithelial cell differentiation and exogenous stimuli. Restoration of the loss-of-function mutation of the adenomatous polyposis coli (APC) gene in colorectal cancer cells does not seem to be a realistic approach with currently available medical technologies, and only signaling molecules downstream of the APC gene product can be considered as targets of pharmacological intervention. Nuclear proteins associated with the ,-catenin,TCF-4 complex may include feasible targets for molecular therapy against colorectal cancer. Recently, an inhibitor of the interaction between CREB-binding protein and ,-catenin was shown to efficiently shut down the transcriptional activity of TCF-4 and induce apoptosis of colorectal cancer cells. We also summarize current strategies in the development of drugs against Wnt signaling. (Cancer Sci 2008; 99: 631,637) [source] Treatment of insomnia in patients with mood disordersDEPRESSION AND ANXIETY, Issue 1 2001Peter D. Nowell M.D. Abstract Mood disorders and chronic insomnia share complex theoretical and clinical relationships. This article reviews the subjective symptoms and polysomnographic findings of subjects with mood and insomnia syndromes. The polysomnographic findings reviewed include macro-architectural and micro-architectural data. Various treatments of patients with insomnia and mood disorders will be presented, including both behavioral and pharmacological interventions. Depression and Anxiety 14:7,18, 2001. © 2001 Wiley-Liss, Inc. [source] Schizophrenia and weight management: a systematic review of interventions to control weightACTA PSYCHIATRICA SCANDINAVICA, Issue 5 2003G. Faulkner Objective: Weight gain is a frequent side effect of antipsychotic medication which has serious implications for a patient's health and well being. This study systematically reviews the literature on the effectiveness of interventions designed to control weight gain in schizophrenia. Method: A systematic search strategy was conducted of major databases in addition to citation searches. Study quality was rated. Results: Sixteen studies met the inclusion criteria. Five of eight pharmacological intervention studies reported small reductions in weight (<5% baseline body weight). All behavioural (including diet and/or exercise) interventions reported small reductions in, or maintenance of, weight. Conclusion: Weight loss may be difficult but it is not impossible. Given the inconsistent results, the widespread use of pharmacological interventions cannot be recommended. Both dietary and exercise counselling set within a behavioural modification programme is necessary for sustained weight control. [source] Preventing Type 2 diabetes and the dysmetabolic syndrome in the real world: a realistic viewDIABETIC MEDICINE, Issue 9 2003P. Zimmet The last two decades have seen an explosive increase in the number of people with diabetes globally. There is now an urgent need for strategies to prevent the emerging global epidemic. Several recent successful intervention studies, both lifestyle and pharmacological, targeting subjects with impaired glucose tolerance (IGT) have stimulated enthusiasm for prevention of Type 2 diabetes. Lifestyle interventions reduced the incidence of diabetes by over 50% in the Finnish Diabetes Prevention Study and the Diabetes Prevention Program. Can the findings of these two studies be applied globally? Underpinning the enthusiasm, there needs to be a realistic approach to interventions in both developed and developing nations, and in ethnic groups where a better understanding of the socio-economic, cultural and demographic issues and perceptions surrounding chronic diseases such as diabetes is required. Whether the strategies used in these two studies can be translated into a ,real world' scenario is doubtful. In practice, it is more than likely that a number of strategies will be needed to compliment the lifestyle approach. These will include pharmacological approaches with metformin, acarbose and other agents used to treat diabetes and its complications, currently under investigation. Longer-term follow-up studies will also clarify whether both lifestyle and pharmacological interventions actually prevent Type 2 diabetes, or merely delay its onset. [source] Are differences in guidelines for the treatment of nicotine dependence and non-nicotine dependence justified?ADDICTION, Issue 12 2009John R. Hughes ABSTRACT Despite the many similarities between nicotine dependence and other drug dependences, national guidelines for their treatment differ in several respects. The recent national guideline for the treatment of nicotine dependence has (i) less emphasis on detailed assessment; (ii) less emphasis on treatment of psychiatric comorbidity; (iii) less acceptance of reduction of use as an initial treatment goal; (iv) greater emphasis on pharmacological interventions; and (v) less emphasis on psychosocial treatment than national guidelines for non-nicotine dependences. These treatment differences may occur because (i) nicotine does not cause behavioral intoxication; (ii) psychiatric comorbidity is less problematic with nicotine dependence; (iii) psychosocial problems are less severe with nicotine dependence; and (iv) available pharmacotherapies for nicotine dependence are safer, more numerous and more easily available. However, it is unclear whether these treatment differences are, in fact, justifiable because of the scarcity of empirical tests. We suggest several possible empirical tests. [source] | ||||||||||||||||||||||||||||||||||