Home About us Contact
|
Home About us Contact | ||
|
|
||
Human Trials (human + trials)
Selected AbstractsAlloantigen gene therapy for head and neck cancer: Evaluation of animal models,HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 4 2003Lyon L. Gleich MD Abstract Background. Human trials of alloantigen gene therapy, using the class I major histocompatibility complex (MHC) HLA-B7, have demonstrated the potential efficacy of this treatment for head and neck cancer. Its mechanism remains unclear. An immune-competent mouse model of MHC gene therapy to test factors potentially important to the tumor response is needed. Methods. Two cell lines were used, B4B8 cells that grow in Balb/c mice and SCC-VII cells that grow in C3H mice. The mouse MHC H2-Kb was used as the therapeutic gene, because it is an alloantigen to both mice strains. Plasmids that encode the H2-Kb cDNA were prepared, and the cell lines were transfected. Mice were injected subcutaneously with naive cells to determine the tumor kinetics and serve as controls. Mice were injected with H2-Kb transfected cells and tumor growth was compared with controls. Mice that did not grow tumor were rechallenged with naive cells to assess for tumor immunity. Mice were injected with transfected and naive cells admixed to determine whether the concentration of the alloantigen is important. Results. B4B8 tumors grew slowly, whereas SCC-VII tumors grew rapidly. Transfection with H2-Kb plasmid prevented or inhibited tumor growth of both the B4B8 and SCC-VII tumors. This growth inhibition was independent of the number of cells injected. In the mice that did not grow tumor, tumor immunity was demonstrated after challenge with naive cells in both models. There was no relationship between induction of immunity and the timing of the challenge or initial cell quantity. The mice injected with a mixture of naive and transfected cells grew tumor, although growth was delayed in the B4B8 model. Conclusions. The results demonstrate that the two mouse models can serve as a rapid and slow growing tumor model of alloantigen gene therapy. In addition, it was noted that initial tumor cell number is not a significant factor for predicting tumor response and demonstrated that in both of these models alloantigen gene therapy results in significant antitumor immunity. © 2003 Wiley Periodicals, Inc. Head Neck 25: 274,279, 2003 [source] Controversies related to red blood cell transfusion in critically ill patientsJOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 2 2010DACVECC, DACVIM, Jennifer E. Prittie DVM Abstract Objective , To review the evolution of and controversies associated with allogenic blood transfusion in critically ill patients. Data sources , Veterinary and human literature review. Human Data Synthesis , RBC transfusion practices for ICU patients have come under scrutiny in the last 2 decades. Human trials have demonstrated relative tolerance to severe, euvolemic anemia and a significant outcome advantage following implementation of more restricted transfusion therapy. Investigators question the ability of RBCs stored longer than 2 weeks to improve tissue oxygenation, and theorize that both age and proinflammatory or immunomodulating effects of transfused cells may limit efficacy and contribute to increased patient morbidity and mortality. Also controversial is the ability of pre- and post-storage leukoreduction of RBCs to mitigate adverse transfusion-related events. Veterinary Data Synthesis , While there are several studies evaluating the transfusion trigger, the RBC storage lesion and transfusion-related immunomodulation in experimental animal models, there is little research pertaining to clinical veterinary patients. Conclusions , RBC transfusion is unequivocally indicated for treatment of anemic hypoxia. However, critical hemoglobin or Hct below which all critically ill patients require transfusion has not been established and there are inherent risks associated with allogenic blood transfusion. Clinical trials designed to evaluate the effects of RBC age and leukoreduction on veterinary patient outcome are warranted. Implementation of evidence-based transfusion guidelines and consideration of alternatives to allogenic blood transfusion are advisable. [source] Chemistry And Biological Effects Of Dietary Phenolic Compounds: Relevance To Cardiovascular DiseaseCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2000Lincoln W Morton SUMMARY 1. There has been considerable recent interest in the possibility that increased intake of dietary anti-oxidants may protect against cardiovascular disease. This is partly due to the knowledge that oxidative events in vivo may play a role in the pathogenesis of atherosclerosis. 2. While dietary anti-oxidants, such as vitamins E and C, have received considerable attention in this regard, relatively little is known about a similar anti-oxidant role for plant-derived polyphenolic compounds, such as the flavonoids and phenolic acids. A review of the distribution, bioavailability and biological activity of these compounds suggests that they may have a physiological role as anti-oxidants. 3. Human trials on the anti-oxidant effects of beverages rich in polyphenolics, such as red wine, fruit juice or tea, have been limited and results are, at present, inconclusive. This is due, in part, to poor methodologies available to measure oxidative damage in vivo. 4. There is a sound rationale for considering polyphenolics as important contributors to the dietary anti-oxidant intake derived from fruits and vegetables. However, continuing research is needed using appropriate biomarkers of oxidant damage in vivo before these compounds can be conclusively considered as dietary anti-oxidants with nutritional benefit. [source] Curiosity and cure: Translational research strategies for neural repair-mediated rehabilitationDEVELOPMENTAL NEUROBIOLOGY, Issue 9 2007Bruce H. Dobkin Abstract Clinicians who seek interventions for neural repair in patients with paralysis and other impairments may extrapolate the results of cell culture and rodent experiments into the framework of a preclinical study. These experiments, however, must be interpreted within the context of the model and the highly constrained hypothesis and manipulation being tested. Rodent models of repair for stroke and spinal cord injury offer examples of potential pitfalls in the interpretation of results from developmental gene activation, transgenic mice, endogeneous neurogenesis, cellular transplantation, axon regeneration and remyelination, dendritic proliferation, activity-dependent adaptations, skills learning, and behavioral testing. Preclinical experiments that inform the design of human trials ideally include a lesion of etiology, volume and location that reflects the human disease; examine changes induced by injury and by repair procedures both near and remote from the lesion; distinguish between reactive molecular and histologic changes versus changes critical to repair cascades; employ explicit training paradigms for the reacquisition of testable skills; correlate morphologic and physiologic measures of repair with behavioral measures of task reacquisition; reproduce key results in more than one laboratory, in different strains or species of rodent, and in a larger mammal; and generalize the results across several disease models, such as axonal regeneration in a stroke and spinal cord injury platform. Collaborations between basic and clinical scientists in the development of translational animal models of injury and repair can propel experiments for ethical bench-to-bedside therapies to augment the rehabilitation of disabled patients. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007 [source] Tolerance and near-tolerance strategies in monkeys and their application to human renal transplantationIMMUNOLOGICAL REVIEWS, Issue 1 2001Stuart J. Knechtle Summary: Studies in non-human primates to evaluate tolerance strategies in organ transplantation have led to innovation in human transplantation. The two strategies we have studied in detail in non-human primates are T-cell depletion by anti-CD3 immunotoxin and co-stimulation blockade. Each of these strategies has been extended into early human trials in renal transplantation. The results of these human and non-human primate studies are summarized. Continued progress in better and safer immunosuppressive methods remains closely linked to research using non-human primates. However, there has not been a one-to-one correspondence between efficacy in the primate and efficacy in humans. Rather, principles can be derived from non-human primate studies that can be extended into human trials with the knowledge that regimens will likely differ in humans compared to non-human primates. [source] Taking stem cells to the clinic: Major challengesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2008Ariff Bongso Abstract Stem cell therapy offers tremendous promise in the treatment of many incurable diseases. A variety of stem cell types are being studied but human embryonic stem cells (hESCs) appear to be the most versatile as they are pluripotent and can theoretically differentiate into all the tissues of the human body via the three primordial germ layers and the male and female germ lines. Currently, hESCs have been successfully converted in vitro into functional insulin secreting islets, cardiomyocytes, and neuronal cells and transfer of such cells into diabetic, ischaemic, and parkinsonian animal models respectively have shown successful engraftment. However, hESC-derived tissue application in the human is fraught with the problems of ethics, immunorejection, tumorigenesis from rogue undifferentiated hESCs, and inadequate cell numbers because of long population doubling times in hESCs. Human mesenchymal stem cells (hMSC) though not tumorigenic, also have their limitations of multipotency, immunorejection, and are currently confined to autologous transplantation with the genuine benefits in allogeneic settings not conclusively shown in large controlled human trials. Human Wharton's jelly stem cells (WJSC) from the umbilical cord matrix which are of epiblast origin and containing both hESC and hMSC markers appear to be less troublesome in not being an ethically controversial source, widely multipotent, not tumorigenic, maintain "stemness" for several serial passages and because of short population doubling time can be scaled up in large numbers. This report describes in detail the hurdles all these stem cell types have to overcome before stem cell-based therapy becomes a genuine reality. J. Cell. Biochem. 105: 1352,1360, 2008. © 2008 Wiley-Liss, Inc. [source] Helicobacter pylori as a class I carcinogen: Physiopathology and management strategiesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2007Paraskevi Vogiatzi Abstract The gram-negative bacterium Helicobacter pylori is known as a persistent colonizer of the human stomach, and probably less known is that it is also involved in extraintestinal diseases. Public awareness of its contribution in the development of gastric cancer is less than 15 years old. The efficacy of the current therapies based on antibiotics against H. pylori has been limited by difficulties such as antibiotic resistance and recurrence. As a consequence, the development of promising vaccines was prompted as the best preventive measure. Unfortunately, so far vaccines failed the transition from animal models to human trials. This keynote presentation is to provide a bird's eye view of H. pylori -related gastric diseases, including gastric cancer, with a synthesis of the molecular mechanisms involved, and an exhaustive presentation and discussion of the current therapeutic guidelines and future strategies for prevention or therapy. J. Cell. Biochem. 102: 264,273, 2007. © 2007 Wiley-Liss, Inc. [source] Review article: omega-3 fatty acids , a promising novel therapy for non-alcoholic fatty liver diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2010G. S. MASTERTON Aliment Pharmacol Ther,31, 679,692 Summary Background, Non-alcoholic fatty liver disease affects 10,35% of the adult population worldwide; there is no consensus on its treatment. Omega-3 fatty acids have proven benefits for hyperlipidaemia and cardiovascular disease, and have recently been suggested as a treatment for non-alcoholic fatty liver disease. Aims, To review the evidence base for omega-3 fatty acids in non-alcoholic fatty liver disease and critically appraise the literature relating to human trials. Methods, A Medline and PubMed search was performed to identify relevant literature using search terms ,omega-3', ,N-3 PUFA', ,eicosapentaenoic acid', ,docosahexaenoic acid', ,non-alcoholic fatty liver disease' and ,NAFLD'. Results, Omega-3 fatty acids are important regulators of hepatic gene transcription. Animal studies demonstrate that they reduce hepatic steatosis, improve insulin sensitivity and reduce markers of inflammation. Clinical trials in human subjects generally confirm these findings, but have significant design inadequacies. Conclusions, Omega-3 fatty acids are a promising treatment for non-alcoholic fatty liver disease which require to be tested in randomized placebo-controlled trials. [source] Use of dopamine in acute renal failureJOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 2 2007DACVECC, Nadja E. Sigrist DrMedVet Abstract Objective: To review the current understanding of dopamine and its use in the prevention and treatment of acute renal failure (ARF). Data sources: Original research articles and scientific reviews. Human data synthesis: Low-dose dopamine administration has been shown to increase natriuresis and urinary output in both healthy individuals and in a few small studies in human patients with renal insufficiency. However, in several large meta-analyses, dopamine treatment did not change mortality or the need for dialysis. Due to the potential side effects, the use of dopamine for prevention and treatment of ARF is no longer recommended in human medicine. Veterinary data synthesis: Low-dose dopamine increases urinary output in healthy animals and animal models of ARF if given before the insult. There are no available studies looking at the effect of low-dose dopamine therapy in naturally occurring ARF in dogs or cats. Conclusion: Due to the potential side effects of low-dose dopamine therapy, the results from large human trials, and the lack of information in veterinary medicine, the use of dopamine for treatment of ARF in veterinary patients should be further evaluated. [source] Gentamicin fails to increase dystrophin expression in dystrophin-deficient muscleMUSCLE AND NERVE, Issue 5 2003Patrick Dunant PhD Abstract A recent report that aminoglycoside antibiotics restored the expression of functional dystrophin to skeletal muscles of mdx mice, a model of Duchenne muscular dystrophy (DMD), raised hopes that DMD may be treatable by a conventional drug. Subsequently, several human trials were initiated for evaluating gentamicin therapy in selected DMD patients. An increase of dystrophin expression was not detected in one human trial that was fully reported. Here, we report that we were unable to replicate previously published beneficial results by gentamicin treatment in the mdx mouse. Therefore, we believe that additional animal experimentation is required to further evaluate the possibility of in vivo aminoglycoside therapy of DMD. Muscle Nerve 27: 624,627, 2003 [source] Novel pharmacology: asimadoline, a ,-opioid agonist, and visceral sensationNEUROGASTROENTEROLOGY & MOTILITY, Issue 9 2008M. Camilleri Abstract, Asimadoline is a potent ,-opioid receptor agonist with a diaryl acetamide structure. It has high affinity for the , receptor, with IC50 of 5.6 nmol L,1 (guinea pig) and 1.2 nmol L,1 (human recombinant), and high selectively with , : , : , binding ratios of 1 : 501 : 498 in human recombinant receptors. It acts as a complete agonist in in vitro assay. Asimadoline reduced sensation in response to colonic distension at subnoxious pressures in healthy volunteers and in irritable bowel syndrome (IBS) patients without alteration of colonic compliance. Asimadoline reduced satiation and enhanced the postprandial gastric volume (in female volunteers). However, there were no significant effects on gastrointestinal transit, colonic compliance, fasting or postprandial colonic tone. In a clinical trial in 40 patients with functional dyspepsia (Rome II), asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, asimadoline, 0.5 mg, significantly decreased satiation in patients with higher postprandial fullness scores, and daily postprandial fullness severity (over 8 weeks); the asimadoline 1.0 mg group was borderline significant. In a clinical trial in patients with IBS, average pain 2 h post- on-demand treatment with asimadoline was not significantly reduced. Post hoc analyses suggest that asimadoline was effective in mixed IBS. In a 12-week study in 596 patients, chronic treatment with 0.5 mg and 1.0 mg asimadoline was associated with adequate relief of pain and discomfort, improvement in pain score and number of pain-free days in patients with IBS-D. The 1.0 mg dose was also efficacious in IBS-alternating. There were also weeks with significant reduction in bowel frequency and urgency. Asimadoline has been well tolerated in human trials to date. [source] Stem cell implantation in ischemic mouse heart: a high-resolution magnetic resonance imaging investigation,NMR IN BIOMEDICINE, Issue 6 2005Ekkehard Küstermann Abstract Advances in the biology of stem cells have evoked great interest in cell replacement therapies for the regeneration of heart tissue after myocardial infarction. However, results from human trials are controversial, since the destination of the injected cells, their engraftment and their long-term fate have remained unclear. Here we investigate whether transplanted cells can be identified in the intact and lesioned murine myocardium employing high-resolution MRI. Cardiac progenitor cells, expressing the enhanced green fluorescent protein (EGFP), were labeled with ultra-small paramagnetic iron-oxide (USPIO) nanoparticles and transplanted into the intact or injured myocardium of mice. Their precise location was determined with high-resolution MRI and compared with histological tissue sections, stained with Prussian blue for iron content. These experiments showed that iron nanoparticle-loaded cells could be identified at high resolution in the mouse heart. However, ischemic myocardium (after cryoinjury or left coronary artery ligation) was characterized by a signal attenuation similar to that induced by USPIO-labeled cells in T -weighted MR images, making detection of labeled stem cells in this area by T -sensitive contrast rather difficult. In animals with myocardial injury only, the signal attenuated areas were of the same size in proton density- and T -weighted MR images. In injured animals also receiving labeled cells the lesioned area appeared larger in T - than in proton density-weighted MR images. This sequence-dependent lesion size change is due to the increased signal loss caused by the iron oxide nanoparticles, most sensitively detectable in the T -sensitive images. Thus, using the novel combination of these two parameter weightings, USPIO-labeled cells can be detected at high resolution in ischemic myocardium. Copyright © 2005 John Wiley & Sons, Ltd. [source] Probiotics: Considerations for Human HealthNUTRITION REVIEWS, Issue 3 2003Mary Ellen Sanders PhD Evidence for the role of probiotics in maintenance of health or prevention of disease is mounting and is supported in some cases by blinded, placebo-controlled human trials. Today, in an era of antibiotic-resistant pathogens and other looming microbial threats, the value of prevention of infection is recognized. Probiotics may play an important role in helping the body protect itself from infection, especially along the colonized mucosal surfaces of the gastrointestinal tract. Probiotic products are available in many different forms worldwide, including pills, powders, foods, and infant formula. In some cases, general health claims are made that cannot be substantiated for the specific strains and levels being used and consumers must therefore beware. [source] Intradiscal Electrothermal Coagulation and Percutaneous Neuromodulation Therapy in the Treatment of Discogenic Low Back PainPAIN PRACTICE, Issue 3 2005Dima Rozen MD Abstract: Low back pain (LBP) is a major physical and socioeconomic entity. A significant percentage of LBP is attributable to internal disc disruption. The management of internal disc disruption has traditionally been limited to either conservative treatment or spinal fusion. Intradiscal electrothermal coagulation (IDET) and percutaneous neuromodulation therapy (PNT) are now being performed as an alternative to these therapies. Scientific data regarding the pathophysiology, biologic effects, and clinical results are relatively scarce. Early biomechanical and histologic investigations into the effects of IDET are conflicting. However, in early prospective human trials, IDET seems to provide some benefit with little risk. PNT represents a new less invasive technique for the treatment of discogenic pain, but limited research is available to determine long-term clinical efficacy. IDET and PNT are potentially beneficial treatments for internal disc disruption in carefully selected patients as an alternative to spinal fusion. More basic science and clinical research with long-term follow-up evaluation is necessary. [source] MULTIDISCIPLINARY PAIN ABSTRACTS: 39PAIN PRACTICE, Issue 1 2004Article first published online: 15 MAR 200 A literature review was conducted to review the anatomy, pathophysiology, diagnosis, procedure, and clinical results of intradiscal electrothermal therapy (IDET). Low back pain is a major physical and socioeconomic entity. A significant percentage of low back pain is attributable to internal disc disruption. The management of internal disc disruption has traditionally been limited to either conservative treatment or spinal fusion. IDET has been performed as an alternative to these therapies. The available literature was reviewed. Scientific data regarding the pathophysiology, biologic effects, and clinical results are relatively scarce. Early biomechanical and histologic investigations into the effects of IDET are conflicting. However, in early prospective human trials, IDET seems to provide some benefit with little risk. It was concluded that IDET is a potentially beneficial treatment for internal disc disruption in carefully selected patients as an alternative to spinal fusion. More basic science and clinical research with long-term follow-up evaluation is necessary. [source] Health-related quality of life measures in genetic disorders: An outcome variable for consideration in clinical trials,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 3 2009David A. Stevenson Abstract The field of medical genetics is rapidly advancing, and therapeutic options to treat genetic syndromes are becoming increasingly available. An understanding of the pathophysiology of various genetic disorders has provided researchers the opportunity to propose and test pharmacologic agents in preclinical murine models with hopes of translation to human trials. The development of clinical trials can be costly and time consuming, particularly for rare conditions. Pilot feasibility studies should be performed when designing clinical trials for genetic disorders. The development and selection of appropriate outcome measures are particularly paramount in the implementation of clinical trials. The selection of inappropriate outcome measures can lead to non-measurable differences or clinically insignificant findings. In addition, just as age appropriate measures are needed, some instruments may not apply to populations with specific genetic disorders that have significant cognitive and physical impairment, as the measures may not be sensitive enough to identify clinically significant changes. In the last decade, health-related quality of life measures (HRQOL) have been increasingly included as an outcome measure in clinical trials. While traditional clinical outcomes are important, these newly developed instruments should be considered along with clinical indicators as measures of effect in clinical trials of interventions in genetic disorders. © 2009 Wiley-Liss, Inc. [source] Treatment of Olfactory Dysfunction, II: Studies With Minocycline,THE LARYNGOSCOPE, Issue 12 2004R C. Kern MD Abstract Objectives/Hypothesis: The treatment of anosmia has changed minimally since the early 1970s, despite dramatic advances in the understanding of the molecular biology of olfaction. Recent studies from the authors' laboratory have suggested that most common causes of clinical olfactory dysfunction, including rhinosinusitis, appear to be associated with increased apoptotic death of olfactory sensory neurons. This appears to result in a decline in the number of functioning mature olfactory sensory neurons, despite the capacity of the olfactory epithelium for regeneration. The current study evaluated the ability of the antibiotic minocycline to inhibit olfactory sensory neuron apoptosis. This drug is known to inhibit apoptosis separate from its anti-infective properties. Olfactory sensory neuron apoptosis was triggered by surgical deafferentation ("bulbectomy"), the standard experimental model. Earlier studies have indicated that bulbectomy and sinusitis invoke similar proteolytic enzyme cascades in olfactory sensory neurons. Study Design: Histological analysis of animal olfactory tissue. Methods: Mice underwent unilateral olfactory bulbectomy to induce apoptotic olfactory sensory neuron death, with and without 45 mg/kg intraperitoneal minocycline given 12 hours before surgery and every 12 hours until death. Mice were killed at 2 and 4 days after bulbectomy and assessed for activation of capsase-3 and olfactory sensory neuron survival by immunohistochemical analysis. Results: Minocycline resulted in partial suppression of cell death at 2 days after surgery when compared with untreated animals. Conclusion: Minocycline inhibits olfactory sensory neuron death in the face of a potent pro-apoptotic stimulus. This drug is well tolerated and is currently undergoing human trials for the management of a variety of neurological disorders associated with apoptosis. The current results suggest that minocycline may be efficacious in the management of peripheral olfactory loss as well. [source] Praziquantel efficacy in mice infected with PZQ non-susceptible S. mansoni isolate treated with artemether: parasitological, biochemical and immunohistochemical assessmentAPMIS, Issue 9 2010Sanaa S. Botros Botros SS, Hammam O, Mahmoud M, Bergquist R. Praziquantel efficacy in mice infected with PZQ non-susceptible S. mansoni isolate treated with artemether: parasitological, biochemical and immunohistochemical assessment. APMIS 2010; 118: 692,702. Based on the fact that artemether (ART) affects immature schistosomes and that the effect of praziquantel (PZQ) mainly targets mature schistosomes, this work investigates the possible enhanced efficacy of PZQ in combination with ART in mice harboring a PZQ non-susceptible Schistosoma mansoni isolate. Associated schistosomal, inflammatory, hepatic histopathological changes have been investigated by examining the tissue markers expressing apoptosis using FAS (CD95), anti-apoptosis (Bcl2) and angiogenesis [vascular endothelial growth factor (VEGF)]. A batch of Swiss albino mice infected with a PZQ non-susceptible (EE10) S. mansoni isolate was divided into 12 groups. Animals of the first group were left without treatment as infected controls, while groups 2,6 received PZQ in increasing doses. The animals of group 7 received ART in double doses. Those comprising groups 8,12 received combined therapy of PZQ and ART in the same doses and at the same timings postinfection (PI) as those belonging to groups 2,6. Parasitological parameters, liver function, and histopathological and immunohistochemical studies of FAS, Bcl2 and VEGF antibodies were assessed. Combined administration of ART and PZQ reduced the ED50 (the dose at which the worm burden was decreased by 50%) of PZQ. Typical granulomas were not seen in animals treated with ART alone and combined with PZQ, with least expression of FAS and VEGF and increased expression of Bcl2. The minimal histopathological changes recorded in mice treated with both ART and PZQ could be related to a synergistic/additive effect of ART, markedly reducing the intensity of infection. Improved liver function tests support the less severe histopathological changes under the influence of this treatment protocol. This study encourages human trials especially in areas where malaria is not endemic, and differing combination doses should be investigated in view of the antagonistic effect noticed with some dose regimens. [source] Intrinsic Toxicity of Hemoglobin: How to Counteract ItARTIFICIAL ORGANS, Issue 2 2009Jan Simoni Abstract The development of safe and effective blood substitutes is of great importance in both civilian and military medicine. The currently tested hemoglobin (Hb)-based oxygen carriers, however, have toxicity and efficacy problems. A number of unwanted effects have been observed in human trials, creating doubts about their clinical usefulness. In some subjects, vasoconstriction and decreased blood flow to the vital organs, heart attack, stroke, systemic inflammation, organ damage, and even death, have been attributed to the transfusion of these experimental products. Hb is a well-known pressor agent and strong oxidant, although the full understanding of its intrinsic toxicity is yet to be uncovered. In particular, the complete mechanism of Hb-induced vasoconstriction needs full elucidation. Knowledge of the biological events that trigger the induction of genes upon treatment with redox-active Hb, as well as its catabolism, is still incomplete. It seems that our limited knowledge of free Hb effects in vivo is the main reason for not yet having a viable substitute of human blood. The future for universal red cell substitutes is in the new-generation products that address all of Hb's intrinsic toxicity issues. [source] Exposure to inhomogeneous static magnetic field ceases mechanical allodynia in neuropathic pain in miceBIOELECTROMAGNETICS, Issue 6 2009Miklós Antal Abstract Magnetic therapy as a self-care intervention has led to the conduct of numerous human trials and animal experiments. Results concerning the analgesic efficacy of magnetic exposure, however, are inconsistent. By using a magnetic device generating an inhomogeneous static magnetic field (iSMF), here we studied how the whole-body exposure to iSMF may influence the mechanical withdrawal threshold (MWT) of the hind paw in different stages of neuropathic pain evoked by partial ligation of the sciatic nerve in mice. It was found that iSMF exposure did not prevent the decrease of MWT in the first postoperative week. A 2-week long iSMF treatment that was started just after the nerve ligation elevated MWT values to a modest extent. However, the effectiveness of a daily exposure to iSMF was much more prominent when it was applied between postoperative days 15 and 28. In this case, MWT was already noticeably increased after the first treatment and it practically reached the control values by the end of the 2-week long exposure period. The results suggest that exposure to iSMF cannot prevent the development of mechanical allodynia, but can inhibit processes that maintain the increased sensitivity to mechanical stimuli in neuropathic pain. Bioelectromagnetics 30:438,445, 2009. © 2009 Wiley-Liss, Inc. [source] arNOX activity of saliva as a non-invasive measure of coenzyme Q10 response in human trialsBIOFACTORS, Issue 1-4 2008D. James Morré arNOX is a coenzyme Q10 -inhibited, aging-related ECTO-NOX protein of the cell surface also present in sera. It is capable of Superoxide generation measured as Superoxide dismutase-inhibited reduction of ferricytochrome c and is a potential contributor to atherogenic risk. Here, we report an arNOX activity of saliva of older individuals also inhibited by coenzyme Q10. The activity first appears after age 30 to a near maximum at about age 55. Those surviving beyond age 55 usually have reduced arNOX activities. Our studies demonstrate significant (25 to 30%) reduction of arNOX levels with coenzyme Q10 supplementation of 60 mg (2 × 30 mg) per day for 28 days. Activity correlated with age. Response to coenzyme Q10 increased with age being greatest between ages 60 and 65. Saliva arNOX levels varied in a regular pattern throughout the day so it was important that samples be collected at approximately the same time each day for comparative purposes. The coenzyme Q10 response was reversible and within 12 h after the last intake of coenzyme Q10, the salivary arNOX levels returned to base line. The findings suggest that salivary arNOX provides a convenient and non-invasive method to monitor arNOX levels in clinical coenzyme Q10 intervention trials with the response levels paralleling those seen with serum and cellular arNOX. [source] Concord grape juice supplementation reduces blood pressure in Korean hypertensive men: Double-blind, placebo controlled intervention trialBIOFACTORS, Issue 1-4 2004Yoo Kyoung Park Abstract Many of the flavonoids found in grapes and grape products such as juice or wine have been known to exert antioxidant, anti-inflammatory, platelet inhibitory and arterial relaxing effects either in vitro, in animal studies and in human trials. This study was designed to test the effect of Concord grape juice consumption on altering blood pressure in hypertensive patients. Forty subjects were given 5.5 ml/kg body weight/day of either Concord grape juice (CGJ) or a calorie-matched placebo drink every day for 8 weeks. Blood pressure (BP) was measured on weeks 0, 4 and 8. Compared to baseline, in the CGJ group systolic BP was reduced on average by 7.2 mm Hg (p = 0.005) and diastolic BP was reduced on average by 6.2 mm Hg (p = 0.001) at the end of 8 weeks. Comparable changes in the group getting the placebo product were -3.5 mm Hg (NS) and -3.2 mm Hg (p = 0.05) Consuming Concord grape juice, which is high in polyphenolic compounds, may favorably affect BP in hypertensive individuals. [source] Multiple Imputation Methods for Treatment Noncompliance and Nonresponse in Randomized Clinical TrialsBIOMETRICS, Issue 1 2009L. Taylor Summary Randomized clinical trials are a powerful tool for investigating causal treatment effects, but in human trials there are oftentimes problems of noncompliance which standard analyses, such as the intention-to-treat or as-treated analysis, either ignore or incorporate in such a way that the resulting estimand is no longer a causal effect. One alternative to these analyses is the complier average causal effect (CACE) which estimates the average causal treatment effect among a subpopulation that would comply under any treatment assigned. We focus on the setting of a randomized clinical trial with crossover treatment noncompliance (e.g., control subjects could receive the intervention and intervention subjects could receive the control) and outcome nonresponse. In this article, we develop estimators for the CACE using multiple imputation methods, which have been successfully applied to a wide variety of missing data problems, but have not yet been applied to the potential outcomes setting of causal inference. Using simulated data we investigate the finite sample properties of these estimators as well as of competing procedures in a simple setting. Finally we illustrate our methods using a real randomized encouragement design study on the effectiveness of the influenza vaccine. [source] Incorporation of 3T3-L1 Cells To Mimic Bioaccumulation in a Microscale Cell Culture Analog Device for Toxicity StudiesBIOTECHNOLOGY PROGRESS, Issue 2 2004Kwanchanok Viravaidya Deficiencies in the early ADMET (absorption, distribution, metabolism, elimination, and toxicity) information on drug candidates extract a significant economic penalty on pharmaceutical firms. We have developed a microscale cell culture analog (,CCA) device that can potentially provide better, faster, and more efficient prediction of human and animal responses to a wide range of chemicals. The system described in this paper is a simple four-chamber ,CCA ("lung","liver","fat","other tissue") designed on the basis of a physiologically based pharmacokinetics (PBPK) model of a rat. Cultures of L2, HepG2/C3A, and differentiated 3T3-L1 adipocytes were selected to mimic the key functions of the lung, liver, and fat compartments, respectively. Here, we have demonstrated the application of the ,CCA system to study bioaccumulation, distribution, and toxicity of selected compounds. Results from the bioaccumulation study reveal that hydrophobic compounds such as fluoranthene preferentially accumulated in the fat chamber. Only a small amount of fluoranthene was observed in the liver and lung chambers. In addition, the presence of the differentiated 3T3-L1 adipocytes in the ,CCA device significantly reduced naphthalene and naphthoquinone-induced glutathione (GSH) depletion. These findings suggest the potential utilization of the ,CCA system to assess ADMET characteristics of the compound of interest prior to animal or human trials. [source] 19 Cytosolic phospholipase A2 increases proliferation, inhibits apoptosis and facilitates angiogenesis in prostate cancer: a potential new therapeutic targetBJU INTERNATIONAL, Issue 2006M.I. PATEL The end-products from the arachadonic acid (AA) pathway have been shown to be tumourigenic in prostate cancer (CaP). Cytosolic phospholipase A2 (cPLA2) is the enzyme that liberates AA from plasma membranes and feeds it to the cycloxygenase and lipoxygenase pathways. In this study we aim to determine the importance of cPLA2 in prostate cancer by examining human prostate cancer specimens and in vitro cell line models. Immunohistochemistry of human prostate specimens revealed that activated cPLA2 levels were significantly higher in prostate cancer compared to benign glands.. Next to determine if inhibition of cPLA2 would lead to decreases in prostate cancer growth, we treated three CaPcell lines (PC3, DU145 and LNCaP) with pyrrolidine 2 (P2), a specific cPLA2 inhibitor and showed it significantly inhibited the growth of all three cell lines at concentrations between 1,10,M by MTS assay. P2 treatment induced a cell cycle block at G0/G1 and a corresponding reduction in BrdU incoprporation by flow cytometry and 3H-Thymidine incorporation. In addition cPLA2 knock by siRNA also showed a similar inhibition in proliferation, confirming the importance of cPLA2 in CaP proliferation. P2 also induced apoptosis in CaP cell lines by Caspase 3/7 assay. Treatment of Endothelial cell (HUVECs) cells with P2 had a very significant inhibitory effect on capillary tube formation in matrigel. We conclude that cytosolic phospholipase A2 is overactive in human prostate cancer. It leads to CaP proliferation as well as apoptosis. cPLA2 also is required in endothelial angiogenesis. Inhitibion of cPLA2 by P2 will reduce cancer growth, induce apoptosis and inhibit angiogeneisis in an in vitro model. Together, these findings suggest that cPLA2 could be a potential target in CaP treatment and warrants further validation in animal and human trials. [source] Dronedarone: Current Evidence and Future QuestionsCARDIOVASCULAR THERAPEUTICS, Issue 1 2010Jeremy A. Schafer Atrial fibrillation (AF) is the most common sustained arrhythmia, affecting more than 2.2 million Americans. ACC/AHA/ESC guidelines for the management of patients with AF recommend amiodarone for maintaining sinus rhythm. Dronedarone is a derivative of amiodarone indicated for the treatment of AF. To provide an overview of dronedarone with a focus on the phase III trials and discuss unresolved questions of dronedarone. A literature search was conducted via the PubMed database using the keyword "dronedarone." Search was limited to human trials in english. The FDA website was searched for briefing documents and subcommittee meetings on dronedarone. Clinicaltrials.gov was searched with the keyword dronedarone for upcoming or unpublished clinical trials. Five phase III trials are available for dronedarone: ANDROMEDA, EURIDIS/ADONIS, ATHENA, ERATO, and DIONYSIS. EURIDIS/ADONIS and ATHENA demonstrated a reduction AF recurrence with dronedarone compared to placebo. The ANDROMEDA trial recruited patients with recent hospitalization for heart failure and was terminated due to an excess of deaths in the dronedarone group. The DIONYSIS trial was a comparative effectiveness trial that demonstrated less efficacy for dronedarone but improved tolerability compared to amiodarone. Dronedarone represents an option in the management of AF in select patients. Dronedarone is not appropriate in patients with recently decompensated heart failure or those treated with strong CYP3A4 inhibitors or medications prolonging the QT interval. Dronedarone appears to have improved tolerability at the expense of decreased efficacy when compared to amiodarone. Questions remain on the long-term safety, use in patients with heart failure, retreatment after dronedarone or amiodarone failure, and comparative efficacy with a rate control strategy. [source] Anatomical considerations for natural orifice translumenal endoscopic surgeryCLINICAL ANATOMY, Issue 5 2009Erica A. Moran Abstract Success in surgical procedures relies on the surgeon's understanding of anatomy and the ways in which the internal organs relate to one another. Recently, a new surgical technique has been introduced. Natural orifice translumenal endoscopic surgery (NOTES) uses the body's natural orifices (mouth, anus, urethra, or vagina) as entrance points to the peritoneal cavities (through the stomach, rectum, bladder, or posterior vaginal fornix). NOTES techniques have proven feasible in both animal and early human trials. While it remains to be seen what advantages NOTES possesses over traditional surgical approaches, a clear understanding of human anatomy will be critical for successful, safe NOTES procedures. This article summarizes the development and the basic techniques of NOTES and reviews those anatomical considerations specific to NOTES. Clin. Anat. 22:627,632, 2009. © 2009 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||