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Drug Efficacy (drug + efficacy)
Selected AbstractsCNS response to a thermal stressor in human volunteers and rats may predict the clinical utility of analgesicsDRUG DEVELOPMENT RESEARCH, Issue 1 2007David Borsook Abstract fMRI was used to test the hypothesis that global brain activation following a stressor (a thermal stimulus) that activates multiple brain circuits in healthy subjects can predict which drugs have higher potential for clinical utility for neuropathic pain. The rationale is that a drug will modulate multiple neural circuits that are activated by the system-specific stressor (e.g., pain). In neuropathic pain, some brain circuits have altered function, but most brain systems are "normal." Thus, the manner in which a drug effect on neural circuits is modulated by the stressor may provide insight into the clinical utility based on the readout of brain activation in response to the stimulus. Six drugs with known clinical efficacy (or lack thereof) in treating neuropathic pain were selected and the CNS response to each drug in the presence or absence of a pain stimulus was examined. The present results suggest that it is possible to identify potentially effective drugs based on patterns of brain activation in healthy human subjects and indicate that CNS activity is a more sensitive measure of drug action than standard psychophysical measures of pain intensity. This approach was repeated in rats and showed that a similar fMRI paradigm segregates these drugs in a similar manner suggesting a potential "translational tool" in evaluating drug efficacy for neuropathic pain. The sensitivity of this paradigm using fMRI allows clinical screening in small groups of healthy subjects, suggesting it could become a useful tool for drug development as well as for elucidating the mechanisms of neuropathic disease and therapy. Drug Dev. Res. 68:23,41, 2007. © 2007 Wiley-Liss, Inc. [source] The Pharmacokinetics of Antiepileptic Drugs in Rats: Consequences for Maintaining Effective Drug Levels during Prolonged Drug Administration in Rat Models of EpilepsyEPILEPSIA, Issue 7 2007Wolfgang Löscher Summary:, Rodent models of chronic epilepsy with spontaneous recurrent seizures likely represent the closest parallel to the human condition. Such models may be best suited for therapy discovery for pharmacoresistant epilepsy and for antiepileptogenic or disease-modifying therapeutics. However, the use of such rodent models for therapy discovery creates problems with regard to maintaining effective drug levels throughout a prolonged testing period. This is particularly due to the fact that rodents such as rats and mice eliminate most drugs much more rapidly than humans. Thus, knowledge about elimination rate of a test drug in a laboratory species is essential for development of a treatment paradigm that allows maintaining adequate drug levels in the system over the period of treatment. Currently, the most popular models of epilepsy with spontaneous seizures are poststatus epilepticus models of temporal lobe epilepsy in rats. Such models are both used for studies on antiepileptogenesis and drug resistance. For validation of these models, current antiepileptic drugs (AEDs) have to be used. In this article, the elimination rates of these AEDs and their effective plasma levels in rats are reviewed as a guide for developing treatment protocols for chronic drug testing. The advantages and disadvantages of several technologies for drug delivery are discussed, and some examples for calculation of adequate treatment protocols are given. As shown in this review, because of the rapid elimination of most AEDs in rats, it is no trivial task to maintain effective steady-state AED levels in the plasma throughout the day over multiple days to ensure that there will be adequate levels in the system for the purpose of the experiment. However, the use of an adequate dosing regimen that is based on elimination rate is an absolute prerequisite when using rat models for discovery of new antiepileptogenic therapies or therapies for pharmacoresistant epilepsy, because otherwise such models may lead to erroneous conclusions about drug efficacy. [source] New Insights into the Clinical Management of Partial EpilepsiesEPILEPSIA, Issue S5 2000Prof. Edouard Hirsch Summary The diagnosis, treatment, and prognosis of seizure disorders depend on the correct identification of epileptic syndromes. Partial epilepsies are heterogeneous and can be divided into idiopathic, cryptogenic, and symptomatic epilepsies. The most common of the idiopathic localization-related epilepsies is benign epilepsy with rolandic or centrotemporal spikes (BECTS). Seizures remain rare and the use of antiepileptic drug (AED) treatment in all patients does not appear justified. Children who present with some of the electroclinical characteristics of BECTS may also display severe unusual neurologic, neuropsychological, or atypical symptoms. In some cases, carbamazepine has been implicated as a triggering factor. Primary reading epilepsy and idiopathic occipital lobe epilepsies with photosensitivity are examples of an overlap between idiopathic localization-related and generalized epilepsies and respond well to sodium valproate. Autosomal dominant nocturnal frontal lobe epilepsy and benign familial infantile convulsions are recently described syndromes, differing in several ways from classical idiopathic localization-related epileptic syndromes. In cryptogenic or symptomatic epilepsy, the topography of the epileptogenic zone might influence drug efficacy. An individualized approach to AED selection, tailored to each patient's needs, should be used. Resistance of seizures to antiepileptic therapy may be due to diagnostic and/or treatment error or may be the result of noncompliance. Increasing the dosage, discontinuation or replacement of a drug, or addition of a second drug is indicated in truly resistant cases. The use of more than two AEDs rarely optimizes seizure control, and in some cases reduction of treatment may improve seizure control while lessening side effects. EEG-video assessment of patients with refractory epilepsy is important. Indications for and timing of epilepsy surgery should be reconsidered. Surgical therapy should probably be used more often and earlier than it is at present. [source] Feasibility and challenges of independent research on drugs: the Italian Medicines Agency (AIFA) experienceEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 1 2010Italian Medicines Agency (AIFA) Research & Development Working Group Eur J Clin Invest 2010; 40 (1): 69,86 Key points ,,National Health Service (NHS) is becoming increasingly aware of the need to support independent research to answer some important questions for patient care in areas of scant commercial interest. ,,This article reports the main features and strategies of the independent research programme on drugs launched by the Italian Medicines Agency (AIFA) in 2005. ,,In the three bids launched between 2005 and 2007, a total of 151 studies have been approved for funding for a total of about 78 million Euro. ,,In this article we describe the Italian legislative framework under which the programme was launched, the types of research funded and discuss how the supported studies could contribute, in an international framework, to the knowledge needed on drug efficacy, effectiveness and safety. [source] Pharmacogenomics in dermatology: from susceptibility genes to personalized therapyEXPERIMENTAL DERMATOLOGY, Issue 4 2009Carlo Pincelli Abstract:, A significant proportion of patients with skin disease do not respond to treatment and adverse drug reactions are a common problem. Genetic factors are important determinants for both drug efficacy and toxicity. The fields of pharmacogenetics and pharmacogenomics examine inter-individual variations in the DNA sequence that are related to drug efficacy and toxicity. Here, we present pharmacogenomic data relevant to dermatology and explore the role of dermatologists in identifying patients who may respond to treatment or experience adverse drug reactions. [source] Evaluation of drugs in pediatrics using K-PD models: perspectivesFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2008M. Tod Abstract Some pharmacodynamic (PD) models, called K-PD models, have been developed for the description of drug action kinetics in the absence of drug concentration measurements. Because blood samples for drug measurements are not needed, these models may be very useful in pediatric studies, by reducing their invasiveness. In addition, a number of PD measurements are also non-invasive and specific devices exist for measures in children. Therefore, the kinetics of drug action may be characterized with minimal invasiveness. A brief description of the key features of these models is given, and a number of examples of application are presented. K-PD models are expected to be most useful when the drug kinetics is simple (i.e. when the one-compartment model is a reasonable description), or when the response kinetics is slow compared with drug kinetics. K-PD models have already demonstrated their usefulness in animal and adult studies. They are very attractive for pediatric studies and they should facilitate the assessment of drug efficacy and safety. [source] Pharmacogenetics and personalised medicineFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2002Werner Kalow ABSTRACT The traditional concern of pharmacogenetics was Mendelian (monogenic) variation, which visibly affected some drug responses. Pharmacogenetics was broadened by the observation that multifactorial genetic influences, in conjunction with environmental factors, usually determine drug responses. Variability of gene expression, a new theme of the science of genetics, also affects pharmacogenetics; for example, enhanced enzyme activity does not necessarily indicate a mutation, but may be the consequence of a drug-induced enhancement of gene expression. Methodological advances permit the conversion of pharmacogenetics into the broad practice of pharmacogenomics; this improves the possibility of identifying genetic causes of common diseases, which means establishing new drug targets, thereby stimulating the search for new drugs. While the main medical effect of pharmacogenetics was an improvement of drug safety, pharmacogenomics is hoped to improve drug efficacy. On the way to personalized medicine, we may stepwise improve the chances of choosing the right drug for a patient by categorizing patients into genetically definable classes that have similar drug effects (as, for example, human races, or any population group carrying a particular set of genes). It is wise to expect that, even after we have reached the goal to establish personalized medicine, we will not have eliminated all uncertainties. [source] Modeling complex decay profiles of hepatitis B virus during antiviral therapy,,HEPATOLOGY, Issue 1 2009Harel Dahari Typically, hepatitis B virus (HBV) decays in patients under therapy in a biphasic manner. However, more complex decay profiles of HBV DNA (e.g., flat partial response, triphasic, and stepwise), for which we have no clear understanding, have also been observed in some treated patients. We recently introduced the notion of a critical drug efficacy, ,c, such that if overall drug efficacy, ,tot, is higher than the critical drug efficacy (i.e., ,tot > ,c) then viral levels will continually decline on therapy, while if ,tot < ,c, then viral loads will initially decline but will ultimately stabilize at a new set point, as seen in flat partial responders. Using the idea of critical efficacy and including hepatocyte proliferation in a viral kinetic model, we can account for these complex HBV DNA decay profiles. The model predicts that complex profiles such as those exhibiting a plateau or shoulder phase, as well as a class of stepwise declines, occur only in patients in whom the majority of hepatocytes are infected before therapy. Conclusion: We show via kinetic modeling how a variety of HBV DNA decay profiles can arise in treated patients. (HEPATOLOGY 2009;49:32-38.) [source] Involvement of calcium in the differential induction of heat shock protein 70 by heat shock protein 90 inhibitors, geldanamycin and radicicol, in human non-small cell lung cancer H460 cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2006Yuo-Sheng Chang Abstract Both geldanamycin (GA) and radicicol (RA) are HSP90 binding agents that possess antitumour activities. Although the in vitro data indicated that the inhibitory constant of RA is much bigger than that of GA, the in vivo data on drug efficacy might reveal different results. We have recently shown that treatment with GA induces a heat-shock response and that calcium mobilization may be involved in the process. By using induction of HSP70 as the endpoint assay, we found changes in upstream signaling mediators, including HSF1 and calcium mobilization, as well as possible involvement of protein kinase in human non-small cell lung cancer H460 cells treated with GA and RA. Our results demonstrated that calcium mobilization, a calcium dependent and H7-sensitive protein kinase, along with HSF1 activation by phosphorylation, are all involved in the HSP70 induction process triggered by the drugs. However, only GA, but not RA, can provoke a rapid calcium mobilization and thereby result in an instant induction of HSP70. Furthermore, the rapid calcium influx, followed by instant HSP induction, could be achieved in GA- or RA-treated cells placed in a medium containing excessive calcium while the response was completely abolished in cells depleted of calcium. Taken together, our findings suggest that differential calcium signaling may account for the differential induction of HSP and the action of GA and RA. J. Cell. Biochem. © 2005 Wiley-Liss, Inc. [source] Rescue strategies against non-steroidal anti-inflammatory drug-induced gastroduodenal damageJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2009Yun Jeong Lim Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drugs worldwide, which attests to their efficacy as analgesic, antipyretic and anti-inflammatory agents as well as anticancer drugs. However, NSAID use also carries a risk of major gastroduodenal events, including symptomatic ulcers and their serious complications that can lead to fatal outcomes. The development of "coxibs" (selective cyclooxygenase-2 [COX-2] inhibitors) offered similar efficacy with reduced toxicity, but this promise of gastroduodenal safety has only partially been fulfilled, and is now dented with associated risks of cardiovascular or intestinal complications. Recent advances in basic science and biotechnology have given insights into molecular mechanisms of NSAID-induced gastroduodenal damage beyond COX-2 inhibition. The emergence of newer kinds of NSAIDs should alleviate gastroduodenal toxicity without compromising innate drug efficacy. In this review, novel strategies for avoiding NSAID-associated gastroduodenal damage will be described. [source] Use of volumetric computerized tomography as a primary outcome measure to evaluate drug efficacy in the prevention of peri-prosthetic osteolysis: A 1-year clinical pilot of etanercept vs. placeboJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2003Edward M. Schwarz Although total hip replacement (THR) is amongst the most successful and beneficial medical procedures to date, long-term outcomes continue to suffer from aseptic loosening secondary to peri-prosthetic osteolysis. Extensive research over the last two decades has elucidated a central mechanism for osteolysis in which wear debris generated from the implant stimulates inflammatory cells to promote osteoclastogenesis and bone resorption. The cytokine tumor necrosis factor alpha (TNF,) has been demonstrated to be central to this process and is considered to be a leading target for intervention. Unfortunately, even though FDA approved TNF antagonists are available (etanercept), currently there are no reliable outcome measures that can be used to evaluate the efficacy of a drug to prevent peri-prosthetic osteolysis. To the end of developing an effective outcome measure, we evaluated the progression of lesion size in 20 patients with established peri-acetabular osteolysis (mean = 29.99 cm3, range = 2.9,92.7 cm3) of an uncemented primary THR over 1-year, using a novel volumetric computer tomography (3D-CT) technique. We also evaluated polyethylene wear, urine N-telopeptides and functional assessments (WOMAC, SF-36 and Harris Hip Score) for comparison. At the time of entry into the study baseline CT scans were obtained and the patients were randomized to etanercept (25 mg s.q., twice/week) and placebo in a double-blinded fashion. CT scans, urine and functional assessments were also obtained at 6 and 12 months. No serious adverse drug related events were reported, but one patient had to have revision surgery before completion of the study due to aseptic loosening. No remarkable differences between the groups were observed. However, the study was not powered to see significant drug effects. 3D-CT data from the 19 patients was used to determine the mean increase in lesion size over 48 weeks, which was 3.19 cm3 (p < 0.0013). Analysis of the urine N-telopeptides and functional assessment data failed to identify a significant correlation with wear or osteolysis. In conclusion, volumetric CT was able to measure progression of osteolysis over the course of a year, thus providing a technology that could be used in therapeutic trials. Using the data from this pilot we provide a model power calculation for such a trial. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source] Tumour and dendrimers: a review on drug delivery aspectsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2008Abhinav Agarwal Tumour is a morbid state, characterized by spontaneous outgrowth of an abnormal mass of cells. The evolution of tumours is random, disorganized, a condition of numerous mutations. The properties are biased and incompletely comprehended. It is a malignant or benign condition that encompasses its own rules of morphogenesis, an immortal state that elucidates different physiology. It is a pathological crisis that still haunts the minds of scientists, physicians and patients, a complete cure of which is still a dream to be realized. The unpredictable microenvironment of cancerous cells in all of its existing forms i.e. leukaemic cells, solid tumours and sarcomas is well documented. This phenomenon expressed by cancerous sites in the body poses various obstacles towards drug efficacy. Thus, it has become necessary to address briefly the issues relating to tumour physiology, its vasculature and angiogenesis. The information could provide insight towards the development of tumour-targeted drug delivery. The salient features regarding these have been discussed. [source] Study to compare the efficacy and safety of fluconazole cream with flutrimazole cream in the treatment of superficial mycosis: a multicentre, randomised, double-blind, phase III trialMYCOSES, Issue 6 2010S. M. Yim Summary Fluconazole, which is a drug of the azole family, is safely used in systemic treatment of oral and intravenous injection, but it is difficult to use fluconazole as a topical application because of its large molecular weight and strong hydrophilic property. This study is a multicentre, double-blind, randomised, non-inferiority study to compare the antifungal effect and safety of fluconazole cream 0.5% and 1% with flutrimazole cream 1% in superficial mycosis. A total of 162 subjects selected to participate in this study were equally divided into three groups and assigned to be given fluconazole cream 0.5%, fluconazole cream 1%, and flutrimazole cream 1% in the ratio of 1 : 1. The primary index of drug efficacy was determined by complete mycological cure in which no fungus was detected on KOH smear test 4 weeks after application of fluconazole. The secondary index of efficacy was defined as complete mycological cure 4 weeks after the application of fluconazole, improvement of clinical symptoms and overall effectiveness assessed by the research staff. According to this study, on comparing the efficacy of cure of superficial dermatomycosis after 4 weeks of application, both fluconazole 0.5% and fluconazole 1% cream were found to be equally effective and non-inferior to flutrimazole 1% cream. Given the effectiveness and safety of the drug, both fluconazole 0.5% and 1% cream might be said to be optimal concentration in the treatment of superficial dermatomycosis. [source] Flow cytometric determination of Src phosphorylation in pediatric patients treated with dasatinib,PEDIATRIC BLOOD & CANCER, Issue 6 2009Bella S. Guerrouahen MS Abstract Tyrosine kinase inhibitors, such as imatinib, have dramatically improved the outcomes for patients with selected cancers. For imatinib, western blotting of phospho-CrkL was an insensitive, indirect, and descriptive method to determine drug efficacy. Greater use of targeted therapies should involve more quantitative evaluation of the target's dose-inhibition. The Src/Abl kinase inhibitor dasatinib has recently been approved for use in Ph+ leukemias after failure with imatinib. Src family kinases (SFK) also play a critical role in nonhematologic cancers. We have developed a flow cytometric assay to measure SFK autophosphorylation levels in blood mononuclear cells and observed a direct correlation between its inhibition and patient dosage. This method provides a sensitive, quick, and quantitative tool to assess drug efficacy. Pediatr Blood Cancer 2009;53:1132,1135. © 2009 Wiley-Liss, Inc. [source] Approaches to combat with confounding by indication in observational studies of intended drug effectsPHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 7 2003Alex D. McMahon Abstract There has been a resurgence of controversy about the usefulness of observational data to study the efficacy of drugs. Nearly every week a researcher makes some criticism of clinical trials or justifies observational research into intended effects, with other researchers offering a contradictory viewpoint. Literature reviews are not useful in this regard because the contradictory studies will not usually be carried out. Some methods are discussed which may have potential utility in the study of intended effects. There may be a marginal role for statistical techniques such as propensity scores and confounder scores. More promising techniques may include ecological analyses, restriction of subjects and blinded prospective review. Because it is currently unknown when the observational study of drug efficacy is possible, we should arguably always carry out a study of the determinants of prescribing first, and possibly consider using the various techniques that are outlined in this article. Copyright © 2003 John Wiley & Sons, Ltd. [source] For the good of the patient: risks and benefits of medicines,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 2 2003Alasdair Breckenridge Abstract The basis of regulation of medicines is an assessment of risk and benefit. As the process of drug development has evolved with the advances in scientific knowledge, new and more precise methods of measuring drug efficacy have been created. Pharmacovigilance must also change with as much emphasis being placed on demonstrating the safety of a medicine as on preventing harm. Communication of these issues to interested parties remains problematical with room for considerable improvement. Copyright © 2003 John Wiley & Sons, Ltd. [source] Tissue Distribution of P-Glycoprotein in CatsANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 6 2009S. Van Der Heyden Summary Permeability glycoprotein (P-gp) is a membrane-bound efflux pump that exports various substances out of the cell. Variations in P-gp expression play an important role in susceptibility to toxic substances, drug efficacy and disease risk. In the present study, the distribution of the MDR1 -gene product P-gp was determined in normal tissues of domestic shorthair cats using immunohistochemistry. Two monoclonal antibodies C494 and C219 were used, recognizing a different epitope on the human P-gp molecule. A consistent positive immunolabelling was obtained. The tissue distribution and cellular locations with antibody C494 were similar to those in man and dogs; with liver, colon, adrenal cortex and brain capillaries being consistently and intensely labelled. However, the immunolabelling in the kidney was in contradiction to man and dogs. The C219 antibody seems to react with a specific form of P-gp, only expressed in feline tissues with a barrier function, i.e. endothelia of the brain, testes and ovaries, and intestinal epithelial cells in contact with the lumen. [source] Impact and Quantification of the Sources of Error in DNA Pooling DesignsANNALS OF HUMAN GENETICS, Issue 1 2009A. Jawaid Summary The analysis of genome wide variation offers the possibility of unravelling the genes involved in the pathogenesis of disease. Genome wide association studies are also particularly useful for identifying and validating targets for therapeutic intervention as well as for detecting markers for drug efficacy and side effects. The cost of such large-scale genetic association studies may be reduced substantially by the analysis of pooled DNA from multiple individuals. However, experimental errors inherent in pooling studies lead to a potential increase in the false positive rate and a loss in power compared to individual genotyping. Here we quantify various sources of experimental error using empirical data from typical pooling experiments and corresponding individual genotyping counts using two statistical methods. We provide analytical formulas for calculating these different errors in the absence of complete information, such as replicate pool formation, and for adjusting for the errors in the statistical analysis. We demonstrate that DNA pooling has the potential of estimating allele frequencies accurately, and adjusting the pooled allele frequency estimates for differential allelic amplification considerably improves accuracy. Estimates of the components of error show that differential allelic amplification is the most important contributor to the error variance in absolute allele frequency estimation, followed by allele frequency measurement and pool formation errors. Our results emphasise the importance of minimising experimental errors and obtaining correct error estimates in genetic association studies. [source] Pivotal studies of orphan drugs approved for neurological diseases,ANNALS OF NEUROLOGY, Issue 2 2009Jun Mitsumoto MPH Objective To identify design elements of clinical trials leading to US Food and Drug Administration approval of drugs for neurological diseases with and without orphan indications. Methods We used publicly available information to identify approvals for drugs for neurological diseases with an orphan indication (n = 19) and compared them with recent approvals for drugs for neurological diseases without an orphan indication (n = 20). We identified "pivotal trials" from drug labels and drug approval packages, and assessed them on four elements of clinical trial design: control, blinding, randomization, and size. Results All drugs for neurological diseases (100%) approved without an orphan indication included at least two randomized, double-blind, placebo-controlled trials. In comparison, 32% of drugs with an orphan indication had at least two such trials (p < 0.001) and 74% had at least one (p = 0.02). Thirty-three pivotal trials were conducted for the 19 drugs approved with an orphan indication. Of the 33 trials, 11 (33%) did not use a placebo control, 9 (27%) were not double blind, and 4 (12%) were not randomized. Drugs approved without an orphan indication had more pivotal trials per drug (3.8 vs 1.7 trials; p < 0.001) and a larger mean trial size (506 vs 164 trial participants; p < 0.001). Interpretation The US Food and Drug Administration has approved orphan drugs for neurological diseases without randomized, doubled-blind, placebo-controlled pivotal trials. As orphan drug development grows, demand will likely increase for alternative designs for conducting adequate and well-controlled studies to demonstrate drug efficacy. Ann Neurol 2009;66:184,190 [source] Methotrexate catabolism to 7-hydroxymethotrexate in rheumatoid arthritis alters drug efficacy and retention and is reduced by folic acid supplementationARTHRITIS & RHEUMATISM, Issue 8 2009Joseph E. Baggott Objective To assess the catabolism of methotrexate (MTX) to 7-hydroxy-MTX (7-OH-MTX) in patients with rheumatoid arthritis as well as the effect of folic acid and folinic acid on this catabolism. Methods Urinary excretion of MTX and its catabolite, 7-OH-MTX, was measured in 2 24-hour urine specimens collected after MTX therapy. Urine samples were collected from patients after the sixth and seventh weekly doses of MTX. MTX and 7-OH-MTX concentrations were determined by high-performance liquid chromatography mass spectrometry. Swelling and pain/tenderness indices were used to measure symptoms before and at 6 and 7 weeks of therapy. Patients received either folic acid or folinic acid supplements (1 mg/day) from week 6 to week 7. Results Folic acid inhibited aldehyde oxidase (AO), the enzyme that produces 7-OH-MTX, but folinic acid did not. Excretion of 7-OH-MTX (determined as a percentage of the dose of MTX or as mg 7-OH-MTX/gm creatinine) was not normally distributed (n = 39). Patients with marked improvement in swelling and pain/tenderness indices had a lower mean 7-OH-MTX excretion level (P < 0.05). Patients who received folic acid supplements had decreased 7-OH-MTX excretion (P = 0.03). Relatively high 7-OH-MTX excretion was correlated with relatively high MTX excretion and with relatively low MTX retention in vivo (P < 0.05) (n = 35). Conclusion Our findings of a non-normal distribution of 7-OH-MTX excretion suggest that there are at least 2 phenotypes for this catabolism. Decreased 7-OH-MTX formation suggests folic acid inhibition of AO and a better clinical response, while increased 7-OH-MTX formation may interfere with MTX polyglutamylation and binding to enzymes and, therefore, may increase MTX excretion and decrease MTX retention and efficacy in vivo. [source] The LUNDEX, a new index of drug efficacy in clinical practice: Results of a five-year observational study of treatment with infliximab and etanercept among rheumatoid arthritis patients in southern SwedenARTHRITIS & RHEUMATISM, Issue 2 2006Lars Erik Kristensen Objective To describe the use of the LUNDEX, a new index for comparing the long-term efficacy and tolerability of biologic therapies in rheumatoid arthritis (RA) patients treated in clinical practice. Methods Patients (n = 949) with active RA that had not responded to at least 2 disease-modifying antirheumatic drugs (DMARDs) including methotrexate, in whom biologic therapy was being initiated, were included in a structured clinical followup protocol. The protocol included collection of data on diagnosis, disease duration, previous and ongoing DMARD treatment, and dates on which biologic treatment was started and terminated. In addition, data on efficacy measures used for calculating validated response criteria, i.e., the European League Against Rheumatism and American College of Rheumatology response criteria, were collected at fixed time points. Data were prospectively registered from March 1999 through January 2004. The LUNDEX, a new index combining the proportion of patients fulfilling a selected response criteria set with the proportion of patients adhering to a particular therapy, was designed to compare the efficacy of the different therapies. Results Etanercept had higher overall LUNDEX values compared with infliximab, mostly because of a lower rate of adherence to therapy with infliximab. The relationship between the drugs was consistent irrespective of the response criteria used. Conclusion The LUNDEX is a valuable tool for evaluating drug efficacy in observational studies. It has the advantage of integrating clinical response as well as adherence to therapy in a composite value. Moreover, the LUNDEX has a practical and potentially universal application independent of diagnosis and response criteria. [source] Mathematical modeling of reactive transport of anti-tumor drugs through electro-active membranesASIA-PACIFIC JOURNAL OF CHEMICAL ENGINEERING, Issue 3 2009Parag Saurabh Abstract We present a mathematical modeling and design of an implantable polymer membrane-based drug-release device that uses alternate voltage scans across the electro-active membrane for delivery and reactive uptake of anionic anti-tumor drugs. Our mathematical model comprises Poisson,Boltzmann, Nernst,Planck and Diffusion,Reaction equations written for three compartments, namely, the drug reservoir, the polymer membrane and the diseased tissue, with the governing equations for the compartments being linked to each other through the boundary conditions. An analytical solution for the three-compartment model has been obtained using Laplace transforms and residue integration. We use this solution to quantify the various parameters controlling the spatiotemporal dynamics of drug delivery and analyze the efficacy of the reactive transport process for an anionic chemotherapeutic drug, Irinotecan-HCl, commercially also known as CPT-11. We show that a ,smart pill' with optimal drug efficacy may be designed by altering the thickness and the diffusivity of the electro-active membrane, and by tuning the applied voltage and the duration of the positive and the negative voltage scans such that the drug concentration in the tumor tissue is maintained within its therapeutic range. Copyright © 2009 Curtin University of Technology and John Wiley & Sons, Ltd. [source] Azathioprine for atopic dermatitisCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 5 2001S. J. Meggitt For adults with atopic dermatitis (AD) refractory to topical treatment, the choices of second-line therapy are limited. Furthermore, there are concerns about the long-term safety of treatments such as cyclosporin. Limited open studies suggest that azathioprine may be effective, although controlled trial data is lacking. Nevertheless, many UK dermatologists use azathioprine to treat patients with severe AD, despite the potential risk of serious toxicity. Azathioprine myelotoxicity and drug efficacy are now known to be related to the activity of a key enzyme in azathioprine metabolism, thiopurinemethyltransferase (TPMT). Recently, the facility for TPMT measurement has become more widely available, providing the possibility to optimize the therapeutic effect of azathioprine, yet minimise the risk of toxicity. We review the evidence concerning the use of azathioprine for AD, and have identified 128 cases in eight open studies, including our own prospective trial. Improvement in the majority was noted in seven studies, although objective measures of disease activity were used in only one trial. Measurements of TPMT activity were performed in the two most recent studies only. These data underscore the requirement for a prospective randomised controlled trial, and highlight the need to further investigate the role of TPMT measurement in azathioprine usage. [source] PERSONAL DIGITAL VIDEO: A METHOD TO MONITOR DRUG REGIMEN ADHERENCE DURING HUMAN CLINICAL INVESTIGATIONSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 12 2006Chad C Carroll SUMMARY 1Maintaining patient adherence to a drug regimen has proven to be difficult. Missed doses can impact drug efficacy and disease control, leading to increased health-care costs. 2During clinical drug trials, poor adherence could lead to false conclusions regarding drug efficacy. Therefore, the purpose of the present study was to determine the feasibility of using personal digital video cameras to monitor adherence to a medication regimen during a clinical investigation. 3Older men and women (60,78 years) participated in a double-blind, placebo-controlled trial to determine the effect of ibuprofen or paracetamol on skeletal muscle adaptations to chronic resistance exercise training. Patients took three daily doses of either a placebo or the maximal daily over-the-counter dose of ibuprofen (1.2 g/day) or paracetamol (4.0 g/day) for 12 weeks. Prior to beginning the study, subjects were trained to use a personal digital video camera to record their drug consumption. 4Subjects correctly recorded 4956 of 5375 doses, resulting in an average camera compliance rate of 92% (71,100%). 5We describe a method of monitoring adherence to a prescribed drug regimen during a clinical investigation. Camera compliance rates, which directly confirm drug consumption, were higher than what is typically obtained with other methods of monitoring adherence. This camera compliance method provides the investigator with a simple and convenient means to generate direct evidence of drug consumption. [source] The Efficacy of Esmolol versus Lidocaine to Attenuate the Hemodynamic Response to Intubation in Isolated Head Trauma PatientsACADEMIC EMERGENCY MEDICINE, Issue 1 2001M. Andrew Levitt DO Abstract. Objective: To assess the effect of esmolol vs lidocaine to attenuate the detrimental rise in heart rate and blood pressure during intubation of patients with isolated head trauma. Methods: This was a prospective, double-blind, randomized study, performed at an urban, county teaching emergency department. Participants were 30 patients with isolated head trauma. Each underwent a standardized intubation protocol including esmolol or lidocaine, both at 2 mg/kg. Results: Esmolol was used in 16 patients and lidocaine in 14. Mechanisms of injury included 12 assaults, 6 motor vehicle collisions, 6 falls, 4 auto-vs-pedestrian crashes, and 2 bicycle incidents. Mean ethanol level was 0.116 ± 0.133 SD (range 0-0.482). Mean Glasgow Coma Scale (GCS) score was 7.9 ± 4.0 SD. Cranial computed tomography (CT) hemorrhagic findings included 9 subdural/epidural hematomas, 6 cortex hemorrhages, and 2 multi-hemorrhages. Eleven patients received surgical intervention: 9 patients received a craniotomy, and 2 a ventricular catheter. The 2-minute time interval around intubation was used to assess each drug's efficacy. The mean difference change between groups for heart rate was 4.0 beats/min (95% CI = -17.7 to 9.7 beats/min), for systolic blood pressure was 1.3 mm Hg (95% CI = -27.8 to 30.4 mm Hg), and for diastolic blood pressure was 2.6 mm Hg (95% CI = -27.1 to 21.9 mm Hg). The power of this study was 90% to detect a 20-beat/min difference in heart rate, a 35-mm Hg difference in systolic blood pressure, and a 20-mm Hg difference in diastolic blood pressure. Conclusions: Esmolol and lidocaine have similar efficacies to attenuate moderate hemodynamic response to intubation of patients with isolated head trauma. [source] Effects of bisacodyl on ascending colon emptying and overall colonic transit in healthy volunteersALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 9 2009N. MANABE Summary Background, The mechanism of action of bisacodyl in the unprepared human colon remains unclear. Aim, To evaluate the effect of oral bisacodyl on the overall and regional colonic transit in humans. Methods, In a double-blind, randomized, placebo-controlled study of 25 healthy participants, effects of oral bisacodyl (5 mg p.o. per day) and placebo on colonic transit were compared. A validated scintigraphy method was used to measure colonic transit. The primary transit endpoints, ascending colon emptying t1/2 and geometric centre of colon isotope at 24 h (overall transit), were compared (Wilcoxon rank sum test). Results, There were significant treatment effects on ascending colon t1/2, with the bisacodyl group demonstrating accelerated emptying [median 6.5 h, interquartile range 5.0,8.0 h] relative to the placebo group [11.0 h (7.0,17.1); P = 0.03]. Numerical differences in colonic geometric centre 24 h [bisacodyl median 3.0 (2.2,3.8), placebo 4.0 (3.1,4.6)] were not significant (P = 0.19). There were no significant differences observed in geometric centre 4 h. Conclusion, Oral 5 mg bisacodyl accelerates ascending colon in the unprepared colon in healthy adults; this action may contribute to the drug's efficacy in constipation. [source] Treatment of massive hypertriglyceridemia resistant to PUFA and fibrates: A possible role for the coenzyme Q10?BIOFACTORS, Issue 1 2005A.F.G. Cicero Abstract Objective: to describe the effect of CoQ10 (added to either a fibrate, or PUFA or association of both) in patients affected by massive hypertriglyceridemia (MHTG) resistant to fibrates and PUFA. Design: Open, sequential, comparative intervention study. Setting: Specialised centres for dyslipidemia management. Subjects: 15 subjects (mean age: 45.1 ± 12.5 years) affected by MHTG and hyporesponsive to either fibrates, or PUFA, or fibrates-PUFA association, and 15 age-matched subjects regularly responders to PUFA and fenofibrate treatment. Interventions: Treatment for periods of 6 weeks each with the following consecutive treatments: CoQ10 150 mg/day, PUFA 3000 mg/day, fenofibrate 200 mg/day, PUFA 3000 mg/day + fenofibrate 200 mg/day, PUFA 3000 mg/day + CoQ10 150 mg/day, fenofibrate 200 mg/day + CoQ10 150 mg/day, and finally, fenofibrate 200 mg/day + PUFA 3000 mg/day + CoQ10 150 mg/day. Results: CoQ10 supplementation improved, in the control group, systolic and diastolic blood pressure, creatinine and Lp(a) plasma levels, both during fenofibrate and/or PUFA treatment. In MHTG group, CoQ10 supplementation significantly improved TG, TC, Lp(a), uric acid and blood pressure during fenofibrate treatment, but only Lp(a) and blood pressure during PUFA treatment. Fenofibrate appeared to have better effect on hsCRP and ,-GT plasma levels than PUFA. No significant change was observed in any group and under any treatment in regards to homocysteinemia, PAI-1, or t-PA. Conclusion: Even though the mechanism of action through which the effects were obtained is yet to be elucidated, adding CoQ10 to fenofibrate could improve the drug's efficacy in MHTG patients not responding to fenofibrate alone. [source] Review article: interactions between genotype and response to therapy in inflammatory bowel diseasesALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2006K. R. HERRLINGER Summary Background More than half of the patients with inflammatory bowel diseases are candidates for immunosuppressive therapy. However, even the most effective drugs used in inflammatory bowel disease are only successful in about two-thirds of patients. Adverse events limit their use in a further substantial proportion of patients. Recent research has focussed on the possibility of predicting a drugs' efficacy and/or toxicity by identifying polymorphic variants in the genes encoding enzymes involved in metabolic pathways. Aim To highlight recent advances and limitations in the field of pharmacogenetics in inflammatory bowel disease. Results Recent pharmacogenetic studies have mainly focussed on immunosuppressive agents including corticosteroids, azathioprine, methotrexate and infliximab. Several polymorphic genes encoding enzymes involved in the metabolism of these drugs have been identified including the inosine triphosphate pyrophosphatase in thiopurine therapy, the methylene tetrahydrofolate reductase in methotrexate therapy and polymorphisms in apoptosis genes in infliximab therapy. However, at the present time, genotyping for the variants of the thiopurine methyltransferase gene, an enzyme important for the metabolism of the thiopurine drugs, is the only useful test in clinical practice. Conclusions Although the field of pharmacogenetics in inflammatory bowel disease is promising most new targets have so far failed to translate into clinical practice. Future pharmaceutical trials should include pharmacogenetic research to test appropriate candidate genes in a prospective manner. [source] | ||||||||||||||||||||||||||||