FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2007
Sophie Tambour
Abstract In recent years, advances in neuroscience led to the development of new medications to treat alcohol dependence and especially to prevent alcohol relapse after detoxification. Whereas the earliest medications against alcohol dependence were fortuitously discovered, recently developed drugs are increasingly based on alcohol's neurobiological mechanisms of action. This review discusses the most recent developments in alcohol pharmacotherapy and emphasizes the neurobiological basis of anti-alcohol medications. There are currently three approved drugs for the treatment of alcohol dependence with quite different mechanisms of action. Disulfiram is an inhibitor of the enzyme aldehyde dehydrogenase and acts as an alcohol-deterrent drug. Naltrexone, an opiate antagonist, reduces alcohol craving and relapse in heavy drinking, probably via a modulation of the mesolimbic dopamine activity. Finally, acamprosate helps maintaining alcohol abstinence, probably through a normalization of the chronic alcohol-induced hyperglutamatergic state. In addition to these approved medications, many other drugs have been suggested for preventing alcohol consumption on the basis of preclinical studies. Some of these drugs remain promising, whereas others have produced disappointing results in preliminary clinical studies. These new drugs in the field of alcohol pharmacotherapy are also discussed, together with their mechanisms of action. [source]

Particle beam radiotherapy for head and neck tumors: Radiobiological basis and clinical experience

HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 8 2006
Barbara Alicja Jereczek-Fossa MD
Abstract Background. Head and neck tumors are often located near critical organs, making it impossible to deliver a dose of conventional radiotherapy high enough to eradicate the disease. Our aim was to review the potential benefits and available clinical experience of particle beam therapy (hadrontherapy) in the treatment of these tumors. Methods. A review of the literature was carried out through a MEDLINE search (publications between 1980 and 2005). Results. A review of the available clinical data shows that particle beam therapy can offer several radiobiological and physical advantages over conventional photon radiotherapy: improved dose distribution permits dose escalation within the target and optimal sparing of normal tissue. Preclinical and clinical studies suggest that there may be benefits to using hadrontherapy for tumors characterized by poor radiosensitivity and critical location. At present, the most used hadrons are protons and, as yet on an experimental basis, carbon ions. It is now well accepted that there are certain indications for using proton therapy for skull base tumors (chordoma and chondrosarcoma), paranasal sinus carcinomas, selected nasopharyngeal tumors, and neutron/ion therapy for salivary gland carcinomas (in particular, adenoid cystic tumors). Its viability in other cases, such as locally advanced squamous cell carcinoma, melanoma, soft tissue sarcoma, and bone sarcoma, is still under investigation. Conclusions. Hadrontherapy can be beneficial in the treatment of tumors characterized by poor radiosensitivity and critical location. Further clinical and radiobiological studies are warranted for improved selection of patient population. © 2006 Wiley Periodicals, Inc. Head Neck, 2006 [source]

Influence of rotational speed, torque and operator proficiency on failure of Greater Taper files

INTERNATIONAL ENDODONTIC JOURNAL, Issue 1 2002
G. M. Yared
Abstract Aim The purpose of this study was to evaluate the influence of rotational speed, torque, and operator experience on the incidence of locking, deformation, and separation of instruments when using a specific Ni,Ti rotary instrumentation technique in extracted human teeth. Methodology Greater Taper Ni,Ti rotary instruments (GT) were used in a crown-down technique. In one group (rotational speed evaluation) of canals (n = 300) speeds of 150, 250 and 350 r.p.m. (subgroups 1, 2 and 3) were used. Each one of the subgroups included 100 canals. In a second group (evaluation of torque) (n = 300) torque was set at 20, 30 and 55 Ncm (subgroups 4, 5 and 6). In the third group (evaluation of operator proficiency) (n = 300) three operators with varying experience (subgroups 7, 8 and 9) were also compared. Each subgroup included the use of 10 sets of GT rotary instruments and 100 canals of extracted human molars. Each set of instruments was used in up to 10 canals and sterilized before each case. NaOCl 2.5% was used as an irrigant. The number of locked, deformed, and separated instruments was recorded for each group. Statistical analysis was carried out with pairwise comparisons using Fisher's exact tests for each of the failure type. Results When the influence of rotational speed was evaluated, instrument deformation and separation did not occur in subgroups 1 (150 r.p.m.), 2 (250 r.p.m.), and 3 (350 r.p.m.). Instrument locking occurred in subgroup 3 only. Statistical analysis demonstrated a significant difference between the 150 and 350 r.p.m. groups and between the 250 and 350 r.p.m. groups with respect to instrument locking. In torque evaluation, neither separation, deformation nor locking occurred during the use of the instruments, at 150 r.p.m., and at the different torque values. When the operators were compared, although two instruments were separated in canals prepared by the least experienced operator, Fisher's exact tests did not demonstrate a significant difference between the three subgroups. Instrument locking, deformation, and separation did not occur with the most experienced operator. None of the instruments separated with the trained operator. Conclusions Preclinical training in the use of the GT rotary instruments when used with a crown-down technique at 150 r.p.m. was crucial in avoiding instrument separation and reducing the incidence of instrument locking and deformation. [source]

Epidermal growth factor receptor and cancer: control of oncogenic signalling by endocytosis

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 5a 2008
Michael Vibo Grandal
,,Introduction ,,Endocytosis of EGFR -,Kinase activity -,Clathrin-coated pits -,Ubiquitination -,Effects of EGFR-ErbB2 heterodimerization on EGFR internalization ,,Cellular and molecular requirements for lysosomal degradation of EGFR -,Intracellular EGFR degradation depends on luminal sorting at multivesicular bodies -,Molecular requirements for EGFR sorting in multivesicular endosomes Abstract The epidermal growth factor receptor (EGFR) and other members of the EGFR/ErbB receptor family of receptor tyrosine kinases (RTKs) are important regulators of proliferation, angiogenesis, migration, tumorigenesis and metastasis. Overexpression, mutations, deletions and production of autocrine ligands contribute to aberrant activation of the ErbB proteins. The signalling output from EGFR is complicated given that other ErbB proteins are often additionally expressed and activated in the same cell, resulting in formation of homo-and/or heterodimers. In particular, association of EGFR with ErbB2 prevents its down-regulation, underscoring the importance of the cellular background for EGFR effects. Signalling from ErbB proteins can either be terminated by dissociation of ligand resulting in dephosphorylation, or blunted by degradation of the receptors. Although proteasomal targeting of ErbB proteins has been described, lysosomal degradation upon ligand-induced endocytosis seems to play the major role in EGFR down-regulation. Preclinical and clinical data have demonstrated that EGFR is a central player in cancer, especially in carcinomas, some brain tumours and in non-small cell lung cancer. Such studies have further validated EGFR as an important molecular target in cancer treatment. This review focuses on mechanisms involved in ligand-induced EGFR activation and endocytic down-regulation. A better understanding of EGFR biology should allow development of more tumour-selective therapeutic approaches targeting EGFR-induced signalling. [source]

Review article: pharmacological therapy for hepatocellular carcinoma with sorafenib and other oral agents

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 11-12 2008
M. CHAPARRO
Summary Background, Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Unresectable disease patients have median survival of few months. There is a substantial need for novel treatments for patients with advanced HCC. Aim, To provide an update review of mechanism of hepatocarcinigenesis and systemic therapies for HCC and the relevant role of Sorafenib in patients with advanced disease. Methods, A Medline search was performed to identify pertinent original research and review articles. Selected references in these articles were also evaluated. Results, Systemic chemotherapy for HCC has been quite ineffective. Preclinical studies demonstrated that Raf/MAPK-ERK kinase (MEK)/Extracellular signal regulated kinase (ERK) pathway has a role in HCC. HCC tumours are highly vascularized and vascular endothelial growth factor (VEGF) augments HCC development and metastasis. Sorafenib blocks tumour cell proliferation by targeting Raf/MEK/ERK signalling and exerts an antiangiogenic effect by targeting VEGF receptors-2/3 and platelet derived growth factor receptor , tyrosine kinases. Conclusions, Currently available therapies are not effective for patients with advanced HCC. Sorafenib has demonstrated for the first time to prolong survival in patients with advanced HCC, and it is the new reference standard for systemic treatment in these patients. [source]

Bilastine in allergic rhinoconjunctivitis and urticaria

ALLERGY, Issue 2010
C. Bachert
To cite this article: Bachert C, Kuna P, Zuberbier T. Bilastine in allergic rhinoconjunctivitis and urticaria. Allergy 2010; 65 (Suppl. 93): 1,13. Abstract Allergic rhinoconjunctivitis and urticaria are increasing in prevalence in many developed countries. The role of histamine in such conditions is well documented and clinical guidelines recommend non-sedating H1 -receptor antagonists as first-line treatment choices. Bilastine is a novel non-sedating histamine H1 -receptor antagonist developed for the treatment of allergic rhinoconjunctivitis and urticaria. The aim of this review is to critique the scientific evidence relating to the pharmacological properties of bilastine and the clinical evidence regarding its potential as an antihistamine. In vitro binding studies and investigations in animal tissue have demonstrated the high specificity of bilastine for H1 -receptors, and preclinical animal studies have also yielded promising results in terms of a reduction of histamine-mediated inflammatory effects, including capillary permeability and bronchospasm. In pharmacodynamic studies bilastine was found to down-regulate histamine-induced flare and wheal responses in healthy volunteers. Preclinical and clinical pharmacokinetic studies showed that bilastine has dose-dependent kinetics following oral administration. Excretion is almost exclusively via urine and faeces as unchanged drug. Early clinical trials have shown that bilastine has similar efficacy to other second-generation H1 -receptor antagonists such as cetirizine, desloratadine, fexofenadine and levocetirizine, in terms of reducing allergic symptoms. Clinical findings also indicate that bilastine has a rapid onset of action and a 20 mg single dose is effective throughout a 24-h period. Furthermore, bilastine has been associated with improved quality of life in allergic rhinoconjunctivitis and urticaria patients. Adverse effects have generally been minimal in these studies and doses up to twice those proposed did not exhibit differences in adverse events compared to placebo. Moreover, in vivo investigations have found no evidence of accumulation of bilastine in the central nervous system, and various studies have confirmed minimal effects on psychomotor performance in healthy volunteers administered up to four times the usual dose. Clinical studies have also found no effect of bilastine on the QTc interval and other ECG parameters, even at supratherapeutic dosages, confirming the good cardiac safety profile of this newer antihistamine. Given its pharmacodynamic profile, which appears to be similar to other second-generation H1 -receptor antagonists, and its favourable safety and tolerability, bilastine has the attributes of a potentially clinically useful non-sedating antihistamine. Larger clinical studies are now necessary to fully elucidate the clinical potential of this novel antihistamine. [source]

Preclinical Manufacture of Anti-HER2 Liposome-Inserting, scFv-PEG-Lipid Conjugate.

BIOTECHNOLOGY PROGRESS, Issue 1 2005

Analytical methods optimized for micellar F5cys-MP-PEG(2000)-DPSE protein-lipopolymer conjugate are presented. The apparent micelle molecular weight, determined by size exclusion chromatography, ranged from 330 to 960 kDa. The F5cys antibody and conjugate melting points, determined by differential scanning calorimetry, were near 82 °C. Traditional methods for characterizing monodisperse protein species were inapplicable to conjugate analysis. The isoelectric point of F5cys (9.2) and the conjugate (8.9) were determined by capillary isoelectric focusing (cIEF) after addition of the zwitterionic detergent CHAPS to the buffer. Conjugate incubation with phospholipase B selectively removed DSPE lipid groups and dispersed the conjugate prior to separation by chromatographic methods. Alternatively, adding 2-propanol (29.4 vol %) and n -butanol (4.5 vol %) to buffers for salt-gradient cation exchange chromatography provided gentler, nonenzymatic dispersion, resulting in well-resolved peaks. This method was used to assess stability, identify contaminants, establish lot-to-lot comparability, and determine the average chromatographic purity (93%) for conjugate lots, described previously. The F5cys amino acid content was confirmed after conjugation. The expected conjugate avidity for immobilized HER-2/neu was measured by bimolecular interaction analysis (BIAcore). Mock therapeutic assemblies were made by conjugate insertion into preformed doxorubicin-encapsulating liposomes for antibody-directed uptake of doxorubicin by HER2-overexpressing cancer cells in vitro. Together these developed assays established that the manufacturing method as described in the first part of this study consistently produced F5cys-MP-PEG(2000)-DSPE having sufficient purity, stability, and functionality for use in preclinical toxicology investigations. [source]

Renin Inhibitors in Chronic Heart Failure: The Aliskiren Observation of Heart Failure Treatment Study in Context

CLINICAL CARDIOLOGY, Issue 9 2010
FESC, FRACP, Henry Krum PhD
Renin-angiotensin aldosterone system (RAAS) activation is a key neurohormonal contributor to the progression of chronic heart failure. Strategies that block this activation have consistently demonstrated major beneficial impacts on morbidity and mortality in this setting. Direct renin inhibitors (DRIs) present a novel opportunity to block at an additional or alternative step in this pathway, that being conversion of angiotensinogen to angiotensin I. Theoretical benefits of blocking at the level of renin include: inhibition of the reflex activation of plasma renin activity induced by conventional downstream RAAS blockers. Minimization of angiotensin II and/or aldosterone escape and blocking upstream at the rate-limiting step of angiotensin I production. Preclinical and early-phase clinical studies have largely supported this hypothesis. In the Aliskiren Observation of Heart Failure Treatment study, patients with systolic chronic heart failure receiving background angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers and ,-blockers benefited from aliskiren in reduction vs placebo of plasma levels of brain natriuretic peptide, the primary efficacy endpoint of that study. Large-scale outcome trials are, however, required to definitively determine the benefits of a DRI strategy additional to, or as an alternative to, conventional approaches such as ACE inhibitors in the systolic chronic heart failure setting. Copyright © 2010 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose. [source]

In vivo functions of the prolyl-4-hydroxylase domain oxygen sensors: direct route to the treatment of anaemia and the protection of ischaemic tissues

ACTA PHYSIOLOGICA, Issue 4 2009
D. M. Katschinski
Abstract The prolyl-4-hydroxylase domain (PHD) 1,3 enzymes have been identified based on their ability to regulate the stability of hypoxia-inducible factor , subunits and thus to modify hypoxia-inducible gene expression. Transgenic mouse models provided insights into the isoform-specific functions of these oxygen sensors with physiological implications for angiogenesis, erythropoiesis/oxygen transport, cardiovascular function, metabolism and tissue homeostasis. This knowledge is important for the ongoing development of small molecule PHD inhibitors that are currently tested in preclinical and clinical trials for the treatment of anaemia and for cytoprotection. This review aims at summarizing the insights obtained from key mouse knock-out models as well as first experiences in the therapeutic application of PHD inhibitors. [source]

Insulin glargine and receptor-mediated signalling: clinical implications in treating type 2 diabetes

DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 8 2007
Derek Le Roith
Abstract Most patients with type 2 diabetes mellitus will eventually require insulin therapy to achieve or maintain adequate glycaemic control. The introduction of insulin analogues, with pharmacokinetics that more closely mimic endogenous insulin secretion, has made physiologic insulin replacement easier to achieve for many patients. However, there are also concerns regarding alteration of binding affinities for the insulin receptor (IR) or insulin-like growth factor-1 receptor (IGF-1R) may increase the mitogenic potential of some analogues. Therefore, this article will review the relevant preclinical and clinical data to assess the mitogenic potential of insulin glargine, a basal insulin analogue, compared with regular human insulin (RHI). Searches of the PubMed database were performed using terms that included ,IR,' ,insulin-like growth factor-1,' ,IGF-1R,' ,type 2 diabetes mellitus,' and ,insulin glargine.' Original articles and reviews of published literature were retrieved and reviewed. Although one study reported increased binding affinity of insulin glargine for the IGF-1R and increased mitogenic potential in cells with excess IGF-1Rs (Saos/B10 osteosarcoma cells), most in vitro binding-affinity and cell-culture studies have demonstrated behaviour of insulin glargine comparable to that of RHI for both IR and IGF-1R binding, insulin signalling, and metabolic and mitogenic potential. Currently published in vivo carcinogenic studies and human clinical trial data have shown that insulin glargine is not associated with increased risk for either cancer or the development or progression of diabetic retinopathy. Copyright © 2007 John Wiley & Sons, Ltd. [source]

Hormones and drinking behaviour: New findings on ghrelin, insulin, leptin and volume-regulating hormones.

DRUG AND ALCOHOL REVIEW, Issue 2 2009
An ESBRA Symposium report
Abstract There is growing evidence for a role of appetite-related peptides and volume-regulating hormones in alcoholism. In particular, recent evidence has suggested that hormones, such as ghrelin, insulin and leptin and volume-regulating hormones, could play a role in alcohol-seeking behaviour. The goal of this review is to discuss the results of recent preclinical and clinical investigations on this topic. The findings indicate that neuroendocrinological mechanisms are potentially involved in the neurobiology of alcohol craving. Accordingly, research on this topic could lead to possible development of new therapeutic approaches in the treatment of patients with alcohol problems. [Addolorato G, Leggio L, Hillemacher T, Kraus T, Jerlhag E, Bleich S. Hormones and drinking behaviour: New findings on ghrelin, insulin, leptin and volume-regulating hormones. An ESBRA Symposium report. Drug Alcohol Rev 2009] [source]

Pharmacologic profile of zoledronic acid: A highly potent inhibitor of bone resorption

DRUG DEVELOPMENT RESEARCH, Issue 4 2002
Jonathan R. Green
Abstract Bisphosphonates are effective in treating benign and malignant skeletal diseases characterized by enhanced osteoclastic bone resorption (i.e., osteoporosis, Paget's disease, tumor-induced osteolysis). The nitrogen-containing bisphosphonate pamidronate is currently the standard treatment for hypercalcemia of malignancy (HCM) and skeletal complications of bone metastases. Zoledronic acid, a novel nitrogen-containing bisphosphonate with an imidazole substituent, has demonstrated more potent inhibition of osteoclast-mediated bone resorption than all other bisphosphonates, including pamidronate, in both in vitro and in vivo preclinical models. Zoledronic acid inhibited ovariectomy-induced bone loss in adult monkeys and rats, and long-term treatment prevented skeletal turnover and subsequent bone loss, reduced cortical porosity, and increased mechanical strength. Zoledronic acid also significantly inhibited bone loss associated with arthritis, bone metastases, and prosthesis loosening. The increased potency of zoledronic acid vs. pamidronate has been demonstrated clinically: zoledronic acid (4 or 8 mg iv) was superior to pamidronate (90 mg iv) in normalizing corrected serum calcium in patients with HCM. In patients with bone metastases, low doses of zoledronic acid (, 2 mg) suppressed bone resorption markers , 50% below baseline, whereas pamidronate 90 mg yielded only 20 to 30% suppression. Importantly, the increased potency of zoledronic acid is not associated with an increased incidence of local (bone) or systemic adverse events. Zoledronic acid does not impair bone mineralization and, compared with pamidronate, has a greater renal and intestinal tolerability therapeutic index. Thus, based on preclinical assays and clinical data, zoledronic acid is the most potent bisphosphonate tested to date. Given its potency and excellent safety profile, zoledronic acid is now poised to become the new standard of treatment for HCM and metastatic bone disease. Drug Dev. Res. 55:210,224, 2002. © 2002 Wiley-Liss, Inc. [source]

Allogeneic bone marrow transplantation with reduced conditioning (RC-BMT)

EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2001
Lars Vindeløv
Abstract: Allogeneic bone marrow transplantation with conventional conditioning (CC-BMT) has the potential of curing various malignant and non-malignant diseases. The curative mechanisms encompass 1) stem cell support for myeloablative radio-chemotherapy, 2) the graft-versus-tumor (GVT) effect, 3) gene replacement for genetic diseases and 4) immunoablation for autoimmune diseases. CC-BMT is characterized by high intensity conditioning, the requirement of prolonged and expensive hospital treatment and a treatment related mortality (TRM) of 10,50% depending on diagnosis, disease stage, patient age and donor type. Recent preclinical and clinical progress has resulted in the emergence of new concepts and procedures that allow replacement of patient bone marrow and immune system with that of the donor by a transplant procedure with markedly reduced conditioning (RC-BMT). This type of transplant, sometimes referred to as mini-BMT, activates curative mechanisms 2,4, which for a number of diseases seems sufficient for cure. It avoids the severe organ toxicity of myeloablative radio-chemotherapy and the complications of profound neutropenia. Patients beyond the age limit of conventional BMT (50,60 yr) may therefore be candidates for this type of transplant as well as patients which because of other medical conditions or the type of disease for which the transplant is needed are poor candidates for CC-BMT. The procedure can be performed in an outpatient setting. The resulting cost reduction should contribute to making allogenic BMT more readily available. This review describes basic concepts and procedures involved in RC-BMT and summarizes preliminary results obtained with RC-BMT in different transplant centers. [source]

Clinical Efficacy of Frovatriptan: Placebo-Controlled Studies

HEADACHE, Issue 2002
R. Ryan MD
Objective.,To confirm the clinical efficacy of frovatriptan 2.5 mg. Background.,Frovatriptan is a new 5-hydroxytryptamine (5-HT)1B/1D receptor agonist being developed for the acute treatment of migraine with or without aura. Results from preclinical and clinical pharmacology studies showed frovatriptan to be a potent 5-HT1B receptor agonist with a long terminal elimination half-life (26 hours) and a broad therapeutic index. Design.,Three randomized, placebo-controlled, double-blind, parallel-group trials, in a total of 2676 patients, were performed to confirm the clinical efficacy of frovatriptan 2.5 mg for the acute treatment of migraine. Results.,In all three studies, headache response 2 hours after frovatriptan dosing was significantly greater than that seen with placebo (P.001) with approximately a two-fold measure of effect over placebo for headache response at 2 and 4 hours postdosing. Time to headache response occurred within 1.5 hours in a substantial proportion of patients. The incidence of 24-hour headache recurrence with frovatriptan was low (10% to 25%). Frovatriptan therapy also was associated with a high degree of patient satisfaction. Conclusions.,Frovatriptan represents a consistently effective acute treatment for migraine and accompanying symptoms. [source]

Progress toward liver-based gene therapy

HEPATOLOGY RESEARCH, Issue 4 2009
Takeshi Suda
The liver is involved in the synthesis of serum proteins, regulation of metabolism and maintenance of homeostasis and provides a variety of opportunities for gene therapy. The enriched vasculature and blood circulation, fenestrated endothelium, abundant receptors on the plasma membranes of the liver cells, and effective transcription and translation machineries in the hepatocytes are some unique features that have been explored for delivery, and functional analysis, of genetic sequences in the liver. Both viral and non-viral methods have been developed for effective gene delivery and liver-based gene therapy. This review describes the fundamentals of gene delivery, and the preclinical and clinical progress that has been made toward gene therapy using the liver as a target. [source]

Structural MRI biomarkers for preclinical and mild Alzheimer's disease,

HUMAN BRAIN MAPPING, Issue 10 2009
Christine Fennema-Notestine
Abstract Noninvasive MRI biomarkers for Alzheimer's disease (AD) may enable earlier clinical diagnosis and the monitoring of therapeutic effectiveness. To assess potential neuroimaging biomarkers, the Alzheimer's Disease Neuroimaging Initiative is following normal controls (NC) and individuals with mild cognitive impairment (MCI) or AD. We applied high-throughput image analyses procedures to these data to demonstrate the feasibility of detecting subtle structural changes in prodromal AD. Raw DICOM scans (139 NC, 175 MCI, and 84 AD) were downloaded for analysis. Volumetric segmentation and cortical surface reconstruction produced continuous cortical surface maps and region-of-interest (ROI) measures. The MCI cohort was subdivided into single- (SMCI) and multiple-domain MCI (MMCI) based on neuropsychological performance. Repeated measures analyses of covariance were used to examine group and hemispheric effects while controlling for age, sex, and, for volumetric measures, intracranial vault. ROI analyses showed group differences for ventricular, temporal, posterior and rostral anterior cingulate, posterior parietal, and frontal regions. SMCI and NC differed within temporal, rostral posterior cingulate, inferior parietal, precuneus, and caudal midfrontal regions. With MMCI and AD, greater differences were evident in these regions and additional frontal and retrosplenial cortices; evidence for non-AD pathology in MMCI also was suggested. Mesial temporal right-dominant asymmetries were evident and did not interact with diagnosis. Our findings demonstrate that high-throughput methods provide numerous measures to detect subtle effects of prodromal AD, suggesting early and later stages of the preclinical state in this cross-sectional sample. These methods will enable a more complete longitudinal characterization and allow us to identify changes that are predictive of conversion to AD. Hum Brain Mapp 2009. © 2009 Wiley-Liss, Inc. [source]

Could interchangeable use of dry powder inhalers affect patients?

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 2005
D. Price
Summary The aim of asthma treatment is optimal disease control. Poor asthma control results in considerable patient morbidity, as well as contributing to the considerable burden placed by the disease on healthcare budgets. There is a need for costs to be carefully scrutinised, with the switching of patients to inhaler devices with lower acquisition costs likely to be increasingly considered. However, before such practice becomes widespread, it is important to establish whether or not this could adversely impact on patients and the level of disease control. For approval to have been given, all marketed inhalers must have satisfied current regulatory requirements for devices. Full preclinical and clinical development programmes are not required when application is made for authorisation to market a new inhaler containing an existing chemical entity, although clinical equivalence testing must be used. Both beneficial and adverse effects should be tested, and the limits of equivalence must be clearly defined, based on therapeutic relevance. It should be noted that equivalence studies are invalid when the end point is not responding (i.e. at the top of the dose,response curve) and when equivalence limits approach or are equal to the magnitude of the drug effect. Approval on the basis of regulations designed to safeguard quality of dry powder inhalers does not mean that devices are interchangeable. When using an inhaler, there are many stages between the patient and the therapeutic effect, involving device design, pharmaceutical performance and patient behaviour. Regulations governing new devices cover only a few of the many factors affecting disease control. Furthermore, clinical trials to assess equivalence may not take into account factors in patient behaviour or variations in patient inhaler technique that may affect use of devices in real-life situations. When assessing the consequences of interchangeable use of dry powder inhalers on healthcare costs, it is important to ensure that the acquisition cost of the devices is not the only cost considered. Other costs that should be considered include the cost of time spent demonstrating to the patient how to use the new device, the cost of additional physician visits to address patient concerns and the management costs if disease control is adversely affected. [source]

A critical analysis of current in vitro and in vivo angiogenesis assays

INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 3 2009
Carolyn A. Staton
Summary The study of angiogenesis has grown exponentially over the past 40 years with the recognition that angiogenesis is essential for numerous pathologies and, more recently, with the advent of successful drugs to inhibit angiogenesis in tumours. The main problem with angiogenesis research remains the choice of appropriate assays to evaluate the efficacy of potential new drugs and to identify potential targets within the angiogenic process. This selection is made more complex by the recognition that heterogeneity occurs, not only within the endothelial cells themselves, but also within the specific microenvironment to be studied. Thus, it is essential to choose the assay conditions and cell types that most closely resemble the angiogenic disease being studied. This is especially important when aiming to translate data from in vitro to in vivo and from preclinical to the clinic. Here we critically review and highlight recent advances in the principle assays in common use including those for endothelial cell proliferation, migration, differentiation and co-culture with fibroblasts and mural cells in vitro, vessel outgrowth from organ cultures and in vivo assays such as chick chorioallantoic membrane (CAM), zebrafish, sponge implantation, corneal, dorsal air sac, chamber and tumour angiogenesis models. Finally, we briefly discuss the direction likely to be taken in future studies, which include the use of increasingly sophisticated imaging analysis systems for data acquisition. [source]

Working memory in early Alzheimer's disease: a neuropsychological review

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 2 2010
J. D. Huntley
Abstract Background Reports of the extent of working memory (WM) impairment in early Alzheimer's disease (AD) have been inconsistent. Using the model of WM proposed by Baddeley, neuropsychological evidence for the impairment of WM in early AD is evaluated. Method Literature searches were performed using Medline, PsycINFO and Embase databases. Individual papers were then examined for additional references not revealed by computerised searches. Results Phonological loop function is intact at the preclinical and early stages of AD, becoming more impaired as the disease progresses. In mild AD, there is impairment on tasks assessing visuospatial sketchpad (VSS) function; however, these tasks also require executive processing by the central executive system (CES). There is evidence that the CES is impaired in mild AD and may be affected in the earlier preclinical stage of the disease. Episodic buffer function may be impaired but further research is required. Conclusions Future research into central executive functioning at the earliest stages of the disease, combined with further longitudinal studies, needs to be carried out. Tasks to assess the proposed functions of the episodic buffer and specific tests of the VSS suitable for AD subjects need to be developed and validated. Learning more about these processes and how they are affected in AD is important in understanding and managing the cognitive deficits seen in the early stages of AD. Copyright © 2009 John Wiley & Sons, Ltd. [source]

Laparoscopic radical prostatectomy: Transfer validity

INTERNATIONAL JOURNAL OF UROLOGY, Issue 5 2010
Tibet Erdogru
Objectives: The impact of a formal fellowship training program on the independent practice of the trainees (i.e. transfer validity) has not been evaluated. We analyzed the transfer validity of a structured curriculum in an in-door as well as an out-door setting. Methods: After completing their training, two fourth generation laparoscopic surgeons who started at the same time compared operative parameters and oncological outcomes in their independent practice, prospectively analyzing the next 100 patients in each. One surgeon continued laparoscopic radical prostatectomy (LRP) in the same center of excellence (Group-In), whereas the other implemented the procedure in a separate academic center (Group-Out). Results: The demographics for both groups (Group-In vs Group-Out) were similar regarding age, prostate volume and preoperative prostate-specific antigen levels. Mean operation times (214.8 vs 224.2 min; P = 0.494) and estimated blood loss (472.4 vs 402.6 mL; P = 0.109) did not differ significantly in both groups as well as complication rate (20 vs 24%), median catheter time (8 vs 8.5 days) and continence rates at 12 months (95 vs 95.5%). According to the pathological stages, the rates of positive surgical margins were similar for pT2 (3.2 vs 4.3%) and pT3 (42.8 vs 45.2%), respectively. Conclusions: With a well designed, long-term preclinical and clinical fellowship training program, LRP techniques can be efficiently transferred from the center of excellence to other centers with no significant impact on surgical, functional and oncological outcomes. [source]

Electron microscopic study to compare preclinical Cushing's syndrome with overt Cushing's syndrome

INTERNATIONAL JOURNAL OF UROLOGY, Issue 4 2002
Daisaku Hirano
Abstract Background: No significant differences in gross and light- microscopic features have been reported between preclinical and overt Cushing's adenomas. In this study, the ultrastructural differences between the two syndromes was attempted to be clarified. Methods: Two preclinical Cushing's syndrome adenomas and two overt Cushing's syndrome adenomas obtained from surgical extirpation were examined in an electron microscopic study. Results: Light microscopically, the adenomas of both syndromes were composed predominantly of clear cells, with few compact cells. Ultrastructurally, the prominent differences were of development in each organelle: the preclinical Cushing's adenomas had undeveloped mitochondria, which were smaller in size and had sparse cristae, lysosomes and polysomes, whereas the overt Cushing's adenomas contained well-developed mitochondria which were larger in size and were filled with abundant cristae, smooth endoplasmic reticulum (SER), lysosomes and polysomes. Conclusions: Preclinical Cushing's syndrome adenomas were ultrastructurally characterized by a reduced number of cellular organelles such as mitochondria and SER, which are necessary to synthesize glucocorticoid hormones. However, examination of a greater number of adenomas will be required to be able to draw conclusions on the ultrastructural differences between the two syndromes. [source]

Bisphosphonate-Associated Osteonecrosis of the Jaw: Report of a Task Force of the American Society for Bone and Mineral Research,,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2007
Sundeep Khosla (Chair)
Abstract ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force. Introduction: The increasing recognition that use of bisphosphonates may be associated with osteonecrosis of the jaw (ONJ) led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address a number of key questions related to this disorder. Materials and Methods: A multidisciplinary expert group reviewed all pertinent published data on bisphosphonate-associated ONJ. Food and Drug Administration drug adverse event reports were also reviewed. Results and Conclusions: A case definition was developed so that subsequent studies could report on the same condition. The task force defined ONJ as the presence of exposed bone in the maxillofacial region that did not heal within 8 wk after identification by a health care provider. Based on review of both published and unpublished data, the risk of ONJ associated with oral bisphosphonate therapy for osteoporosis seems to be low, estimated between 1 in 10,000 and <1 in 100,000 patient-treatment years. However, the task force recognized that information on incidence of ONJ is rapidly evolving and that the true incidence may be higher. The risk of ONJ in patients with cancer treated with high doses of intravenous bisphosphonates is clearly higher, in the range of 1,10 per 100 patients (depending on duration of therapy). In the future, improved diagnostic imaging modalities, such as optical coherence tomography or MRI combined with contrast agents and the manipulation of image planes, may identify patients at preclinical or early stages of the disease. Management is largely supportive. A research agenda aimed at filling the considerable gaps in knowledge regarding this disorder was also outlined. [source]

Comparative Pharmacology of Guinea Pig Cardiac Myocyte and Cloned hERG (IKr) Channel

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 11 2004
CHRISTINA DAVIE Ph.D.
Introduction: This study used whole-cell, patch clamp techniques on isolated guinea pig ventricular myocytes and HEK293 cells expressing cloned human ether-a-go-go-related gene (hERG) to examine the action of drugs causing QT interval prolongation and torsades de pointes (TdP) in man. Similarities and important differences in drug actions on cardiac myocytes and cloned hERG IKr channels were established. Qualitative actions of the drugs on cardiac myocytes corresponded with results obtained from Purkinje fibers and measurement of QT interval prolongation in animal and human telemetry studies. Methods and Results: Adult guinea pig ventricular myocytes were isolated by enzymatic digestion. Cells were continuously perfused with Tyrode's solution at 33,35°C. Recordings were made using the whole-cell, patch clamp technique. Action potentials (APs) were elicited under current clamp. Voltage clamp was used to study the effect of drugs on IKr (rapidly activating delayed rectifier potassium current), INa (sodium current), and ICa (L-type calcium current). Dofetilide increased the myocyte action potential duration (APD) in a concentration-dependent manner, with a pIC50 of 7.3. Dofetilide 1 ,M elicited early afterdepolarizations (EADs) but had little affect on ICa or INa. E-4031 increased APD in a concentration-dependent manner, with a pIC50 of 7.2. In contrast, 10 ,M loratadine, desloratadine, and cetirizine had little effect on APD or IKr. Interestingly, cisapride displayed a biphasic effect on myocyte APD and inhibited ICa at 1 ,M. Even at this high concentration, cisapride did not elicit EADs. A number of AstraZeneca compounds were tested on cardiac myocytes, revealing a mixture of drug actions that were not observed in hERG currents in HEK293 cells. One compound, particularly AR-C0X, was a potent blocker of myocyte AP (pIC50 of 8.4). AR-C0X also elicited EADs in cardiac myocytes. The potencies of the same set of drugs on the cloned hERG channel also were assessed. The pIC50 values for dofetilide, E-4031, terfenadine, loratadine, desloratadine, and cetirizine were 6.8, 7.1, 7.3, 5.1, 5.2, and <4, respectively. Elevation of temperature from 22 to 35°C significantly enhanced the current kinetics and amplitudes of hERG currents and resulted in approximately fivefold increase in E-4031 potency. Conclusion: Our study demonstrates the advantages of cardiac myocytes over heterologously expressed hERG channels in predicting QT interval prolongation and TdP in man. The potencies of some drugs in cardiac myocytes were similar to hERG, but only myocytes were able to detect important changes in APD characteristics and display EADs predictive of arrhythmia development. We observed similar qualitative drug profiles in cardiac myocytes, dog Purkinje fibers, and animal and human telemetry studies. Therefore, isolated native cardiac myocytes are a better predictor of drug-induced QT prolongation and TdP than heterologously expressed hERG channels. Isolated cardiac myocytes, when used with high-throughput patch clamp instruments, may have an important role in screening potential cardiotoxic compounds in the early phase of drug discovery. This would significantly reduce the attrition rate of drugs entering preclinical and/or clinical development. The current kinetics and amplitudes of the cloned hERG channel were profoundly affected by temperature, significantly altering the potency of one drug (E-4031). This finding cautions against routine drug testing at room temperature compared to physiologic temperature when using the cloned hERG channel. [source]

Drug-Induced Torsades de Pointes and Implications for Drug Development

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2004
Ph.D., ROBERT R. FENICHEL M.D.
Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug-induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug-induced repolarization changes, their preclinical and clinical evaluation, and the risk-to-benefit interpretation of drug-induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug-related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug-induced torsades within the larger evaluation of drug-related risks and benefits. (J Cardiovasc Electrophysiol, Vol. 15, pp. 475-495, April 2004) [source]

Challenges of antiangiogenic cancer therapy: trials and errors, and renewed hope

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2007
Miguel Ángel Medina
,,Introduction ,,What can we learn from the previous failures? ,,Signs of hope ,,Another turn of the screw: a surrogate marker, at last ,,Future avenues for the vascular therapy of cancer Abstract Angiogenesis inhibition has been proposed as a general strategy to fight cancer. However, in spite of the promising preclinical results, a first generation of antiangiogenic compounds yielded poor results in clinical trials. Conceptual errors and mistakes in the design of trials and in the definition of clinical end-points could account for these negative results. In this context of discouraging results, a second generation of antiangiogenic therapies is showing positive results in phases II and III trials at the beginning of the twenty-first century. In fact, several combined treatments with conventional chemotherapy and antiangiogenic compounds have been recently approved. The discovery and pharmacological development of future generations of angiogenesis inhibitors will benefit from further advances in the understanding of the mechanisms involved in human angiogenesis. New styles of trials are necessary, to avoid missing potential therapeutic effects. Different clinical end-points, new surrogate biomarkers and methods of imaging will be helpful in this process. Real efficacy in clinical trials may come with the combined use of antiangiogenic agents with conventional chemotherapy or radiotherapy, and combinations of several antiangiogenic compounds with different mechanisms of action. Finally, the existing antiangiogenic strategies should include other approaches such as vascular targeting or angioprevention. [source]

Basic pharmacology relevant to drug abuse assessment: tramadol as example

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2008
R. B. Raffa PhD
Summary Tramadol is a centrally acting analgesic in widespread use throughout the world. Although there is extensive preclinical, clinical, post-marketing and epidemiological data indicating relatively low , but not zero , abuse/dependence, questions continue to arise about its abuse potential and appropriate regulatory classification. This article considers these questions from the point of view of the basic pharmacology of tramadol. There is nothing unique about tramadol in this regard, but its multimodal mechanism of action, pharmacologically active enantiomers, and active metabolite make it a particularly instructive and relevant example. [source]

Role of Helicobacter pylori infection in gastric cancer pathogenesis: A chance for prevention

JOURNAL OF DIGESTIVE DISEASES, Issue 1 2010
Peter MALFERTHEINER
Gastric cancer in the absence of strategies implemented for early detection continues to have a dismal prognosis. There are limited options for a curative therapy once patients present with clinical manifestations of this malignant disease. Helicobacter pylori (H. pylori) infection plays a key role in gastric carcinogenesis, supported by epidemiological, preclinical and clinical studies. The recognition of H. pylori infection as a critical risk factor in the development of gastric cancer opens the chance for new venues in prevention strategies. [source]

Natural killer cell-based immunotherapy in cancer: current insights and future prospects

JOURNAL OF INTERNAL MEDICINE, Issue 2 2009
T. Sutlu
Abstract. As our understanding of the molecular mechanisms governing natural killer (NK) cell activity increases, their potential in cancer immunotherapy is growing increasingly prominent. This review analyses the currently available preclinical and clinical data regarding NK cell-based immunotherapeutic approaches in cancer starting from a historical background and an overview of molecular mechanisms taking part in NK cell responses. The status of NK cells in cancer patients, currently investigated clinical applications such as in vivo modulation of NK cell activity, ex vivo purification/expansion and adoptive transfer as well as future possibilities such as genetic modifications are discussed in detail. [source]

Late Thrombosis: A Problem Solved

JOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 1 2003
ANDREW E. AJANI M.D.
Late thrombosis (angiographic total occlusion associated with an acute coronary syndrome) is a potentially life-threatening complication after intracoronary radiation therapy. This review is intended to explore the preclinical and clinical evidence for late thrombosis, to discuss the etiology, and to provide guidelines for future management. Although we have gained a greater understanding of this complex entity, further research is required in a quest to curtail late thrombosis rates. (J Interven Cardiol 2003;16:9,13) [source]

Synthesis and deuterium labelling of the pure selective estrogen receptor modulator (SERM) acolbifene glucuronides

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 3 2007
Jean-Yves Sancéau
Abstract Acolbifene (EM-652·HCl, SCH 57068·HCl), a highly potent and orally active selective estrogen receptor modulator (SERM), is at late stage clinical development for the treatment of estrogen-sensitive breast cancer. Acolbifene-7-glucuronide 1 (major) and acolbifene-4,-glucuronide 2 (minor) were identified as metabolites of acolbifene in the human. The two monoglucuronides and a diglucuronide 3 as well as the corresponding 2H-labelled derivatives 4,6 were synthesised for use as preclinical and clinical standards for LC,MS/MS analysis. All glucuronides were prepared by the Schmidt glycosylation of monoprotected acolbifene with a glucuronyl imidate at ,10°C to prevent epimerisation at the C-2 position. The two monoglucuronides 1 and 2 of acolbifene were separated by semi-preparative HPLC. Incorporation of three deuteriums was achieved by alkylation of chromanone 15 with C2H3MgI followed by dehydration with C2H3CO22H/2H2O. After chemical resolution and salt neutralisation, [2H3]acolbifene 19 was obtained with 99.4% enantiomeric purity and >98% isotopic purity. Copyright © 2007 John Wiley & Sons, Ltd. [source]