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Potential Treatment (potential + treatment)
Terms modified by Potential Treatment Selected AbstractsTranscranial magnetic stimulation: Potential treatment for tinnitus?PSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 2 2006SAXBY PRIDMORE md Abstract, Tinnitus is a common and often severely disabling disorder for which there is no satisfactory treatment. Transcranial magnetic stimulation (TMS) is a new, non-invasive method of modifying the excitability of the cerebral cortex, which has proven effective in auditory hallucinations and other disorders. Some early studies have been published in which TMS has been trialed in the treatment of tinnitus. The aim of the present paper was to examine the literature and consider the potential for TMS as a therapy in tinnitus. A thorough search of the tinnitus and TMS literature was conducted, and all available relevant material was examined. Discussions were held with leaders in both fields. Tinnitus is common and there are no effective treatments. It is frequently associated with deafness, and may be the result of a pathological plastic process, secondary to loss of innervation of the outer hair cells of the cochlea. Neuroimaging studies demonstrate increase blood flow to the primary and secondary auditory cortices, particularly on the left side. Transcranial magnetic stimulation is a non-invasive method of perturbing and inducing change in the cerebral cortex. It uses electromagnetic principles and has been successfully employed in the treatment of other conditions associated with increased activity of the cerebral cortex. A small number of studies have suggested that TMS may be effective in the treatment of tinnitus. There is a good theoretical basis and early research evidence suggesting that TMS may have treatment potential in tinnitus. Further, larger studies are necessary. [source] Pomegranate flower: a unique traditional antidiabetic medicine with dual PPAR-,/-, activator propertiesDIABETES OBESITY & METABOLISM, Issue 1 2008Yuhao Li PPARs are transcription factors belonging to the superfamily of nuclear receptors. PPAR-, is involved in the regulation of fatty acid (FA) uptake and oxidation, inflammation and vascular function, while PPAR-, participates in FA uptake and storage, glucose homeostasis and inflammation. The PPARs are thus major regulators of lipid and glucose metabolism. Synthetic PPAR-, or PPAR-, agonists have been widely used in the treatment of dyslipidaemia, hyperglycaemia and their complications. However, they are associated with an incidence of adverse events. Given the favourable metabolic effects of both PPAR-, and PPAR-, activators, as well as their potential to modulate vascular disease, combined PPAR-,/-, activation has recently emerged as a promising concept, leading to the development of mixed PPAR-,/-, activators. However, some major side effects associated with the synthetic dual activators have been reported. It is unclear whether this is a specific effect of the particular synthetic compounds or a class effect. To date, a medication that may combine the beneficial metabolic effects of PPAR-, and PPAR-, activation with fewer undesirable side effects has not been successfully developed. Pomegranate plant parts are used traditionally for the treatment of various disorders. However, only pomegranate flower has been prescribed in Unani and Ayurvedic medicines for the treatment of diabetes. This review provides a new understanding of the dual PPAR-,/-, activator properties of pomegranate flower in the potential treatment of diabetes and its associated complications. [source] Insulino-mimetic and anti-diabetic effects of vanadium compoundsDIABETIC MEDICINE, Issue 1 2005A. K. Srivastava Abstract Compounds of the trace element vanadium exert various insulin-like effects in in vitro and in vivo systems. These include their ability to improve glucose homeostasis and insulin resistance in animal models of Type 1 and Type 2 diabetes mellitus. In addition to animal studies, several reports have documented improvements in liver and muscle insulin sensitivity in a limited number of patients with Type 2 diabetes. These effects are, however, not as dramatic as those observed in animal experiments, probably because lower doses of vanadium were used and the duration of therapy was short in human studies as compared with animal work. The ability of these compounds to stimulate glucose uptake, glycogen and lipid synthesis in muscle, adipose and hepatic tissues and to inhibit gluconeogenesis, and the activities of the gluconeogenic enzymes: phosphoenol pyruvate carboxykinase and glucose-6-phosphatase in the liver and kidney as well as lipolysis in fat cells contributes as potential mechanisms to their anti-diabetic insulin-like effects. At the cellular level, vanadium activates several key elements of the insulin signal transduction pathway, such as the tyrosine phosphorylation of insulin receptor substrate-1, and extracellular signal-regulated kinase 1 and 2, phosphatidylinositol 3-kinase and protein kinase B activation. These pathways are believed to mediate the metabolic actions of insulin. Because protein tyrosine phosphatases (PTPases) are considered to be negative regulators of the insulin-signalling pathway, it is suggested that vanadium can enhance insulin signalling and action by virtue of its capacity to inhibit PTPase activity and increase tyrosine phosphorylation of substrate proteins. There are some concerns about the potential toxicity of available inorganic vanadium salts at higher doses and during long-term therapy. Therefore, new organo-vanadium compounds with higher potency and less toxicity need to be evaluated for their efficacy as potential treatment of human diabetes. [source] The modified Atkins diet: A potential treatment for developing countriesEPILEPSIA, Issue 9 2008Eric H. Kossoff No abstract is available for this article. [source] Neuroprotective effect of interleukin-6 and IL6/IL6R chimera in the quinolinic acid rat model of Huntington's syndromeEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2001Jean-Charles Bensadoun Abstract Ciliary neurotrophic factor prevents behavioural deficits and striatal degeneration in rat and primate models of Huntington's disease. Interleukin-6, another member of the cytokine family, and the chimeric molecule (IL6/IL6R) in which interleukin-6 and its soluble receptor are fused, have been shown to exert trophic action on various neuronal populations in the central nervous system. Therefore, we investigated the neuroprotective effect of these two molecules in the quinolinic acid model of Huntington's disease. LacZ-, interleukin-6- and IL6/IL6R-expressing lentiviral vectors were stereotaxically injected into the striatum of Wistar rats. Three weeks later the animals were lesioned through the intrastriatal injection of 180 nmol of quinolinic acid. The extent of the striatal damage was significantly diminished in the rats that had been treated with interleukin-6 or IL6/IL6R. The neuroprotective effect was, however, more pronounced with the IL6/IL6R chimera than with interleukin-6 as indicated by the volume of the lesions (38.6 ± 10% in the IL6/IL6R group, 63.3 ± 3.6% in the IL-6 group and 84.3 ± 2.9% in the control group). Quantitative analysis of striatal interneurons further demonstrated that the IL6/IL6R chimera is more neuroprotective than IL-6 on ChAT- and NADPH-d-immunoreactive neurons. These results suggest that the IL6/IL6R chimera is a potential treatment for Huntington's disease. [source] Animal models of inhibitorsHAEMOPHILIA, Issue 2010B. REIPERT Summary., Antibody responses to clotting factor concentrates remain a major treatment limitation. In conjucation with ongoing clinical studies, the pathogenesis and potential treatment of clotting factor immune responses is being evaluated in a variety of animal models. [source] Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone,,HUMAN MUTATION, Issue 2 2008Masaaki Shimotori Abstract Fabry disease is an X-linked recessive inborn metabolic disorder caused by a deficiency of the lysosomal enzyme ,-galactosidase A (EC 3.2.1.22). The causative mutations are diverse, include both large rearrangements and single-base substitutions, and are dispersed throughout the 7 exons of the ,-galactosidase A gene (GLA). Mutation hotspots for Fabry disease do not exist. We examined 62 Fabry patients in Japan and found 24 GLA mutations, including 11 novel ones. A potential treatment reported for Fabry disease is active site specific chaperone (ASSC) therapy using 1-deoxygalactonojirimycin (DGJ), an inhibitor of ,-galactosidase A, at subinhibitory concentrations. We transfected COS-7 cells with the 24 mutant GLAs and analyzed the ,-galactosidase A activities. We then treated the transfected COS-7 cells with DGJ and analyzed its effect on the mutant enzyme activities. The activity of 11 missense mutants increased significantly with DGJ. Although ASSC therapy is useful only for misfolding mutants and therefore not applicable to all cases, it may be useful for treating many Japanese patients with Fabry disease. © 2007 Wiley-Liss, Inc. [source] Olanzapine does not enhance cognition in non-agitated and non-psychotic patients with mild to moderate Alzheimer's dementiaINTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 11 2005John Kennedy Abstract Objective This was an exploratory study of olanzapine as potential treatment for improvement in cognition in patients with Alzheimer's disease without prominent psychobehavioral symptoms. Methods Non-psychotic/non-agitated patients (n,=,268) with Alzheimer's disease, who had baseline Mini-Mental State Examination (MMSE) scores of 14,26 were randomized to treatment with olanzapine (2.5 to 7.5,mg/d) or placebo for 26 weeks. The primary objectives were to determine if treatment with olanzapine improved cognition as indexed by the Alzheimer's disease Assessment Scale for Cognition (ADAS-Cog) and the Clinician's Interview-Based Impression of Change (CIBIC) after 26 weeks of therapy. Results Patients treated with olanzapine vs placebo experienced significant worsening ADAS-Cog scores at weeks 12 (p,=,0.03) and 26 (p,=,0.004). Changes in CIBIC scores were not significantly different between treatment groups at either assessment. A post hoc analysis revealed that olanzapine-treated patients with more cognitive impairment at baseline (MMSE scores of 14,18) (n,=,35) experienced significantly greater deterioration in ADAS-Cog performance than patients in the placebo group (n,=,24; p,<,0.001); whereas in patients with less cognitive impairment (n,=,78, baseline MMSE scores of 23,26) between-group ADAS-Cog changes were not significant. Conclusions In this 26-week study non-psychotic/non-agitated patients with Alzheimer's disease treated with olanzapine experienced significant worsening of cognition as compared to placebo. Copyright © 2005 John Wiley & Sons, Ltd. [source] Characterization of specific egg yolk immunoglobulin (IgY) against mastitis - causing Staphylococcus aureusJOURNAL OF APPLIED MICROBIOLOGY, Issue 5 2008Y.-H. Zhen Abstract Aims:, To evaluate the in vitro activity of egg yolk immunoglobulin (IgY) against mastitis-causing Staphylococcus aureus. Methods and Results:, Specific IgY was produced by immunizing hens with formaldehyde-killed Staph. aureus, using a bacterial strain known to cause mastitis. The IgY, of 94% purity, was obtained from yolks by water dilution, salt precipitations, ultrafiltration and gel filtration. ELISA indicated that the IgY produced was specific to the antigen and five Staph. aureus isolates obtained from mastitic cows. The growth of Staph. aureus was inhibited by specific IgY at concentrations from 1 to 10 mg ml,1 in a dose-dependent manner. The phagocytosis of Staph. aureus by milk macrophages was enhanced in the presence of specific IgY with the highest phagocytic percentage being 30% higher than that without IgY (P < 0·05). Conclusions:, The specific IgY against mastitis-causing Staph. aureus inhibited the growth of Staph. aureus and enhanced the phagocytosis of Staph. aureus by milk macrophages. Significance and Impact of the Study:, Specific IgY would be a potential treatment for bovine mastitis. [source] Synthesis of isotopically labelled [3- 14C]- and [3,3- 2H2]-5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), a new antifungal agent for the potential treatment of onychomycosisJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 4 2007Stephen J. Baker Abstract 5-Fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690) is a new antifungal agent for the potential treatment of onychomycosis. During the preclinical development phase, it was necessary to synthesize the radioisotope [3- 14C]-5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole and the deuterium isotope [3,3- 2H2]-5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole for in vitro studies. We report the synthesis of these two isotopically labelled derivatives. Copyright © 2007 John Wiley & Sons, Ltd. [source] Formation of a defluorinated metabolite of a quinoxaline antiviral drug catalysed by human cytochrome P450 1A2JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2001Peter J. Mutch The in-vitro metabolism of GW420867X ((S)-2-ethyl-7-fluoro-3-oxo-3, 4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester), a quinoxaline drug for the potential treatment of HIV, has been studied with singly expressed human cytochromes P450 (CYP 450). No biotransformation of [14C]GW420867X was evident in the presence of any of the CYP 450 isoforms, with the exception of CYP 450 1A2, where a single metabolite was observed in the HPLC radiochromatograms of enzyme incubations with the test compound. The structure of this metabolite was determined by nuclear magnetic resonance spectroscopy and mass spectrometry, and was shown to correspond to the replacement of the aromatic fluorine of GW420867X with a hydroxyl group. Thus, it appeared that CYP 450 1A2 catalysed the specific defluorination of GW420867X, presumably during formation of an arene oxide intermediate during aromatic hydroxylation. [source] Pilot study: the use of sulfasalazine for the treatment of acute pouchitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2010A. BELLUZZI Summary Background, Acute pouchitis, an idiopathic inflammatory condition of the ileal pouch anal anastomosis, is the most frequent complication after proctocolectomy for ulcerative colitis. Aim, To test the hypothesis that sulfasalazine (SASP) might have a synergistic beneficial effect in acute pouchitis, by combining the anti-inflammatory activity of 5-aminosalicylic Acid and the bacteriostatic effect of sulphapyridine. Methods, Twenty two patients were investigated for acute pouchitis; the Pouchitis Disease Activity Index (PDAI) was calculated and 11 patients with acute pouchitis (PDAI >7) were included in an open study, after obtaining their informed consent. Patients were treated with SASP 500 mg tablets, two tablets three times per day (3000 mg daily), for 2 months. Pouch endoscopy with biopsies was performed at the entry and at the end of the study. Results, According to the PDAI score, 8/11 patients (73%) improved their clinical condition and 7/11 (63%) were in remission at the end of the treatment. At 8 weeks, the median PDAI index decreased from 11.2 ± 2.3 to 6.6 ± 4.7 P < 0.01. No adverse events or toxicity were reported and all patients completed the study. Conclusions, Despite the limitations of the current study, sulfasalazine seems to be a potential treatment for acute pouchitis. Aliment Pharmacol Ther,31, 228,232 [source] Effect of long-term treatment with octreotide on rectal sensitivity in patients with non-constipated irritable bowel syndromeALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2007T. K. KLOOKER Summary Background, Acute administration of octreotide reduces visceral perception and therefore has been suggested as potential treatment for irritable bowel syndrome. Whether prolonged treatment with octreotide also reduces visceral sensitivity and improves gastrointestinal symptoms remains, however, unknown. Aim, To investigate the effect of a slow release preparation of octreotide on rectal sensitivity and symptoms in irritable bowel syndrome patients. Methods, Forty-six non-constipated irritable bowel syndrome patients (52% female, 19,63 years) participated. Before and after 8 weeks of treatment with octreotide (Sandostatin LAR 20 mg i.m.) or placebo, patients underwent a barostat study to assess the rectal sensitivity. During a 2-week run-in period and treatment, abdominal pain, defecation frequency, consistency and symptom relief were scored weekly. Results, Octreotide, but not placebo, significantly increased the threshold for first sensation. Thresholds for urge to defecate and discomfort/pain and rectal compliance were not altered by either treatment. Octreotide improved stool consistency compared with placebo (loose stools after eight weeks: octreotide: 52%, placebo: 81%, P < 0.05). In contrast, abdominal pain and defecation frequency were not affected. Conclusions, Although the threshold of first rectal sensation increased and stool consistency improved, long-term treatment with octreotide, at least at the current dose used, has no visceral analgesic effect and fails to improve irritable bowel syndrome symptoms. [source] Role of photodynamic therapy in psoriasis: a brief reviewPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 5 2008Yasmeen K. Tandon Background and purpose: Photodynamic therapy (PDT) is a light treatment modality which involves either systemic or local application of a photosensitizing compound, which preferentially deposits in the target cells, and is then followed by selective illumination of the lesion with visible light. The purpose of this study was to review the literature to examine the success, side effects, and different protocols used thus far to treat psoriasis using PDT. Methods: A thorough review of the literature was performed and analyzed. Results and conclusions: After a thorough review of the literature, PDT remains a potential treatment for psoriasis. Clinical improvement has been observed in most studies. The major limiting factor seen in many of the studies was the side effect of pain and burning sensations associated with PDT. This highlights the need for other photosensitizers with better tolerability profiles. [source] Reduction of GAG storage in MPS II mouse model following implantation of encapsulated recombinant myoblastsTHE JOURNAL OF GENE MEDICINE, Issue 11 2005Adelaide Friso Abstract Background Hunter syndrome, mucopolysaccharidosis type II (MPS II), is a X-linked inherited disorder caused by the deficiency of the enzyme iduronate-2-sulfatase (IDS), involved in the lysosomal catabolism of the glycosaminoglycans (GAG) dermatan and heparan sulfate. Such a deficiency leads to the intracellular accumulation of undegraded GAG and eventually to a progressive severe clinical pattern. Many attempts have been made in the last two to three decades to identify possible therapeutic strategies for the disorder, including gene therapy and somatic cell therapy. Methods In this study we evaluated the intraperitoneal implantation of allogeneic myoblasts over-expressing IDS, enclosed in alginate microcapsules, in the MPS II mouse model. Animals were monitored for 8 weeks post-implantation, during which plasma and tissue IDS levels, as well as tissue and urinary GAG contents, were measured. Results and conclusions Induced enzyme activity occurred both in the plasma and in the different tissues analyzed. A significant decrease in urinary undegraded GAG between the fourth and the sixth week of treatment was observed. Moreover, a biochemical reduction of GAG deposits was measured 8 weeks after treatment in the liver and kidney, on average 30 and 38%, respectively, while in the spleen GAG levels were almost normalized. Finally, the therapeutic effect was confirmed by histolochemical examination of the same tissues. Such effects were obtained following implantation of about 1.5 × 106 recombinant cells/animal. Taken together, these results represent a clear evidence of the therapeutic efficacy of this strategy in the MPS II mouse model, and encourage further evaluation of this approach for potential treatment of human beings. Copyright © 2005 John Wiley & Sons, Ltd. [source] CAR chasing: canine adenovirus vectors,all bite and no bark?THE JOURNAL OF GENE MEDICINE, Issue S1 2004Eric J. Kremer Abstract This review deals primarily with canine adenovirus serotype 2 (CAV-2) vectors and gives a simplified overview of how the various domains of virology, cellular and molecular biology, as well as immunology, come into play when trying to understand and ameliorate adenovirus (Ad)-mediated gene transfer. The generation of early region 1 (E1)-deleted (,E1) CAV-2 vectors, the lack of pre-existing humoral immunity, trafficking, the use of the coxsackie B adenovirus receptor (CAR), the surprising neuronal tropism, and the ability to migrate via axons to afferent regions of the central and peripheral nervous system, are described. Due to these intrinsic properties, CAV-2 vectors may be powerful tools for the study of the pathophysiology and potential treatment of neurodegenerative diseases like lysosomal storage disorders, Parkinson's, Alzheimer's, Huntington's, amyotrophic lateral sclerosis, and others. Other potential uses include anti-tumoral and anti-viral vaccines, tracer of synaptic junctions, pain therapy, cancer therapy (e.g. K9 CRAds), and gene transfer to other somatic tissues. Copyright © 2004 John Wiley & Sons, Ltd. [source] Neurologic Diagnosis and Treatment in Patients with Computed Tomography and Nasal Endoscopy Negative Facial PainTHE LARYNGOSCOPE, Issue 11 2004Eric P. Paulson MD Abstract Objective: To determine the helpfulness of specialist neurology referral for patients with facial pain, a normal sinus computed tomography (CT) scan, and normal nasal endoscopy findings. Study Design: Prospective identification of patients and analysis of data approved by the Institutional Review Board. Methods: The data of 104 consecutive patients presenting with facial pain, a normal sinus CT scan, and normal nasal endoscopy findings were reviewed. The patients presented to a single rhinologist in a tertiary care institution. All patients were referred for specialist neurologic evaluation and potential treatment. Further information was obtained from a patient survey. Results: Of the 104 patients, 81 were women and 23 were men. The average age was 46 years (range, 22,85). Fifty-six had clear CT scans, 48 had minimal change, and all had negative endoscopies. Twenty-nine had previous unsuccessful sinus surgery. The average follow-up period was 10.5 months. Forty of 75 patients seeing a neurologist were seen on multiple occasions. Four percent of patients seen by a neurologist had an unsuspected serious intracranial diagnosis. The most common diagnoses were migraine (37%), rebound headache (17%), chronic daily headache (17%), and obstructive sleep apnea (16%). Overall, 58% improved on medical therapy; 60% of those with a clear CT scan improved, and 53% of those with minimal change on CT scan improved (P = .749). Conclusions: Facial pain remains a difficult symptom to diagnose and treat in rhinologic practice. Patients often undergo surgery without help. Most patients with facial pain, a normal sinus CT scan, and normal endoscopy findings benefit from neurologic consultation. Serious intracranial pathologic conditions can be excluded and diagnosis-specific pharmacogenetic therapy instituted with improvement in more than 50%. [source] Valproic acid increases SMN levels in spinal muscular atrophy patient cells,ANNALS OF NEUROLOGY, Issue 5 2003Charlotte J. Sumner MD Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1). Although a centromeric copy of the survival motor neuron gene (SMN2) is retained in all patients with SMA, it differs from SMN1 at a critical nucleotide such that the majority of SMN2 transcripts lack exon 7 and encode an unstable, truncated protein. Here, we show that valproic acid increases levels of exon 7,containing SMN transcript and SMN protein in type I SMA patient,derived fibroblast cell lines. Valproic acid may increase SMN levels both by activating the SMN promoter and by preventing exon 7 skipping in SMN transcripts. Valproic acid and related compounds warrant further investigation as potential treatment for SMA. Ann Neurol 2003;54:647,654 [source] A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat modelsARTHRITIS & RHEUMATISM, Issue 7 2009Vijaykumar M. Baragi Objective Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity. Methods Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA),induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors. Results A number of non,hydroxamic acid,containing compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompetitive inhibition, and Dixon plot analysis from competition studies with a zinc chelator (acetoxyhydroxamic acid) and ALS 1-0635 demonstrated nonexclusive binding. ALS 1-0635 inhibited bovine articular cartilage degradation in a dose-dependent manner (48.7% and 87.1% at 500 nM and 5,000 nM, respectively) and was effective in inhibiting interleukin-1,, and oncostatin M,induced C1,C2 release in human OA cartilage cultures. ALS 1-0635 modulated cartilage damage in the rat MIA model (mean ± SEM damage score 1.3 ± 0.3, versus 2.2 ± 0.4 in vehicle-treated animals). Most significantly, when treated twice daily with oral ALS 1-0635, rats with surgically induced medial meniscus tear exhibited histologic evidence of chondroprotection and reduced cartilage degeneration, without observable musculoskeletal toxicity. Conclusion The compounds investigated in this study represent a novel class of MMP-13 inhibitors. They are mechanistically distinct from previously reported broad-spectrum MMP inhibitors and do not exhibit the problems previously associated with these inhibitors, including selectivity, poor pharmacokinetics, and MSS liability. MMP-13 inhibitors exert chondroprotective effects and can potentially modulate joint pain, and are, therefore, uniquely suited as potential disease-modifying osteoarthritis drugs. [source] Experimental Setup to Evaluate the Performance of Percutaneous Pulmonary Valved Stent in Different Outflow Tract MorphologiesARTIFICIAL ORGANS, Issue 1 2009Riccardo Vismara Abstract Percutaneous pulmonary valve implantation is a potential treatment for right ventricular outflow tract (RVOT) dysfunction. However, RVOT implantation site varies among subjects and the success of the procedure depends on RVOT morphology selection. The aim of this study was to use in vitro testing to establish percutaneous valve competency in different previously defined RVOT morphologies. Five simplified RVOT geometries (stenotic, enlarged, straight, convergent, and divergent) were manufactured by silicone dipping. A mock bench was developed to test the percutaneous valve in the five different RVOTs. The bench consists of a volumetric pulsatile pump and of a hydraulic afterload. The pump is made of a piston driven by a low inertia programmable motor. The hydraulic afterload mimics the pulmonary input impedance and its design is based on a three element model of the pulmonary circulation. The mock bench can replicate different physiological and pathological hemodynamic conditions of the pulmonary circulation. The mock bench is here used to test the five RVOTs under physiological-like conditions: stroke volume range 40,70 mL, frequency range 60,80 bpm. The valved stent was implanted into the five different RVOT geometries. Pressures upstream and downstream of the valved stent were monitored. Flow rates were measured with and without the valved stent in the five mock RVOTs, and regurgitant fraction compared between the different valved stent RVOTs. The percutaneous valved stent drastically reduced regurgitant flow if compared with the RVOT without the valve. RVOT geometry did not significantly influence the flow rate curves. Mean regurgitant fractions varied from 5% in the stenotic RVOT to 7.3% in the straight RVOT, highlighting the influence of the RVOT geometry on valve competency. The mock bench presented in this study showed the ability to investigate the influence of RVOT geometry on the competence of valved stent used for percutaneous pulmonary valve treatment. [source] Characterization of a Hollow Fiber Bioartificial Liver DeviceARTIFICIAL ORGANS, Issue 5 2005Susan Fugett Abu-Absi Abstract:, A three-compartment bioartificial liver (BAL) has been developed for potential treatment of fulminant hepatic failure. It has been shown previously that viability and liver-specific functions were maintained in laboratory-scale bioreactors of such design. In this study, the performance of hepatocytes in a clinical-scale bioartificial liver was verified by sustained specific production rates of albumin and urea, along with oxygen consumption rates for up to 56 h and liver-specific gene expression for up to 72 h. In addition, transmission of porcine endogenous retrovirus and other type C retroviral particles across the hollow fibers was not detected under both normal and extreme operating fluxes. These results demonstrate that the clinical-scale BAL performs at a level similar to the laboratory scale ,and, that, it, offers, a, viral, barrier, against, porcine , retroviruses. [source] In Vitro and In Vivo Evaluation of Albumin Synthesis Rate of Porcine Hepatocytes in a Flat-Plate BioreactorARTIFICIAL ORGANS, Issue 7 2001Masaya Shito Abstract: Several configurations of extracorporeal bioartificial liver devices have been developed for the potential treatment of fulminant hepatic failure or as a bridge to liver transplantation. Recently, we developed a microchannel flat-plate bioreactor with an internal membrane oxygenator in which porcine hepatocytes are cultured as a monolayer on the bottom glass surface. In the present study, we investigated synthetic function of porcine hepatocytes in the bioreactor in both in vitro and in vivo flow circuit models. In vitro, albumin synthesis was stable in the bioreactor for up to 4 days of perfusion. In vivo, with the extracorporeal connection of the bioreactor to rat vasculature, porcine albumin was detectable for 24 h in the rat plasma. We also developed a simple mathematical model to predict the in vivo porcine albumin concentration in rat plasma. These results indicate that this configuration of a microchannel flat-plate bioreactor has potential as a liver support device and warrants further investigation. [source] LC-MS/MS determination of 2-(4-((2-(2S,5R)-2-Cyano-5-ethynyl-1-pyrrolidinyl)-2-oxoethylamino)-4-methyl-1-piperidinyl)-4-pyridinecarboxylic acid (ABT-279) in dog plasma with high-throughput protein precipitation sample preparationBIOMEDICAL CHROMATOGRAPHY, Issue 11 2007Joseph Kim Abstract As an effective DPP-IV inhibitor, 2-(4-((2-(2S,5R)-2-Cyano-5-ethynyl-1-pyrrolidinyl)-2-oxoethylamino)-4-methyl-1-piperidinyl)-4-pyridinecarboxylic acid (ABT-279), is an investigational drug candidate under development at Abbott Laboratories for potential treatment of type 2 diabetes. In order to support the development of ABT-279, multiple analytical methods for an accurate, precise and selective concentration determination of ABT-279 in different matrices were developed and validated in accordance with the US Food and Drug Administration Guidance on Bioanalytical Method Validation. The analytical method for ABT-279 in dog plasma was validated in parallel to other validations for ABT-279 determination in different matrices. In order to shorten the sample preparation time and increase method precision, an automated multi-channel liquid handler was used to perform high-throughput protein precipitation and all other liquid transfers. The separation was performed through a Waters YMC ODS-AQ column (2.0 × 150 mm, 5 µm, 120 Å) with a mobile phase of 20 mm ammonium acetate in 20% acetonitrile at a flow rate of 0.3 mL/min. Data collection started at 2.2 min and continued for 2.0 min. The validated linear dynamic range in dog plasma was between 3.05 and 2033.64 ng/mL using a 50 µL sample volume. The achieved r2 coefficient of determination from three consecutive runs was between 0.998625 and 0.999085. The mean bias was between ,4.1 and 4.3% for all calibration standards including lower limit of quantitation. The mean bias was between ,8.0 and 0.4% for the quality control samples. The precision, expressed as a coefficient of variation (CV), was ,4.1% for all levels of quality control samples. The validation results demonstrated that the high-throughput method was accurate, precise and selective for the determination of ABT-279 in dog plasma. The validated method was also employed to support two toxicology studies. The passing rate was 100% for all 49 runs from one validation study and two toxicology studies. Copyright © 2007 John Wiley & Sons, Ltd. [source] Hematopoietic stem cell transplantation in multiple sclerosisACTA NEUROLOGICA SCANDINAVICA, Issue 6 2009C. Rogojan Intensive immunosuppresion followed by hematopoietic stem cell transplantation (HSCT) has been suggested as potential treatment in severe forms of multiple sclerosis (MS). Since 1995 ca. 400 patients have been treated with HSCT. Stabilization or improvement occurred in almost 70% of cases at least for 3 years post-transplant. Magnetic resonance revealed the capacity of autologous HSCT to suppress or markedly reduce gadolinium-enhancing lesions. The progression of brain atrophy declined after two years post-HSCT. The profound immunological changes following autologous HSCT may result in restoration of self-tolerance. Relatively young patients with active inflammatory lesions of relatively short duration and rapidly progressive disease, but still low disability scores, unresponsive to conventional therapy seem the best candidates for transplantation. Transplant-related mortality was 6% in the first EBMT report and 5.3% in the second one. No deaths were reported since 2001. Very high-intensity conditioning regimen is associated with higher risk of toxicity without significant increase in efficacy. The effects of transplantation and transplantation-related morbidity are dependent on patient-selection, time of transplantation and conditioning regimens used. This review is a comprehensive study of the results obtained in several single-center and multicenter studies. Patient characteristics, transplantations steps, toxicity and clinical outcome have been monitored and compared. [source] Self-expanding intracoronary stent for symptomatic myocardial bridgingCATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS, Issue 7 2007S. Hinan Ahmed MD Abstract Myocardial bridging has been recognized as a potential cause of symptoms of angina, arrhythmias and even infarction. Various treatment strategies including beta-blockers, surgery and more recently intra-coronary stents have been used to manage bridging. We report a novel case of use of self-expanding stent for myocardial bridging in a patient with symptoms of angina and ischemia on nuclear imaging. We further present the 18-month follow up showing minima in-stent stenosis. To our knowledge, this is the first report of using a self-expanding stent in myocardial bridging. The use of self-expanding stents could be a potential treatment for symptomatic myocardial bridging. © 2007 Wiley-Liss, Inc. [source] Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4-(4H -1,2,4-triazol-4-ylamino)benzonitrile: SAR, Crystal Structures, in,vitro and in,vivo ActivitiesCHEMMEDCHEM, Issue 11 2008Christian Bubert Dr. Abstract 4-(((4-Cyanophenyl)(4H -1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (6,a) was the first dual aromatase,sulfatase inhibitor (DASI) reported. Several series of its derivatives with various linker systems between the steroid sulfatase (STS) and the aromatase inhibitory pharmacophores were synthesised and evaluated in JEG-3 cells. The X-ray crystal structures of the aromatase inhibitors, DASI precursors 42,d and 60, and DASI 43,h were determined. Nearly all derivatives show improved in,vitro aromatase inhibition over 6,a but decreased STS inhibition. The best aromatase inhibitor is 42,e (IC50=0.26,nM) and the best DASI is 43,e (IC50,aromatase=0.45,nM, IC50,STS=1200,nM). SAR for aromatase inhibition shows that compounds containing an alkylene- and thioether-based linker system are more potent than those that are ether-, sulfone-, or sulfonamide-based, and that the length of the linker has a limited effect on aromatase inhibition beyond two methylene units. Compounds 43,d,f were studied in,vivo (10,mg,kg,1, single, p.o.). The most potent DASI is 43,e, which inhibited PMSG-induced plasma estradiol levels by 92,% and liver STS activity by 98,% 3,h after dosing. These results further strengthen the concept of designing and developing DASIs for potential treatment of hormone-related cancers. [source] Mycobacterium vaccae administration during allergen sensitization or challenge suppresses asthmatic featuresCLINICAL & EXPERIMENTAL ALLERGY, Issue 8 2003J. J. Smit Summary Background and objective The hygiene hypothesis suggests that a lack of bacterial infections would favour the development of allergic disease. For this reason, bacteria or their components can be used as potential treatment for allergic asthma. We investigated whether heat-killed Mycobacterium vaccae is either able to suppress the induction of allergic asthma or able to suppress already established allergic asthma. Methods Mice were sensitized with ovalbumin (OVA)/alum on days 0 and 14. Thereafter, mice were challenged on days 35, 39 and 42 by inhalation of either OVA or saline aerosols. M. vaccae -treated mice received an injection with 106, 107 or 108 CFU heat-killed M. vaccae on days 0 and 14 or 107 CFU on days 35 and 39. On day 43, the airway responsiveness of the mice to increasing concentrations of methacholine was assessed, blood was withdrawn to measure serum parameters, and lung lavage was performed to detect cytokines and inflammatory cell number. Results Treatment of OVA-sensitized mice with 107 CFU M. vaccae either during sensitization or challenge suppresses airway hyper-responsiveness, airway eosinophilia and IL-5 production after OVA challenge. The increases in OVA-specific serum IgE and in IL-4 by respiratory challenges with OVA were only diminished after M. vaccae treatment (107 CFU) during sensitization. Conclusions Heat-killed M. vaccae prevents allergic and asthmatic manifestations in a mouse model and, more importantly, M. vaccae treatment during challenge suppresses features of asthma, which opens up possibilities for new therapeutic interventions. [source] Androgens, insulin resistance and vascular disease in menCLINICAL ENDOCRINOLOGY, Issue 3 2005D. Kapoor Summary Type 2 diabetes mellitus is increasing globally and is an established risk factor for the development of atherosclerotic vascular disease. Insulin resistance is the hallmark feature of type 2 diabetes and is also an important component of the metabolic syndrome. There is evidence to suggest that testosterone is an important regulator of insulin sensitivity in men. Observational studies have shown that testosterone levels are low in men with diabetes, visceral obesity (which is strongly associated with insulin resistance), coronary artery disease and metabolic syndrome. Short-term interventional studies have also demonstrated that testosterone replacement therapy produces an improvement in insulin sensitivity in men. Thus hypotestosteronaemia may have a role in the pathogenesis of insulin-resistant states and androgen replacement therapy could be a potential treatment that could be offered for improvements in glycaemic control and reduction in cardiovascular risk, particularly in diabetic men. [source] New potential treatments for protection of pancreatic B-cell function in Type 1 diabetesDIABETIC MEDICINE, Issue 11 2008S. Cernea Abstract Type 1 diabetes mellitus results from the progressive and specific autoimmune destruction of insulin-secreting pancreatic B-cells, which develops over a period of years and continues after the initial clinical presentation. The ultimate goal of therapeutic intervention is prevention or reversal of the disease by the arrest of autoimmunity and by preservation/restoration of B-cell mass and function. Recent clinical trials of antigen-specific or non-specific immune therapies have proved that modulation of islet specific autoimmunity in humans and prevention of insulin secretion loss in the short term after the onset of disease is achievable. The identification of suitable candidates for therapy, appropriate dosage and timing, specificity of intervention and the side-effect profile are crucial for the success of any approach. Considering the complexity of the disease, it is likely that a rationally designed approach of combined immune-based therapies that target suppression of B-cell specific autoreactivity and maintenance of immune tolerance, coupled with islet regeneration or replacement of the destroyed B-cell mass, will prove to be most effective in causing remission/reversal of disease in a durable fashion. [source] RESEARCH FOCUS ON COMPULSIVE BEHAVIOUR IN ANIMALS: Pre-exposure to environmental cues predictive of food availability elicits hypothalamic,pituitary,adrenal axis activation and increases operant responding for food in female ratsADDICTION BIOLOGY, Issue 4 2009Carlo Cifani ABSTRACT The present study was undertaken to develop an animal model exploiting food cue-induced increased motivation to obtain food under operant self-administration conditions. To demonstrate the predictive validity of the model, rimonabant, fluoxetine, sibutramine and topiramate, administered 1 hour before the experiment, were tested. For 5 days, female Wistar rats were trained to self-administer standard 45 mg food pellets in one daily session (30 minutes) under FR1 (fixed ratio 1) schedule of reinforcement. Rats were then trained to an FR3 schedule and finally divided into two groups. The first group (control) was subjected to a standard 30 minutes FR3 food self-administration session. The second group was exposed to five presentations of levers and light for 10 seconds each (every 3 minutes in 15 minutes total). At the completion of this pre-session phase, a normal 30-minute session (as in the control group) started. Results showed that pre-exposure to environmental stimuli associated to food deliveries increased response for food when the session started. Corticosterone and adrenocorticotropic hormone plasma levels, measured after the 15-minute pre-exposure, were also significantly increased. No changes were observed for the other measured hormones (growth hormone, prolactin, thyroid-stimulating hormone, luteinizing hormone, insulin, amylin, gastric inhibitor polypeptide, ghrelin, leptin, peptide YY and pancreatic polypeptide). Rimonabant, sibutramine and fluoxetine significantly reduced food intake in both animals pre-exposed and in those not pre-exposed to food-associated cues. Topiramate selectively reduced feeding only in pre-exposed rats. The present study describes the development of a new animal model to investigate cue-induced increased motivation to obtain food. This model shows face and predictive validity, thus, supporting its usefulness in the investigation of new potential treatments of binge-related eating disorders. In addition, the present findings confirm that topiramate may represent an important pharmacotherapeutic approach to binge-related eating. [source] | ||||||||||||||||||||||||||||||||||