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Therapeutic Window (therapeutic + window)
Kinds of Therapeutic Window Selected AbstractsTherapeutic Window for Bioactive Nanocomposites Fabricated by Laser Ablation in Polymer-Doped Organic Liquids,ADVANCED ENGINEERING MATERIALS, Issue 5 2010Anne Hahn Abstract Polymeric nanomaterials are gaining increased interest in medical applications due to the sustained release of bioactive agents. Within this study nanomaterials are fabricated using laser ablation of silver and copper in polymer-doped organic liquids thus allowing to produce customized drug release systems. A strategy is shown to determine the therapeutic window for cells relevant for cochlear implant electrodes, defined by the viability of L929 fibroblasts, PC12 neuronal cells, and spiral ganglion cells on different concentrations of silver and copper ions. The distribution of nanoparticles within the silicone polymer matrix is determined using transmission electron microscopy. Hexane doped with 1% silicone resin is found to be an appropriate liquid matrix to fabricate a nanocomposite with a constant ion release rate. Silver ions of 10,µmol L,1 or copper ions of 100,µmol L,1 cause a suppression of tissue growth without inhibiting neuronal cell growth. The copper nanoparticle content of 0.1,wt% of the silicone composite releases ion concentrations which fit the therapeutic window. [source] Variable expression of CYP and Pgp genes in the human small intestineEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2003M. Lindell Abstract Background ,The small intestine is receiving increased attention for its importance in drug metabolism. However, knowledge of the intervariability and regulation of the enzymes involved, cytochrome P450 and P-Glycoproteins (CYP and Pgp), is poor when compared with the corresponding hepatic enzymes. Methods ,The expression of eight different CYP genes and the Pgp were determined by reverse transcription polymerase chain reaction (RT-PCR) in 51 human duodenum biopsies. And the variability and correlation of expression was analyzed. Results ,Extensive interindividual variability was found in the expression of most of the genes. Only CYP2C9, CYP3A4 and Pgp were found in all samples. CYP1A2, CYP2A6 and CYP2E1 exhibited the highest interindividual variability. No strong correlation of expression existed between the genes. But a highly significant correlation was found between CYP2D6/1A2, 2D6/2E1, 1A2/2E1 and 2B6/2C9. Acetylsalicylic acid and omeprazole significantly increased the expression of CYPs 2A6, 2E1 and 3A4, respectively. Conclusions ,Extensive interindividual variability is characteristic for the expression of drug-metabolizing CYP and Pgp genes in human duodenum, and external factors such as drugs may further increase the variability. It is possible that the large interindividual variability may lead to variable bioavailability of orally used drugs and hence complicate optimal drug therapy, especially for drugs with a small therapeutic window. Elucidation of factors contributing to clinically important variances warrants further investigation. [source] Rivaroxaban , an oral, direct Factor Xa inhibitor , lessons from a broad clinical study programmeEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2009Sylvia Haas Abstract Anticoagulants are recommended for the prevention and treatment of venous thromboembolism (VTE), prevention of stroke in patients with atrial fibrillation (AF) and secondary prevention in patients with acute coronary syndrome (ACS). There is a clinical need for novel anticoagulants offering improvements over current standard of care, such as fixed oral dosing and no need for routine monitoring. Rivaroxaban, an oral, once-daily, direct Factor Xa inhibitor, has recently completed the RECORD phase III programme for the prevention of VTE in patients undergoing total hip or knee replacement (THR or TKR), an indication for which it is approved in Europe and Canada. It is being investigated in large-scale phase III studies for VTE treatment and prevention of stroke in patients with AF, and phase III studies will soon commence for secondary prevention in patients with ACS. Phase I studies demonstrated that no routine anticoagulation monitoring was required, while phase II studies suggested that fixed daily doses had a wide therapeutic window. The four RECORD studies consistently showed that rivaroxaban was significantly more effective than enoxaparin in the prevention of VTE after THR and TKR, with a similar safety profile. This review describes the development of this novel anticoagulant, from bench to bedside. [source] Therapeutic Window for Bioactive Nanocomposites Fabricated by Laser Ablation in Polymer-Doped Organic Liquids,ADVANCED ENGINEERING MATERIALS, Issue 5 2010Anne Hahn Abstract Polymeric nanomaterials are gaining increased interest in medical applications due to the sustained release of bioactive agents. Within this study nanomaterials are fabricated using laser ablation of silver and copper in polymer-doped organic liquids thus allowing to produce customized drug release systems. A strategy is shown to determine the therapeutic window for cells relevant for cochlear implant electrodes, defined by the viability of L929 fibroblasts, PC12 neuronal cells, and spiral ganglion cells on different concentrations of silver and copper ions. The distribution of nanoparticles within the silicone polymer matrix is determined using transmission electron microscopy. Hexane doped with 1% silicone resin is found to be an appropriate liquid matrix to fabricate a nanocomposite with a constant ion release rate. Silver ions of 10,µmol L,1 or copper ions of 100,µmol L,1 cause a suppression of tissue growth without inhibiting neuronal cell growth. The copper nanoparticle content of 0.1,wt% of the silicone composite releases ion concentrations which fit the therapeutic window. [source] A Gene Therapy Technology-Based Biomaterial for the Trigger-Inducible Release of Biopharmaceuticals in MiceADVANCED FUNCTIONAL MATERIALS, Issue 15 2010Michael M. Kämpf Abstract Gene therapy scientists have developed expression systems for therapeutic transgenes within patients, which must be seamlessly integrated into the patient's physiology by developing sophisticated control mechanisms to titrate expression levels of the transgenes into the therapeutic window. However, despite these efforts, gene-based medicine still faces security concerns related to the administration of the therapeutic transgene vector. Here, molecular tools developed for therapeutic transgene expression can readily be transferred to materials science to design a humanized drug depot that can be implanted into mice and enables the trigger-inducible release of a therapeutic protein in response to a small-molecule inducer. The drug depot is constructed by embedding the vascular endothelial growth factor (VEGF121) as model therapeutic protein into a hydrogel consisting of linear polyacrylamide crosslinked with a homodimeric variant of the human FK-binding protein 12 (FM), originally developed for gene therapeutic applications, as well as with dimethylsuberimidate. Administrating increasing concentrations of the inducer molecule FK506 triggers the dissociation of FM thereby loosening the hydrogel structure and releasing the VEGF121 payload in a dose-adjustable manner. Subcutaneous implantation of the drug depot into mice and subsequent administration of the inducer by injection or by oral intake triggers the release of VEGF121 as monitored in the mouse serum. This study is the first demonstration of a stimuli-responsive hydrogel that can be used in mammals to release a therapeutic protein on demand by the application of a small-molecule stimulus. This trigger-inducible release is a starting point for the further development of externally controlled drug depots for patient-compliant administration of biopharmaceuticals. [source] A nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemiaJOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2010Masahiko Sato Abstract Vitamin D3 analogues were shown to be beneficial for osteoporosis and other indications, but their narrow therapeutic window between efficacy and hypercalcemia has limited their clinical utility. A nonsecosteroidal, tissue-selective, orally bioavailable, vitamin D receptor (VDR) ligand was ascertained to be efficacious in bone while having modest calcemic effects in vivo. This compound (VDRM2) potently induced Retinoid X Receptor alpha (RXR)-VDR heterodimerization (EC50,=,7.1,±,1.6,nM) and induced osteocalcin promoter activity (EC50,=,1.9,±,1.6,nM). VDRM2 was less potent in inducing Ca2+ channel transient receptor potential cation channel, subfamily V, member 6 (TRPV6) expression (EC50,=,37,±,12,nM). VDRM2 then was evaluated in osteopenic ovariectomized (OVX) rats and shown to dose-dependently restore vertebral bone mineral density (BMD) from OVX to sham levels at 0.08,µg/kg per day. Hypercalcemia was observed at a dose of 4.6,µg/kg per day of VDRM2, suggesting a safety margin of 57 [90% confidence interval (CI) 35,91]. 1,,25-dihydroxyvitamin D3 [1,,25(OH)2D], ED71, and alfacalcidol restored BMD at 0.030, 0.0055, and 0.046,µg/kg per day, respectively, whereas hypercalcemia was observed at 0.22, 0.027, and 0.23,µg/kg per day, indicating a safety margin of 7.3, 4.9, and 5.0, respectively (90% CIs 4.1,13, 3.2,7.7, and 3.5,6.7, respectively). Histomorphometry showed that VDRM2 increased cortical bone area and stimulated the periosteal bone-formation rate relative to OVX at doses below the hypercalcemic dose. By contrast, ED71 increased the periosteal bone-formation rate only above the hypercalcemic dose. VDRM2 suppressed eroded surface on trabecular bone surfaces at normal serum calcium dosage levels, suggesting dual anabolic and antiresorptive activity. In summary, vitamin D analogues were more potent than VDRM2, but VDRM2 had a greater safety margin, suggesting possible therapeutic potential. © 2010 American Society for Bone and Mineral Research [source] A simple and rapid high-performance liquid chromatographic (HPLC) method for 5-fluorouracil (5-FU) assay in plasma and possible detection of patients with impaired dihydropyrimidine dehydrogenase (DPD) activityJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2004J. Ciccolini PharmD PhD Summary Background:, Dihydropyrimidine dehydrogenase (DPD) gene polymorphism may lead to severe toxicity with 5-fluorouracil (5-FU), a major anticancer drug extensively used in clinical oncology. Drug monitoring combined with early detection of patients at risk would enable timely dose adaptation so as to maintain drug concentrations within a therapeutic window. However, the best method to identify such patients remains to be determined. Objective:, The aim of this study was to develop a rapid and simple high-performance liquid chromatographic (HPLC) method for estimating uracil/dihydrouracil (U/UH2) ratio in plasma, as an index of DPD status, and for assaying 5-FU as part of drug level monitoring. Method:, Assay of 5-FU, and U/UH2 detection were performed on a HPLC system equipped with UV detector. Analytes were separated at room temperature using a 5 ,m particles, 25 cm RP-18 X-Terra column. The mobile-phase consisted of a KH2PO4 salt solution (0·05 m) + 0·1% triethylamine (TEA) pumped at 0·4 mL/min. Detection of 5-FU and 5-bromouracil were performed at 254 nm; U and UH2 elution was monitored at 210 nm. Results:, The method was sensitive and specific for assaying 5-FU within the 5,500 ng/mL concentration range, which covers exposure levels currently met in clinical practice. The method was simple, and relatively cheap, and rapid, with an analytical run time of about 30 min. Data from a patient with 5-FU toxicity suggest that the method was capable of identifying DPD metabolic phenotype in cancer patients, based on measurement of plasma U/UH2 ratio. Conclusion:, The method described should be suitable both for detecting patients at high risk of 5-FU toxicity, and for drug level monitoring during chemotherapy. [source] MRI Assessment Followed by Successful Mechanical Recanalization of a Complete Tandem (Internal Carotid/Middle Cerebral Artery) Occlusion and Reversal of a 10-Hour Fixed DeficitJOURNAL OF NEUROIMAGING, Issue 1 2008Catalina C. Ionita MD ABSTRACT BACKGROUND Mechanical clot extraction up to 8 hours after stroke onset is an alternative strategy for opening large vessels, especially for patients ineligible for intravenous thrombolysis. Safety beyond this therapeutic window is untested. METHODS An 81-year-old woman presented 8 hours after she developed left-sided weakness and dysarthria with a National Institutes of Health Stroke Scale (NIHSS) score fluctuating between 6 and 13. Neuroimaging revealed a large perfusion deficit with no diffusion abnormalities. An emergent cerebral angiogram revealed a complete internal carotid artery terminus occlusion. RESULTS Successful mechanical thrombectomy was performed without complication and resulted in almost complete reversal of the patient's deficit to an NIHSS score of 1, 10 hours after stroke onset. CONCLUSION Patients with large hypoperfused areas and minimal diffusion abnormalities on the MRI may benefit from mechanical thrombectomy beyond an 8-hour window. [source] Macrophage contribution to the response of the rat organ of Corti to amikacinJOURNAL OF NEUROSCIENCE RESEARCH, Issue 9 2007Sabine Ladrech Abstract Transdifferentiation of nonsensory supporting cells into sensory hair cells occurs naturally in the damaged avian inner ear. Such transdifferentiation was achieved experimentally in the cochlea of deaf guinea pigs through Atoh 1 gene transfection. Supporting cells may therefore serve as targets for transdifferentiation therapy. Supporting cells rapidly degenerate after hair cell disappearance, however, limiting the therapeutic window for gene transfer. We studied the time course of ultrastructural and phenotypical changes occurring in Deiters cells (hair cell supporting cells) after ototoxic treatment in the rat. The presence of macrophages in the cochlea was also investigated, to study any deleterious effects they may have on pathologic tissues. One week after treatment most hair cells had disappeared. Deiters cells no longer expressed the glial marker vimentin but instead displayed typical hair cell markers, the calcium binding proteins calbindin and parvalbumin. This suggests that a process of transdifferentiation of Deiters cells into hair cells was activated. By 3 weeks post-treatment, however, the Deiters cells began to degenerate and by 10 weeks post-treatment the organ of Corti was degraded fully. Interestingly, a marked increase in macrophage density was seen after the end of amikacin treatment to 10 weeks post-treatment. This suggests chronic inflammation is involved in epithelium degeneration. Consequently, early treatments with anti-inflammatory factors might promote supporting cell survival, thus improving the efficacy of more specific strategies aimed to regenerate hair cells from nonsensory cells. © 2007 Wiley-Liss, Inc. [source] Biowaiver monographs for immediate release solid oral dosage forms: Quinidine sulfate,,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2009S. Grube Abstract Literature data are reviewed relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing quinidine sulfate. Quinidine sulfate's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. The available data are not fully conclusive, but do suggest that quinidine sulfate is highly soluble and moderately to highly permeable and would likely be assigned to BCS Class I (or at worst BCS III). In view of the inconclusiveness of the data and, more important, quinidine's narrow therapeutic window and critical indication, a biowaiver based approval of quinidine containing dosage forms cannot be recommended for either new multisource drug products or for major postapproval changes (variations) to existing drug products. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2238,2251, 2009 [source] Kufor Rakeb Disease: Autosomal recessive, levodopa-responsive parkinsonism with pyramidal degeneration, supranuclear gaze palsy, and dementiaMOVEMENT DISORDERS, Issue 10 2005David R. Williams MBBS, FRACP Abstract Kufor Rakeb disease is an autosomal recessive disorder characterized by subacute, juvenile-onset, levodopa-responsive parkinsonism, pyramidal signs, dementia, and a supranuclear gaze palsy. It was originally described more than a decade ago, and linkage analysis identified a locus on chromosome 1p36 that was previously assigned PARK9. We have further characterized the clinical picture and specifically re-assessed the response to levodopa in the original family, in the northern highlands of Jordan. In the 4 surviving patients, there has been a narrowing of the therapeutic window for levodopa with the emergence of peak-dose dyskinesias with increased spasticity and cognitive decline. Several new features were identified, including facial-faucial-finger mini-myoclonus, visual hallucinations, and oculogyric dystonic spasms. © 2005 Movement Disorder Society [source] The effects of low level laser irradiation on osteoblastic cellsORTHODONTICS & CRANIOFACIAL RESEARCH, Issue 1 2001A. R. Coombe Low level laser therapy has been used in treating many conditions with reports of multiple clinical effects including promotion of healing of both hard and soft tissue lesions. Low level laser therapy as a treatment modality remains controversial, however. The effects of wavelength, beam type, energy output, energy level, energy intensity, and exposure regime of low level laser therapy remain unexplained. Moreover, no specific therapeutic window for dosimetry and mechanism of action has been determined at the level of individual cell types. The aim of this study was to investigate the effects of low level laser irradiation on the human osteosarcoma cell line, SAOS-2. The cells were irradiated as a single or daily dose for up to 10 days with a GaAlAs continuous wave diode laser (830 nm, net output of 90 mW, energy levels of 0.3, 0.5, 1, 2, and 4 Joules). Cell viability was not affected by laser irradiation, with the viability being greater than 90% for all experimental groups. Cellular proliferation or activation was not found to be significantly affected by any of the energy levels and varying exposure regimes investigated. Low level laser irradiation did result in a heat shock response at an energy level of 2 J. No significant early or late effects of laser irradiation on protein expression and alkaline phosphatase activity were found. Investigation of intracellular calcium concentration revealed a tendency of a transient positive change after irradiation. Low level laser irradiation was unable to stimulate the osteosarcoma cells utilised for this research at a gross cell population level. The heat shock response and increased intracellular calcium indicate that the cells do respond to low level laser irradiation. Further research is required, utilising different cell and animal models, to more specifically determine the effects of low level laser irradiation at a cellular level. These effects should be more thoroughly investigated before low level laser therapy can be considered as a potential accelerator stimulus for orthodontic tooth movement. [source] Cyclosporine drug monitoring with C0 and C2 concentrations in children with stable renal allograft functionPEDIATRIC TRANSPLANTATION, Issue 2 2006Mukaddes Kalyoncu Abstract:, Cyclosporin A (CsA) has a narrow therapeutic window and necessitates monitoring of blood concentration. We aimed to evaluate trough (C0) and second hour (C2) level after ingestion of drug monitoring in renal allograft recipients. In this retrospective study, 12 children eight boys and four girls; mean age at transplantation 14.6 ± 3.7 yr (ranges: 7.0,19.0), mean age post-transtplant 17.8 ± 4.9 yr (ranges: 9.0,24.0) who were transplanted >6 months were enrolled in this evaluation. Ten were recipients of a living related donor and two deceased donor grafts. While six children were receiving CsA, steroids and azathioprine, the other six received CsA, steroids and mycophenolate mofetil. Clinical course, blood pressure, renal and liver function tests were recorded. Mean C0 and C2 were 96.2 ± 59.5 and 504 ± 305.4 ng/mL respectively. Mean serum creatinine level was 1.2 ± 0.45 mg/dL and mean creatinine clearance (CrCl) was 89.2 ± 36.8 mL/min/1.73 m2. There was a correlation between serum creatinine level, CsA dose and C2 levels,whereas,there was no correlation between age, blood pressure, CrCl and C2 levels. However, no correlation was found between C0 levels and any of the above parameters. In conclusion, our data suggest that C2 levels are correlated better with dose and serum creatinine level. [source] Pharmacologic transgene control systems for gene therapyTHE JOURNAL OF GENE MEDICINE, Issue 5 2006Wilfried Weber Abstract Pharmacologic transgene-expression dosing is considered essential for future gene therapy scenarios. Genetic interventions require precise transcription or translation fine-tuning of therapeutic transgenes to enable their titration into the therapeutic window, to adapt them to daily changing dosing regimes of the patient, to integrate them seamlessly into the patient's transcriptome orchestra, and to terminate their expression after successful therapy. In recent years, decisive progress has been achieved in designing high-precision trigger-inducible mammalian transgene control modalities responsive to clinically licensed and inert heterologous molecules or to endogenous physiologic signals. Availability of a portfolio of compatible transcription control systems has enabled assembly of higher-order control circuitries providing simultaneous or independent control of several transgenes and the design of (semi-)synthetic gene networks, which emulate digital expression switches, regulatory transcription cascades, epigenetic expression imprinting, and cellular transcription memories. This review provides an overview of cutting-edge developments in transgene control systems, of the design of synthetic gene networks, and of the delivery of such systems for the prototype treatment of prominent human disease phenotypes. Copyright © 2006 John Wiley & Sons, Ltd. [source] Differential Dose Adjustments of Immunosuppressants after Resuming Boosted versus Unboosted HIV-Protease Inhibitors Postliver TransplantAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009G. Guaraldi Pharmacokinetic (PK) interactions between protease inhibitors (PIs) and immunosuppressive agents (IS) are critical elements in the management of HIV-infected patients who undergo liver transplantation (LTx). The primary objective of this study was to evaluate the decreases in IS dosages necessary to maintain an appropriate therapeutic window (TW) after initiating PI-based antiretroviral therapy regimens post-LTx. Single-center, PK cross-sectional study of consecutive HIV-infected adult patients who underwent LTx was done. Blood trough concentrations (Ct) of IS were obtained using a commercial MEIA test; plasma Ct of PIs were measured using HPLC. Twelve consecutive HIV-infected adult patients (11 males, 1 female) were enrolled. More rapid increases in IS plasma Ct were observed 48 h after initiating ritonavir (RTV)-boosted PI therapy post-LTx than when using unboosted PIs. Seven patients developed acute renal failure. The median fold decrease in IS dosages required to regain IS concentrations that were in the TW was 7.5 (range 6,14) after resuming boosted PIs and 2.9 (range 2,4) after unboosted PIs. The overall median time necessary to reach IS TW after dose adjustment was 3.5 days (range 0,15). Unboosted PIs exhibited lesser PK interactions with IS than did RTV-boosted PIs and were thus more amenable to use in the post-LTx setting. [source] Mycophenolate Blood Level Monitoring: Recent ProgressAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2009T. Van Gelder The concentration,effect relationship for mycophenolic acid (MPA), and the high variability in MPA concentrations in patients on standard dose mycophenolate mofetil (MMF) therapy, for some centers has provided enough evidence to implement therapeutic drug monitoring (TDM) for MMF in daily practice. Two randomized trials Adaption de Posologie du MMF en Greffe Renale (APOMYGRE) and fixed-dose versus concentration controlled (FDCC) investigated the added benefit of TDM for MMF in renal transplant recipients. The APOMYGRE study showed a significant reduction in the incidence of acute rejection in concentration-controlled patients, while the FDCC study had a negative outcome, despite a similar study design. Although it was expected that these prospective trials would give the final answer to the question of whether or not TDM for MMF would be of benefit, it seems that the studies have not had much impact on patient management. Several trials have shown the importance of early adequate exposure to MPA in the first week after transplantation. As it will be hard to improve MPA exposure with TDM, this early, ongoing study now investigates the use of an increased starting dose. The increased starting dose will avoid underexposure to MPA in higher proportions of patients shortly after transplantation but may result in more toxicity in patients with MPA exposures exceeding the upper threshold of the therapeutic window. [source] Recombinant C1 inhibitor in brain ischemic injury,ANNALS OF NEUROLOGY, Issue 3 2009Raffaella Gesuete BD Objective C1 inhibitor (C1-INH) is an endogenous inhibitor of complement and kinin systems. We have explored the efficacy and the therapeutic window of the recently available human recombinant (rh) C1-INH on ischemic brain injury and investigated its mechanism of action in comparison with that of plasma-derived (pd) C1-INH. Methods rhC1-INH was administered intravenously to C57Bl/6 mice undergoing transient or permanent ischemia, and its protective effects were evaluated by measuring infarct volume and neurodegeneration. The binding profiles of rhC1-INH and pdC1-INH were assessed in vitro using surface plasmon resonance. Their localization in the ischemic brain tissue was determined by immunohistochemistry and confocal analysis. The functional consequences of rhC1-INH and pdC1-INH administration on complement activation were analyzed by enzyme-linked immunosorbent assay on plasma samples. Results rhC1-INH markedly reduced cerebral damage when administered up to 18 hours after transient ischemia and up to 6 hours after permanent ischemia, thus showing a surprisingly wide therapeutic window. In vitro rhC1-INH bound mannose-binding lectin (MBL), a key protein in the lectin complement pathway, with high affinity, whereas pdC1-INH, which has a different glycosylation pattern, did not. In the ischemic brain, rhC1-INH was confined to cerebral vessels, where it colocalized with MBL, whereas pdC1-INH diffused into the brain parenchyma. In addition, rhC1-INH was more active than pdC1-INH in inhibiting MBL-induced complement activation. Interpretation rhC1-INH showed a surprisingly wider time window of efficacy compared with the corresponding plasmatic protein. We propose that the superiority of rhC1-INH is due to its selective binding to MBL, which emerged as a novel target for stroke treatment. Ann Neurol 2009;66:332,342 [source] A population analysis of VEGF transgene expression and secretionBIOTECHNOLOGY & BIOENGINEERING, Issue 5 2008Golnaz Karoubi Abstract The induction of therapeutic angiogenesis with gene therapy approaches has received considerable interest and some limited clinical success. A major drawback to this approach is a lack of understanding of the pharmacokinetics of therapeutic protein delivery. This has become increasingly more relevant as recent studies have illustrated a defined therapeutic window for angiogenic protein secretion into the local microenvironment. For cell based gene therapies, with cells widely distributed throughout the tissue, this implies that any individual cell must attain a specific secretion rate to produce a local angiogenic response. Here we report a reproducible technique enabling the study of growth factor secretion from individual cells following transient plasmid transfection. We demonstrate significant variability in single cell vascular endothelial growth factor (VEGF) secretion with the majority of total protein secretion arising from a small subpopulation of transfected cells. We demonstrate that VEGF secretion is linearly correlated to intracellular plasmid copy number and protein secretion does not appear to reach saturation within the cell population. The selection of gene therapy approaches that optimize individual cell secretion profiles may be essential for the development of effective gene therapies. Biotechnol. Bioeng. © 2008 Wiley Periodicals, Inc. [source] Variability in non-nucleoside reverse transcriptase and protease inhibitor concentrations among HIV-infected adults in routine clinical practiceBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2006José Moltó What is already known about this subject ,,The concentration of protease and non-nucleoside reverse transcriptase inhibtors in plasma has been related to both efficacy and toxicity. ,,Most antiretroviral concentration data come from selected populations of patients undergoing therapeutic drug monitoring programmes, which may overestimate interindividual variability. What this study adds ,,Our study has demonstrated the large interindividual variability in antiretroviral drug concentrations in an unselected population of patients during routine clinical practice. ,,These results may provide interesting information to clinicians for the management of antiretroviral therapy in HIV-infected patients. Aims The objective of this study was to assess interindividual variability in trough concentrations of plasma of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults in a routine outpatient setting. Methods One hundred and seventeen patients who attended our clinic for routine blood tests, and who were receiving antiretroviral therapy which included NNRTI or PI were studied. Patients were not informed that drug concentrations were going to be measured until blood sampling. The times of the last antiretroviral dose and of blood sampling were recorded. Drug concentrations were considered optimal if they were above the proposed minimum effective value. In addition, efavirenz, nevirapine and atazanavir concentrations were considered potentially toxic if they were >,4.0 mg l,1, >,6.0 mg l,1 and >,0.85 mg l,1, respectively. Results Overall, interindividual variability of NNRTI and PI concentrations in plasma was approximately 50%, and only 68.4% of the patients had drug concentrations within the proposed therapeutic range. Poor adherence explained only 35% of subtherapeutic drug concentrations. Conclusion Interindividual variability in trough concentrations of NNRTI and PI among HIV-infected adults is large in routine clinical practice, with drug concentrations being outside the therapeutic window in a significant proportion of patients. These findings provide further evidence that therapeutic drug monitoring may be useful to guide antiretroviral therapy in clinical practice. [source] The effects of lamotrigine on the pharmacokinetics of lithiumBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2000Chao Chen Aims The treatment of bipolar disorder often includes use of multiple drug therapies. Lithium is one of the most commonly used treatments, but has a narrow therapeutic window. Lamotrigine, an established antiepileptic drug, is emerging as a potentially important new therapy in the treatment of bipolar disorder. The objective of this two-treatment crossover study was to determine whether lamotrigine affects lithium pharmacokinetics. Methods Twenty healthy adult men completed the study. Subjects took 2 g lithium gluconate anhydrous every 12 h in the morning and evening for 5 days and in the morning of day 6, with or without 100 mg lamotrigine once daily in the morning for 6 days. Blood and urine samples were collected on day 6 of both treatments to characterize the pharmacokinetics of lithium using noncompartmental methods. Results The geometric least-square mean ratio for renal clearance of lithium between the combination treatment and lithium alone treatment was 0.93 (95% confidence interval 0.85,1.02). Both treatments were well tolerated. Conclusions Lamotrigine does not cause significant change in the pharmacokinetics of lithium. [source] Molecularly targeted therapy for hepatocellular carcinomaCANCER SCIENCE, Issue 1 2009Shinji Tanaka Accumulated understanding of the molecular pathways regulating cancer progression has led to the development of novel targeted therapies. Hepatocellular carcinoma (HCC) remains a highly lethal disease that is resistant to conventional cytotoxic chemotherapy and radiotherapy. Unlike conventional chemotherapy, molecular-targeted agents offer the potential advantages of a relatively high therapeutic window and use in combination with other anticancer strategies without overlapping toxicity. It is hoped that these drugs will become valuable therapeutic tools within the multimodal approach to treating cancer. A recent clinical trial revealed an oral multikinase inhibitor, sorafenib, as the first agent that has demonstrated improved overall survival in patients with advanced HCC. The present review summarizes molecular abnormalities of HCC with a focus on clinical studies, and current status as well as problems of the targeted strategies for HCC. (Cancer Sci 2009; 100: 1,8) [source] Gene therapy mediates cone rescue and rejuvenation in the R91W mutant form of Rpe65-deficiency miceACTA OPHTHALMOLOGICA, Issue 2009Y ARSENIJEVIC Purpose Given the advances of gene therapy studies to cure RPE65-derived Leber Congenital Amaurosis (LCA) (clinical trials phase I), it is of prime importance to examine how cones can be rescued in different mutant contexts. Consequently, we evaluated the effect on retinal activity and cone survival of lentivirus-mediated gene therapy in the R91W knock-in mouse model expressing the mutant Rpe65R91W gene. Methods An HIV-1-derived lentiviral vector (LV) expressing either the GFP or the mouse Rpe65 cDNA under the control of a 0.8 kb fragment of the human Rpe65 promoter (R0.8) was produced. LV-R0.8-RPE65 or GFP was injected into 5-days-old (P5) or 1 month-old R91W mice. Functional and morphological retinal rescues were investigated at 4 months of age. Results Increased light sensitivity was detected by ERG and pupillary light responses in animals injected with LV-R0.8-RPE65 at both P5 and 1 month compared to controls. Histological analysis showed improved expression of cone markers and cone outersegment morphology. Furthermore, the density of cones in the region of RPE65 delivery after treatment at P5 reached the wild type level. However, before injection at 1 month of age, only a fraction of the cones (40% of the number found in WT animals) in the Rpe65R91W/R91W mice expressed cone transducin, this fraction increased to 64% after treatment. Moreover, these cones appeared normal. Conclusion We show that lentivirus-mediated Rpe65 gene transfer is very efficacious in early treatments and still efficient during the course of cone degeneration. Moreover, the treatment at 1 month shows a rejuvenation process of the diseased cones. Thus patient suffering from R91W mutation might benefit from a prolonged therapeutic window. [source] Prodrug Strategies in Anticancer ChemotherapyCHEMMEDCHEM, Issue 1 2008Felix Kratz Dr. Abstract The majority of clinically approved anticancer drugs are characterized by a narrow therapeutic window that results mainly from a high systemic toxicity of the drugs in combination with an evident lack of tumor selectivity. Besides the development of suitable galenic formulations such as liposomes or micelles, several promising prodrug approaches have been followed in the last decades with the aim of improving chemotherapy. In this review we elucidate the two main concepts that underlie the design of most anticancer prodrugs: drug targeting and controlled release of the drug at the tumor site. Consequently, active and passive targeting using tumor-specific ligands or macromolecular carriers are discussed as well as release strategies that are based on tumor-specific characteristics such as low pH or the expression of tumor-associated enzymes. Furthermore, other strategies such as ADEPT (antibody-directed enzyme prodrug therapy) and the design of self-eliminating structures are introduced. Chemical realization of prodrug approaches is illustrated by drug candidates that have or may have clinical importance. [source] Novel Inhibitors of Checkpoint Kinase,1CHEMMEDCHEM, Issue 11 2007Kenneth Inhibition of Chk1 kinase has garnered attention as a possible complement to DNA-damaging chemotherapeutic agents, widening their therapeutic window. As a result, several distinct classes of Chk1 inhibitors have been recently identified with selected compound advancing to clinical trials stage. This review focuses on the challenges and recent progress achieved in this area from a medicinal chemistry perspective. [source] Opposite effects of uracil and adenine nucleotides on the survival of murine cardiomyocytesJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 2 2008Alessia Mazzola Abstract We previously showed that the human heart expresses all known P2X and P2Y receptors activated by extra-cellular adenine or uracil nucleotides. Despite evidence that, both in humans and rodents, plasma levels of ATP and UTP markedly increase during myocardial infarction, the differential effects mediated by the various adenine- and uracil-preferring myocardial P2 receptors are still largely unknown. Here, we studied the effects of adenine and uracil nucleotides on murine HL-1 cardiomyocytes. RT-PCR analysis showed that HL-1 cardiomyocytes express all known P2X receptors (except for P2X2), as well as the P2Y2,4,6,14 subtypes. Exposure of cardiomyocytes to adenine nucleotides (ATP, ADP or BzATP) induced apoptosis and necrosis, as determined by flow-cytometry. Cell death was exacerbated by tumour necrosis factor (TNF)-,, a cytokine implicated in chronic heart failure progression. Conversely, uracil nucleotides (UTP, UDP and UDPglucose) had no effect ,per se', but fully counteracted the deleterious effects induced by adenine nucleotides and TNF-,, even if added to cardiomyocytes after beginning exposure to these cell death-inducing agents. Thus, exposure of cardiomyocytes to elevated concentrations of ATP or ADP in the presence of TNF-, contributes to cell death, an effect which is counteracted by uracil-preferring P2 receptors. Cardiomyocytes do not need to be ,primed' by uracil nucleotides to become insensitive to adenine nucleotides-induced death, suggesting the existence of a possible ,therapeutic' window for uracil nucleotides-mediated protection. Thus, release of UTP during cardiac ischaemia and in chronic heart failure may protect against myocardial damage, setting the basis for developing novel cardioprotective agents that specifically target uracil-preferring P2Y receptors. [source] | ||||||||||||||||||||||||||||||||||