19 results on '"Calias P"'
Search Results
2. Safety evaluation of chronic intrathecal administration of heparan N-sulfatase in juvenile cynomolgus monkeys
- Author
-
Pfeifer, Richard W., Felice, Brian R., Boyd, Robert B., Butt, Mark T., Ruiz, Juan A., Heartlein, Michael W., and Calias, Pericles
- Published
- 2012
- Full Text
- View/download PDF
3. Drug delivery to the CNS
- Author
-
Calias, Pericles
- Published
- 2012
- Full Text
- View/download PDF
4. Modest Blood-Brain Barrier Permeability of the Cyclodextrin Kleptose: Modification by Efflux and Luminal Surface Binding
- Author
-
Banks, W.A., Engelke, Kory, Hansen, Kim M., Bullock, Kristin M., and Calias, Pericles
- Abstract
Cyclodextrins (CDs) have a variety of uses from acting as excipients to aiding the ability of lipid soluble drugs to cross the blood-brain barrier (BBB). They are being investigated as an active pharmaceutical ingredient, most recently for the treatment of Niemann-Pick disease, a lysosomal storage disease. Cyclodextrins are helpful in animal models and human subjects/patients afflicted with Neimann-Pick disease, including improving the neurologic component of the disease. The improvement in brain disease by intravenous administration implies that CDs can cross the BBB; however, there are only a few studies that have directly addressed this. In the current studies, multiple-time regression analysis indicated that 2-hydroxypropyl-β-cyclodextrin [Kleptose (Klep)] radioactively labeled with 14C (C-Klep) crossed the BBB at a slow rate by a nonsaturable mechanism consistent with transcellular diffusion. However, the rate of transport varied greatly by the brain region with no detectable uptake by the spinal cord; additionally, many regions rapidly reached equilibrium between the brain and blood. The presence of a brain-to-blood efflux system was also detected and much of the C-Klep did not completely cross the BBB, but loosely adhered to the luminal surface of brain endothelial cells. Peripheral tissues also took up C-Klep, with the kidney taking up the most, which is consistent with renal clearance. In conclusion, we demonstrated minimal uptake of the β-cyclodextrin Kleptose by the brain with accumulation being affected by efflux and reversible luminal binding.
- Published
- 2019
- Full Text
- View/download PDF
5. 2-Hydroxypropyl-β-cyclodextrins and the Blood-Brain Barrier: Considerations for Niemann-Pick Disease Type C1
- Author
-
Calias, Pericles
- Abstract
The rare, chronic, autosomal-recessive lysosomal storage disease Niemann-Pick disease type C1 (NPC1) is characterized by progressively debilitating and ultimately fatal neurological manifestations. There is an urgent need for disease-modifying therapies that address NPC1 neurological pathophysiology, and passage through the blood-brain barrier represents an important consideration for novel NPC1 drugs. Animal investigations of 2-hydroxypropyl-β-cyclodextrins (HPβCD) in NPC1 in mice demonstrated that HPβCD does not cross the blood-brain barrier in significant amounts but suggested a potential for these complex oligosaccharides to moderately impact CNS manifestations when administered subcutaneously or intraperitoneally at very high doses; however, safety concerns regarding pulmonary toxicity were raised. Subsequent NPC1 investigations in cats demonstrated far greater HPβCD efficacy at much lower doses when the drug was administered directly to the CNS. Based on this, a phase 1/2a clinical trial was initiated with intrathecal administration of a specific, wellcharacterized mixture of HPβCD, with a tightly controlled molar substitution specification and a defined molecular “fingerprint” of the different species. The findings were very encouraging and a phase 2b/3 clinical trial has completed enrollment and is underway. In addition, phase 1 clinical studies utilizing high-dose intravenous administration of a different HPβCD are currently recruiting. Independent studies are needed for each product to satisfactorily address questions of safety, efficacy, dosing, and route of administration. The outcomes cannot be assumed to be translatable between HPβCD products and/or routes of administration.
- Published
- 2017
- Full Text
- View/download PDF
6. Intrathecal delivery of recombinant human iduronate-2-sulfatase (idursulfase-IT)
- Author
-
Calias, P., primary, Pan, J., additional, Huang, Y., additional, Alessandrini, M., additional, Liu, N., additional, Pfeifer, R.W., additional, Wright, T.L., additional, Felice, B.R., additional, Powell, J., additional, Savioli, N., additional, Lotterhand, J., additional, and Heartlein, M.W., additional
- Published
- 2011
- Full Text
- View/download PDF
7. Synthesis of inositol 2-phosphate-quercetin conjugates
- Author
-
Calias, P, primary
- Published
- 1996
- Full Text
- View/download PDF
8. Iodine-124 as a Label for Pharmacological PET Imaging
- Author
-
Belov, Vasily V., Bonab, Ali A., Fischman, Alan J., Heartlein, Michael, Calias, Pericles, and Papisov, Mikhail I.
- Abstract
With the growing number of biotechnology products and drug delivery systems entering preclinical and clinical studies, pharmacological imaging studies with PET play an increasingly significant role. Such studies often require investigation of slow and complex pharmacokinetics (PK). This suggests labeling of the drug candidate with radionuclides that have long physical half-lives. Among the currently available PET positron emitters, 124I has the longest physical half-life (4.2 days). This, combined with the well-investigated behavior of iodine in vivo, makes 124I very attractive for pharmacological studies. However, the high energy of the positrons emitted by 124I and the presence of single photons in the 124I emission can potentially introduce limitations in the quantitative analysis of the images. The objective of this research was to determine whether the use of 124I as a PET label provides data quality suitable for PK studies. The study was carried out using MicroPET P4 scanner (Siemens/Concorde Microsystems). Spatial resolution, count-rate performance, sensitivity and scatter fraction were measured using a line source and a cylindrical phantom. Model animal studies in rats and cynomolgus monkeys were carried out using human recombinant proteins. The proteins were labeled with 124I, up to 185 MBq/mg. The transaxial and axial spatial resolutions in the center of the camera were satisfactory and higher for OSEM3D/MAP than FORE-2DFBP (FWHM 2.52 vs 3.31 mm, and 3.10 vs 3.69 mm). Linearity of the true coincidence count-rate was observed up to 44 MBq. Animal studies demonstrated excellent delineation and resolution of even very small organs. At optimal doses, 2−10 MBq per animal for rodents and 4−10 MBq per kg of body weight for larger animals, the quality of numerical data was appropriate for PK analysis in all experimental timeframes from minutes (dynamic studies) to 10 days. Overall, the data suggest that 124I is an excellent label for quantitative pharmacological PET imaging studies.
- Published
- 2011
- Full Text
- View/download PDF
9. Synthesis of inositol glycan cyclic phosphates
- Author
-
Jaworek, C. H., Iacobucci, S., Calias, P., and d'Alarcao, M.
- Published
- 2001
- Full Text
- View/download PDF
10. CNS Penetration of Intrathecal-Lumbar Idursulfase in the Monkey, Dog and Mouse: Implications for Neurological Outcomes of Lysosomal Storage Disorder
- Author
-
Calias, Pericles, Pan, Jing, Savioli, Nancy, Huang, Yan, Lotterhand, Jason, Alessandrini, Mary, Liu, Nan, Fischman, Alan J., Powell, Jan L., Heartlein, Michael W., Papisov, Mikhail, and Belov, Vasily
- Subjects
biology ,anatomy and physiology ,molecular cell biology ,cellular types ,signal transduction ,neuroscience ,neurochemistry ,neurophysiology ,medicine ,clinical research design ,metabolic disorders ,neurology ,veterinary science ,animal types - Abstract
A major challenge for the treatment of many central nervous system (CNS) disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome) is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S). I2S is a large, highly glycosylated enzyme. Intravenous administration is not likely to be an effective therapy for disease-related neurological outcomes that require enzyme access to the brain cells, in particular neurons and oligodendrocytes. We demonstrate that intracerebroventricular and lumbar intrathecal administration of recombinant I2S in dogs and nonhuman primates resulted in widespread enzyme distribution in the brain parenchyma, including remarkable deposition in the lysosomes of both neurons and oligodendrocytes. Lumbar intrathecal administration also resulted in enzyme delivery to the spinal cord, whereas little enzyme was detected there after intraventricular administration. Mucopolysaccharidosis II model is available in mice. Lumbar administration of recombinant I2S to enzyme deficient animals reduced the storage of glycosaminoglycans in both superficial and deep brain tissues, with concurrent morphological improvements. The observed patterns of enzyme transport from cerebrospinal fluid to the CNS tissues and the resultant biological activity (a) warrant further investigation of intrathecal delivery of I2S via lumbar catheter as an experimental treatment for the neurological symptoms of Hunter syndrome and (b) may have broader implications for CNS treatment with biopharmaceuticals., Version of Record
- Published
- 2012
- Full Text
- View/download PDF
11. Synthesis of an inositol-containing trisaccharide related to insulin signal transduction
- Author
-
Jaworek, Christine H., Calias, Pericles, Iacobucci, Sarah, and d'Alarcao, Marc
- Abstract
A synthesis of D-mannosyl-(α1–4)-D-glucosaminyl-(α1–6)-D- myo-inositol-1:2-cyclic phosphate ( 1) from D-xylose, D-mannose, and D-glucal is reported. Compound 1constitutes the terminal structure of the PI-PLC-released VSG membrane anchor of Trypanosomes and is structurally related to the inositol phoshate glycan implicated as an insulin second messenger in higher organisms.
- Published
- 1999
- Full Text
- View/download PDF
12. ChemInform Abstract: Synthesis of Inositol Glycan Cyclic Phosphates.
- Author
-
Jaworek, Christine H., Iacobucci, Sarah, Calias, Pericles, and d'Alarcao, Marc
- Abstract
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
- Published
- 2001
- Full Text
- View/download PDF
13. The therapeutic mavericks: Potent immunomodulating chaperones capable of treating human diseases.
- Author
-
Eggleton P, De Alba J, Weinreich M, Calias P, Foulkes R, and Corrigall VM
- Subjects
- Humans, Molecular Chaperones metabolism, Carrier Proteins metabolism, Cytokines metabolism, Anti-Inflammatory Agents, Endoplasmic Reticulum Chaperone BiP, Heat-Shock Proteins metabolism
- Abstract
Two major chaperones, calreticulin (CRT) and binding immunoglobulin protein (GRP78/BiP) dependent on their location, have immunoregulatory or anti-inflammatory functions respectively. CRT induces pro-inflammatory cytokines, dendritic cell (DC) maturation and activates cytotoxic T cells against tumours. By contrast, GRP78/BiP induces anti-inflammatory cytokines, inhibits DC maturation and heightens T-regulatory cell responses. These latter functions rebalance immune homeostasis in inflammatory diseases, such as rheumatoid arthritis. Both chaperones are therapeutically relevant agents acting primarily on monocytes/DCs. Endogenous exposure of CRT on cancer cell surfaces acts as an 'eat-me' signal and facilitates improved elimination of stressed and dying tumour cells by DCs. Therefore, therapeutics that promote endogenous CRT translocation to the cell surface can improve the removal of cancer cells. However, infused recombinant CRT dampens this cancer cell eradication by binding directly to the DCs. Low levels of endogenous BiP appear as a surface biomarker of endoplasmic reticulum (ER) stress in some types of tumour cells, a reflection of cells undergoing proliferation, in which resulting hypoxia and nutrient deprivation perturb ER homeostasis triggering the unfolded protein response, leading to increased expression of GRP78/BiP and altered cellular location. Conversely, infusion of an analogue of GRP78/BiP (IRL201805) can lead to long-term immune resetting and restoration of immune homeostasis. The therapeutic potential of both chaperones relies on them being relocated from their intracellular ER environment. Ongoing clinical trials are employing therapeutic interventions to either enhance endogenous cell surface CRT or infuse IRL201805, thereby triggering several disease-relevant immune responses leading to a beneficial clinical outcome., (© 2023 Revolo Biotherapeutics Inc. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
14. Brain uptake and distribution patterns of 2-hydroxypropyl-ß-cyclodextrin after intrathecal and intranasal administration.
- Author
-
Banks WA, Calias P, Hansen KM, Bullock KM, and Engelke K
- Subjects
- Administration, Intranasal, Blood-Brain Barrier, Brain, Humans, Hypromellose Derivatives, Cyclodextrins, Niemann-Pick Diseases
- Abstract
Objectives: Cyclodextrins are increasingly used therapeutically. For example, 2-hydroxypropyl-ß-cyclodextrin (kleptose) is used for the treatment of Niemann-Pick disease. Kleptose crosses the blood-brain barrier poorly, in part because of a central nervous system (CNS)-to-blood (efflux) transporter, and so is administered by the intrathecal (IT) route in the treatment of Niemann-Pick disease., Methods: Here, we evaluated the uptake and distribution of kleptose by the brain and spinal cord after intranasal (IN) or IT delivery., Key Findings: Kleptose distributed to all regions of the brain and spinal cord after IN administration, with only 3.27% of the administered dose entering the bloodstream. Intrathecal delivery produced levels in the whole brain about 40 times higher than intranasal administration and about 20 times higher than previously found after intravenous administration. About 70-90% of the IT dose rapidly entered the bloodstream, in part because of the previously described efflux transporter. The uptake by CNS after IN and IT was both non-saturable. The uptake by the olfactory bulb, hypothalamus and pons-medulla was favoured by all routes of administration., Conclusions: Kleptose was taken up by all regions of the CNS after either IN or IT administration, but IN administration resulted in only a fraction of the uptake of the IT route., (Published by Oxford University Press on behalf of the Royal Pharmaceutical Society 2022.)
- Published
- 2022
- Full Text
- View/download PDF
15. Intrathecal delivery of protein therapeutics to the brain: a critical reassessment.
- Author
-
Calias P, Banks WA, Begley D, Scarpa M, and Dickson P
- Subjects
- Animals, Biological Transport physiology, Humans, Hydrodynamics, Injections, Spinal, Blood-Brain Barrier metabolism, Central Nervous System Diseases drug therapy, Cerebrospinal Fluid metabolism, Recombinant Proteins administration & dosage
- Abstract
Disorders of the central nervous system (CNS), including stroke, neurodegenerative diseases, and brain tumors, are the world's leading causes of disability. Delivery of drugs to the CNS is complicated by the blood-brain barriers that protect the brain from the unregulated leakage and entry of substances, including proteins, from the blood. Yet proteins represent one of the most promising classes of therapeutics for the treatment of CNS diseases. Many strategies for overcoming these obstacles are in development, but the relatively straightforward approach of bypassing these barriers through direct intrathecal administration has been largely overlooked. Originally discounted because of its lack of usefulness for delivering small, lipid-soluble drugs to the brain, the intrathecal route has emerged as a useful, in some cases perhaps the ideal, route of administration for certain therapeutic protein and targeted disease combinations. Here, we review blood-brain barrier functions and cerebrospinal fluid dynamics and their relevance to drug delivery via the intrathecal route, discuss animal and human studies that have investigated intrathecal delivery of protein therapeutics, and outline several characteristics of protein therapeutics that can allow them to be successfully delivered intrathecally., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
16. Safety evaluation of chronic intrathecal administration of idursulfase-IT in cynomolgus monkeys.
- Author
-
Felice BR, Wright TL, Boyd RB, Butt MT, Pfeifer RW, Pan J, Ruiz JA, Heartlein MW, and Calias P
- Subjects
- Animals, Case-Control Studies, Dose-Response Relationship, Drug, Enzyme Replacement Therapy methods, Iduronate Sulfatase administration & dosage, Iduronate Sulfatase blood, Iduronate Sulfatase cerebrospinal fluid, Immunohistochemistry, Infusion Pumps, Implantable, Injections, Spinal, Macaca fascicularis, Male, No-Observed-Adverse-Effect Level, Iduronate Sulfatase toxicity, Meninges drug effects, Meninges pathology
- Abstract
Recombinant human idursulfase, an intravenous enzyme replacement therapy indicated for treatment of somatic symptoms of mucopolysaccharidosis II (Hunter syndrome), is anticipated to have minimal benefit for the cognitive impairment associated with the severe phenotype. Because intrathecal (IT) administration of enzyme replacement therapy for other lysosomal enzyme disorders has shown efficacy in animal models, an IT formulation of idursulfase (idursulfase-IT) and a drug-delivery device (subcutaneous port connected to a lumbar IT catheter) were developed for treating central nervous system (CNS) involvement. In this chronic safety study, cynomolgus monkeys were dosed weekly with IV idursulfase (0.5 mg/kg) and every four weeks with idursulfase-IT (3, 30, and 100 mg) for six months, with device and vehicle controls treated similarly (n = 6, all groups). Necropsies were performed twenty-four hours post-final IT dose or after a recovery period (four weeks post-final dose in vehicle-control, 3 mg, and 100 mg IT groups: n = 6). No clinical signs or gross central nervous system lesions were observed. Compared to controls, more pronounced cellular infiltrates in brain and spinal cord meninges were noted, which largely resolved after the recovery period. Central nervous sytem levels of idursulfase-IT were dose dependent, as determined by enzyme activity and immunohistochemistry. The no-observed-adverse-effect level of idursulfase-IT was 100 mg.
- Published
- 2011
- Full Text
- View/download PDF
17. Simultaneous but not prior inhibition of VEGF165 enhances the efficacy of photodynamic therapy in multiple models of ocular neovascularization.
- Author
-
Ju M, Mailhos C, Bradley J, Dowie T, Ganley M, Cook G, Calias P, Lange N, Adamis AP, Shima DT, and Robinson GS
- Subjects
- Animals, Choroidal Neovascularization metabolism, Choroidal Neovascularization pathology, Chromatography, High Pressure Liquid, Cornea blood supply, Corneal Neovascularization metabolism, Corneal Neovascularization pathology, Drug Therapy, Combination, Male, Mice, Mice, Inbred C57BL, Photosensitizing Agents therapeutic use, Porphyrins therapeutic use, RNA, Messenger metabolism, Thromboplastin genetics, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor Receptor-1 metabolism, Verteporfin, Aptamers, Nucleotide therapeutic use, Choroidal Neovascularization drug therapy, Corneal Neovascularization drug therapy, Disease Models, Animal, Photochemotherapy, Vascular Endothelial Growth Factor A antagonists & inhibitors
- Abstract
Purpose: To investigate the effect of the combined treatment of photodynamic therapy and specific VEGF165 inhibition with pegaptanib sodium (Macugen; Eyetech Pharmaceuticals, Lexington, MA) on ocular neovascularization., Methods: Photodynamic therapy's (PDT's) effects on the integrity of pegaptanib sodium were analyzed by HPLC, a VEGF165-binding assay, and a VEGF165-induced tissue factor gene expression assay. The effects of mono- or combined treatment on vessel growth and regression were determined in a murine corneal neovascularization model. The effects of combined treatment on vessel growth were also determined in a murine choroidal neovascularization model., Results: PDT did not affect the chemical composition of pegaptanib sodium nor the efficacy of pegaptanib sodium in the inhibition of VEGF165 binding to Flt-1 and VEGF165-induced gene expression. In an animal model of effects on existing ocular neovascular lesions (corneal neovascularization), PDT monotherapy yielded an initial regression of these vessels, but there followed a rapid regrowth. In contrast, pegaptanib sodium monotherapy yielded little regression but potently abrogated further vessel growth. The combination of pegaptanib sodium and PDT resulted in the regression of the neovascular lesions, as observed with PDT alone, but also prevented significant vessel regrowth, leading to a significantly greater reduction in lesion size than did each monotherapy. In addition, there was a significantly greater effect of the combination of pegaptanib sodium and PDT on lesion size in choroidal neovascularization than with each monotherapy. Pretreatment with pegaptanib sodium appeared to decrease the efficacy of PDT-induced vessel regression in corneal neovascularization, and as such the enhanced efficacy over monotherapy when the agents were delivered simultaneously was not observed., Conclusions: Although the combined simultaneous treatment of ocular neovascularization with PDT and pegaptanib sodium may provide a more effective approach for the regression and overall treatment of CNV associated with AMD, the order of addition of these treatments may play a role in achieving optimal efficacy.
- Published
- 2008
- Full Text
- View/download PDF
18. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease.
- Author
-
Ng EW, Shima DT, Calias P, Cunningham ET Jr, Guyer DR, and Adamis AP
- Subjects
- Angiogenesis Inhibitors pharmacokinetics, Angiogenesis Inhibitors pharmacology, Animals, Aptamers, Nucleotide pharmacokinetics, Aptamers, Nucleotide pharmacology, Clinical Trials as Topic, Diabetic Retinopathy drug therapy, Drug Delivery Systems, Eye blood supply, Humans, Angiogenesis Inhibitors therapeutic use, Aptamers, Nucleotide therapeutic use, Eye Diseases drug therapy, Neovascularization, Pathologic drug therapy, Vascular Endothelial Growth Factor A antagonists & inhibitors
- Abstract
Aptamers are oligonucleotide ligands that are selected for high-affinity binding to molecular targets. Pegaptanib sodium (Macugen; Eyetech Pharmaceuticals/Pfizer) is an RNA aptamer directed against vascular endothelial growth factor (VEGF)-165, the VEGF isoform primarily responsible for pathological ocular neovascularization and vascular permeability. After nearly a decade of preclinical development to optimize and characterize its biological effects, pegaptanib was shown in clinical trials to be effective in treating choroidal neovascularization associated with age-related macular degeneration. Pegaptanib therefore has the notable distinction of being the first aptamer therapeutic approved for use in humans, paving the way for future aptamer applications.
- Published
- 2006
- Full Text
- View/download PDF
19. Protection against lethal intra-abdominal sepsis by 1-(3-dimethylaminopropyl)-3-ethylurea.
- Author
-
Ruiz-Perez B, Cisneros RL, Matsumoto T, Miller RJ, Vasios G, Calias P, and Onderdonk AB
- Subjects
- Animals, Carboxymethylcellulose Sodium chemistry, Cytokines analysis, Cytokines biosynthesis, Disease Models, Animal, Dose-Response Relationship, Drug, Gels chemistry, Hyaluronic Acid chemistry, Male, Rats, Rats, Wistar, Spleen immunology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Time Factors, Urea administration & dosage, Urea analogs & derivatives, Abdominal Abscess prevention & control, Adjuvants, Immunologic pharmacology, Escherichia coli Infections prevention & control, Gels pharmacology, Sepsis prevention & control, Urea pharmacology
- Abstract
Sodium hyaluronate-carboxymethylcellulose (HA/CMC) formulations are gels that effectively reduce postoperative adhesions in both animals and humans, when placed in the peritoneal or pelvic cavities concomitant with surgical manipulation. However, it has been suggested that the use of these products may increase the risk of peritoneal infection after contamination with intestinal contents during surgery. Using the rat intra-abdominal sepsis model, we found that administration of HA/CMC gels before bacterial challenge did not increase mortality but did significantly protect rats against lethal infection. This effect was dose and time dependent. Protection was conferred not by the HA/CMC gels themselves but by 1-(3-dimethylaminopropyl)-3-ethylurea (EDU), a small molecule released from the gel complex under physiologic conditions. Our results suggest that the protective effect exhibited by EDU is related to down-regulation of T cell-dependent responses and suppression of the proinflammatory-cytokine cascade associated with mortality during the early phase of disease.
- Published
- 2003
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.