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1.
BMC Neurosci ; 9 Suppl 3: S6, 2008 Dec 10.
Article in English | MEDLINE | ID: mdl-19091003

ABSTRACT

This short review outlines the rationale, challenges, and opportunities for intranasal acetylcholinesterases, in particular galantamine. An in vitro screening model facilitated the development of a therapeutically viable formulation. In vivo testing confirmed achievement of therapeutically relevant drug levels that matched or exceeded those for oral dosing, with a dramatic reduction in undesired emetic responses. Intranasal drug delivery is an effective option for the treatment of Alzheimer's disease and other central nervous system disorders.


Subject(s)
Alzheimer Disease/drug therapy , Blood-Brain Barrier/metabolism , Central Nervous System Diseases/drug therapy , Cholinesterase Inhibitors/administration & dosage , Administration, Intranasal , Alzheimer Disease/metabolism , Animals , Central Nervous System Diseases/metabolism , Cholinesterase Inhibitors/pharmacokinetics , Cholinesterase Inhibitors/therapeutic use , Galantamine/administration & dosage , Galantamine/pharmacokinetics , Galantamine/therapeutic use , Humans
2.
Int J Pharm ; 335(1-2): 138-146, 2007 Apr 20.
Article in English | MEDLINE | ID: mdl-17174048

ABSTRACT

The purpose of the current investigation was to optimize an intranasal (IN) galantamine (an acetylcholinesterase inhibitor used for treatment of Alzheimer's disease) formulation using an in vitro tissue model, to correlate those results to in vivo bioavailability, and to compare emetic response to oral dosing. A design-of-experiments (DOE) based formulation screening employing an in vitro tissue model of human nasal epithelium was used to assess drug permeability, tight junction modulation, and cellular toxicity. In vivo studies in rats compared pharmacokinetic (PK) profiles of different formulations dosed intranasally. Finally, studies in ferrets evaluated PK and gastrointestinal (GI) related side effects of oral compared to nasal dosage forms. Galantamine permeation was enhanced without increasing cytotoxicity. Pharmacokinetic testing in rats confirmed the improved drug bioavailability and demonstrated an in vitro-in vivo correlation. Compared to oral dosing, IN galantamine resulted in a dramatically lowered incidence of GI-related side effects, e.g., retching and emesis. These findings illustrate that IN delivery represents an attractive alternative to oral dosing for this important Alzheimer's disease therapeutic. To our knowledge, the data herein represent the first direct confirmation of reducing GI-related side effects for IN galantamine compared to oral dosing.


Subject(s)
Cholinesterase Inhibitors/administration & dosage , Cholinesterase Inhibitors/pharmacokinetics , Excipients/pharmacology , Galantamine/administration & dosage , Galantamine/pharmacokinetics , Vomiting/chemically induced , Administration, Intranasal , Administration, Oral , Analysis of Variance , Animals , Biological Availability , Cell Membrane Permeability/drug effects , Cells, Cultured , Chemistry, Pharmaceutical , Cholinesterase Inhibitors/adverse effects , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Compounding , Edetic Acid/pharmacology , Electric Impedance , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Excipients/chemistry , Factor Analysis, Statistical , Ferrets , Galantamine/adverse effects , Galantamine/chemistry , Humans , Phosphatidylcholines/pharmacology , Rats , Rats, Sprague-Dawley , Respiratory Mucosa/cytology , Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , Tight Junctions/drug effects , Tight Junctions/metabolism , beta-Cyclodextrins/pharmacology
3.
J Immunol ; 177(2): 1017-27, 2006 Jul 15.
Article in English | MEDLINE | ID: mdl-16818758

ABSTRACT

Exogenously delivered antigenic peptides complexed to heat shock proteins (HSPs) are able to enter the endogenous Ag-processing pathway and prime CD8+ CTL. It was determined previously that a hybrid peptide containing a MHC class I-binding epitope and HSP70-binding sequence Javelin (J0) in complex with HSP70 could induce cytotoxic T cell responses in vivo that were more robust than those induced by the minimal epitope complexed with HSP70. The present study introduces a novel, higher-affinity HSP70-binding sequence (J1) that significantly enhances binding of various antigenic peptides to HSP70. A competition binding assay revealed a dissociation constant that was 15-fold lower for the H2-K(b) OVA epitope SIINFEKL-J1 compared with SIINFEKL-J0, indicating a substantially higher affinity for HSP70. Further, modifying the orientation of the hybrid epitope and introducing a cleavable linker sequence between the Javelin and the epitope results in even greater immunogenicity, presumably by greater efficiency of epitope processing. The enhanced immunogenicity associated with Javelin J1 and the cleavable linker is consistently observed with multiple mouse and human epitopes. Thus, by creating a series of epitopes with uniform, high-affinity binding to HSP70, successful multiple epitope immunizations are possible, with equal delivery of each antigenic epitope to the immune system via HSP70. These modified epitopes have the potential for creating successful multivalent vaccines for immunotherapy of both infectious disease and cancer.


Subject(s)
Adjuvants, Immunologic/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , HSP70 Heat-Shock Proteins/metabolism , Peptide Fragments/metabolism , Protein Interaction Mapping , Adjuvants, Immunologic/administration & dosage , Amino Acid Sequence , Animals , Antigen Presentation , CD8-Positive T-Lymphocytes/enzymology , Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Cattle , Cell Line, Tumor , Cross-Priming , Epitopes, T-Lymphocyte/immunology , Epitopes, T-Lymphocyte/metabolism , Female , HSP70 Heat-Shock Proteins/administration & dosage , HSP70 Heat-Shock Proteins/immunology , Humans , Hydrolysis , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Molecular Sequence Data , Ovalbumin/administration & dosage , Ovalbumin/immunology , Ovalbumin/metabolism , Peptide Fragments/administration & dosage , Peptide Fragments/chemical synthesis , Peptide Fragments/immunology , Proteasome Endopeptidase Complex/physiology , Protein Binding/immunology , Thymoma/immunology , Thymoma/pathology , Thymoma/prevention & control
4.
J Pharm Sci ; 95(6): 1364-71, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16625659

ABSTRACT

Previously, a novel tight junction modulating (TJM) peptide was described affording a transient, reversible lowering of transepithelial electrical resistance (TER) in an in vitro model of nasal epithelial tissue. In the current report, this peptide has been further evaluated for utility as an excipient in transepithelial drug formulations. Chemical stability was optimal at neutral to acidic pH when stored at or below room temperature, conditions relevant to therapeutic formulations. The TJM peptide was tested in the in vitro tissue model for potential to enhance permeation of a low-molecular-weight (LMW) drug, namely the acetylcholinesterase inhibitor galantamine, as well as three peptides, salmon calcitonin, parathyroid hormone 1-34 (PTH(1-34)), and peptide YY 3-36 (PYY(3-36)). In all cases, the TJM peptide afforded a dramatic improvement in drug permeation across epithelial tissue. In addition, a formulation containing PYY(3-36) and TJM peptide was dosed intranasally in rabbits, resulting in a dramatic increase in bioavailability. The TJM peptide was as or more effective in enhancing PYY(3-36) permeation in vivo at a 1000-fold lower molar concentration compared to using LMW enhancers. Based on these in vitro and in vivo data, the novel TJM peptide represents a promising advancement in intranasal formulation development.


Subject(s)
Drug Delivery Systems , Peptides , Tight Junctions/metabolism , Administration, Intranasal , Animals , Area Under Curve , Biological Availability , Calcitonin/administration & dosage , Calcitonin/pharmacokinetics , Chemistry, Pharmaceutical , Drug Stability , Electric Impedance , Epithelial Cells/metabolism , Galantamine/administration & dosage , Galantamine/pharmacokinetics , Hydrogen-Ion Concentration , In Vitro Techniques , Parathyroid Hormone/administration & dosage , Parathyroid Hormone/pharmacokinetics , Peptide Fragments/administration & dosage , Peptide Fragments/pharmacokinetics , Peptide YY/administration & dosage , Peptide YY/pharmacokinetics , Peptides/administration & dosage , Peptides/pharmacokinetics , Peptides/therapeutic use , Permeability , Rabbits
5.
J Pharm Sci ; 94(8): 1736-46, 2005 Aug.
Article in English | MEDLINE | ID: mdl-15986464

ABSTRACT

The goal of the current study was to develop an intranasal (IN) formulation of the acetylcholinesterase inhibitor galantamine, an important therapeutic for treating Alzheimer's disease. To allow for delivering a therapeutically relevant dose, it was necessary to greatly enhance drug solubility. Various approaches were examined to this end, including adding co-solvents, cyclodextrins, and counterion exchange. Of these, the latter, for example, replacement of bromide ion with lactate or gluconate, resulted in a dramatic drug solubility increase, more than 12-fold. NMR confirmed the molecular structure of new drug salt forms. An in vitro epithelial tissue model was used to assess drug permeability and cellular toxicity. In vitro, galantamine lactate formulations performed as well as or better than their hydrobromide (HBr) counterparts with respect to drug permeation across the epithelial membrane with minimal toxicity. In vivo studies in rats compared pharmacokinetic (PK) profiles of different formulations. The in vivo studies confirmed that IN galantamine achieves systemic blood levels comparable to those of conventional oral administration. Both the in vitro and in vivo data support the feasibility of IN administration of this important drug.


Subject(s)
Cholinesterase Inhibitors/pharmacokinetics , Galantamine/pharmacokinetics , Lactates/pharmacokinetics , Administration, Intranasal , Administration, Oral , Animals , Area Under Curve , Cell Survival , Cells, Cultured , Chemistry, Pharmaceutical , Cholinesterase Inhibitors/chemistry , Drug Stability , Epithelial Cells/metabolism , Galantamine/administration & dosage , Galantamine/chemistry , Humans , Hydrogen-Ion Concentration , Lactates/chemistry , Magnetic Resonance Spectroscopy , Rats , Rats, Sprague-Dawley , Solubility , Time Factors
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