ABSTRACT
The effectiveness of anti-retroviral therapies (ART) depends on its ultimate ability to clear reservoirs of continuous human immunodeficiency virus (HIV) infection. We reasoned that a principal vehicle for viral dissemination, the mononuclear phagocytes could also serve as an ART transporter and as such improve therapeutic indices. A nanoparticle-indinavir (NP-IDV) formulation was made and taken up into and released from vacuoles of human monocyte-derived macrophages (MDM). Following a single NP-IDV dose, drug levels within and outside MDM remained constant for 6 days without cytotoxicity. Administration of NP-IDV when compared to equal drug levels of free soluble IDV significantly blocked induction of multinucleated giant cells, production of reverse transcriptase activity in culture fluids and cell-associated HIV-1p24 antigens after HIV-1 infection. These data provide "proof of concept" for the use of macrophage-based NP delivery systems for human HIV-1 infections.
Subject(s)
Anti-HIV Agents/pharmacology , Anti-HIV Agents/pharmacokinetics , HIV-1/drug effects , Indinavir/pharmacology , Indinavir/pharmacokinetics , Macrophages/metabolism , Macrophages/virology , Cell Fusion , Cell Survival , Cells, Cultured , Cytoplasm/chemistry , HIV Core Protein p24/biosynthesis , HIV Infections , HIV Reverse Transcriptase/biosynthesis , Humans , Macrophages/chemistry , Macrophages/ultrastructure , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission , Microscopy, Fluorescence , NanoparticlesABSTRACT
Individuals with underlying metabolic disorders are a potential high-risk group for vaccine-preventable diseases. Newborn metabolic screening has provided a means of early identification and treatment for many of these disorders, whereas childhood immunization is one of the most effective means of decreasing the morbidity and mortality resulting from communicable diseases worldwide. There are very few contraindications to the routine administration of vaccines to the healthy, immunocompetent individual. In certain high-risk groups, such as immunocompromised patients, gravid females, and those with a history of previous anaphylactic reaction to a vaccine or its components, selective withholding of immunizations must be considered to decrease potential adverse events. A detailed analysis of the medical literature revealed few specific recommendations regarding appropriate immunization techniques for patients with metabolic disorders. In this review we detail the major metabolic disorder subtypes, elaborate on the available literature on immunizations for patients with these disorders, and provide suggested vaccine recommendations.
Subject(s)
Immunization , Metabolism, Inborn Errors/immunology , Adolescent , Amino Acid Metabolism, Inborn Errors/immunology , Amino Acid Metabolism, Inborn Errors/therapy , Carbohydrate Metabolism, Inborn Errors/immunology , Carbohydrate Metabolism, Inborn Errors/therapy , Child , Child, Preschool , Contraindications , Genetic Predisposition to Disease , Humans , Immunization/methods , Immunization Schedule , Immunologic Deficiency Syndromes/etiology , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Infant , Influenza Vaccines , Intellectual Disability/etiology , Intellectual Disability/genetics , Intellectual Disability/immunology , Lipid Metabolism, Inborn Errors/immunology , Lipid Metabolism, Inborn Errors/therapy , Metabolism, Inborn Errors/classification , Metabolism, Inborn Errors/physiopathology , Metabolism, Inborn Errors/therapy , Purine-Pyrimidine Metabolism, Inborn Errors/immunology , Purine-Pyrimidine Metabolism, Inborn Errors/therapy , Vaccines, InactivatedABSTRACT
This review will provide an in-depth discussion on the previous development of nanoparticle-based drug delivery systems (DDS) and discuss original research data that includes the therapeutic enhancement of antiretroviral therapy. The use of nanoparticle DDS will allow practitioners to use drugs to target specific areas of the body. In the treatment of malignancies, the use of nanoparticles as a DDS is making measurable treatment impact. Medical imaging will also utilize DDS to illuminate tumors, the brain, or other cellular functions in the body. The utility of nanoparticle DDS to improve human health is potentially enormous.
Subject(s)
Anti-Retroviral Agents/administration & dosage , Drug Delivery Systems/methods , Nanoparticles/administration & dosage , Nanotechnology/methods , Animals , Anti-Retroviral Agents/pharmacokinetics , Drug Delivery Systems/trends , Humans , Nanotechnology/trends , Pharmaceutical Preparations/administration & dosageABSTRACT
The human immunodeficiency virus-1 (HIV-1) commonly affects cognitive, behavioral and motor functions during the disease course. The neuropathogenesis of viral infection revolves around neurotoxins produced from infected and immune-activated mononuclear phagocytes (MP; perivascular macrophages and microglia). Direct infection of neurons occurs rarely, if at all. Neurologic disease arises in part as a consequence of MP metabolic dysfunction. Although the advent of highly active antiretroviral therapy (HAART) has attenuated the incidence and severity of neurologic disease, it, nonetheless, remains a common and disabling problem for those living with HIV-1 infection. Adjunctive therapies are currently designed to ameliorate clinical outcomes and are included in the therapeutic armamentarium. Anti-inflammatory drugs that inhibit cytokines, chemokines and interferons linked to neurodegenerative processes can significantly ameliorate neuronal function. HIV-1 neurotoxins have the unique ability to up-regulate glycogen synthase kinase-3beta (GSK-3beta) activity that in turn elicits neuronal apoptosis. GSK-3beta inhibitors are neuroprotective in animal models of Neuro AIDS. They are also currently in Phase 1 clinical trials designed for safety and tolerability in patients with HIV-1 infection. Neurotrophins are only beginning to be realized for their therapeutic potential in HIV-1 associated neurologic disease. This review article provides a broad overview of neuroprotective strategies for HIV-1 infection and details how such strategies act and may be implemented for treatment of human disease.
