Active and Passive Immunization with an Anti-Methamphetamine Vaccine Attenuates the Behavioral and Cardiovascular Effects of Methamphetamine.

Background: Methamphetamine use disorder (MUD) is a growing health concern with no FDA-approved treatment. The present series of studies build upon our previous work developing an anti-methamphetamine (MA) vaccine for MUD. We determined the effects of a formulation that included tetanus-toxoid (TT) conjugated to succinyl-methamphetamine (TT-SMA) adsorbed onto aluminum hydroxide (alum) in combination with the novel Toll-Like Receptor-5 agonist, entolimod.

Preclinical efficacy of an anti-methamphetamine vaccine using E6020 adjuvant.

Background And Objective: Methamphetamine (MA) substance use disorder (SUD) does not have an efficacious pharmacotherapy. We developed a MA vaccine and investigated its potential to attenuate MA induced responses.

Methods: We examined a novel adjuvant, E6020, a Toll-like receptor-4 (TLR-4) agonist combined with tetanus-toxoid conjugated to succinyl-methamphetamine (TT-SMA) adsorbed on aluminum hydroxide (alum).

Attenuation of cocaine-induced locomotor activity in male and female mice by active immunization.

Background And Objectives: Immunotherapy for drug addiction is being investigated in several laboratories but most studies are conducted in animals of one sex. Yet, women show heightened immune responses and are more likely to develop autoimmune diseases than men. The purpose of this study was to compare the effects of an active anti-cocaine vaccine, succinyl-norcocaine conjugated to keyhole limpet hemocyanin, for its ability to elicit antibodies and alter cocaine-induced ambulatory activity in male versus female mice.

The future potential for cocaine vaccines.

Introduction: Addiction to cocaine is a major problem around the world, but especially in developed countries where the combination of wealth and user demand has created terrible social problems. Although only some users become truly addicted, those who are often succumb to a downward spiral in their lives from which it is very difficult to escape. From the medical perspective, the lack of effective and safe, non-addictive therapeutics has instigated efforts to develop alternative approaches for treatment, including anticocaine vaccines designed to block cocaine's pharmacodynamic effects.

Hapten optimization for cocaine vaccine with improved cocaine recognition.

In the absence of any effective pharmacotherapy for cocaine addiction, immunotherapy is being actively pursued as a therapeutic intervention. While several different cocaine haptens have been explored to develop anticocaine antibodies, none of the hapten was successfully designed, which had a protonated tropane nitrogen as is found in native cocaine under physiological conditions, including the succinyl norcocaine (SNC) hapten that has been tested in phase II clinical trials. Herein, we discuss three different cocaine haptens: hexyl norcocaine (HNC), bromoacetamido butyl norcocaine (BNC), and succinyl butyl norcocaine (SBNC), each with a tertiary nitrogen structure mimicking that of native cocaine which could optimize the specificity of anticocaine antibodies for better cocaine recognition.

A morphine conjugate vaccine attenuates the behavioral effects of morphine in rats.

Vaccines for opioid dependence may provide a treatment that would reduce or slow the distribution of the drug to brain, thus reducing the drug's reinforcing effects. We tested whether a conjugate vaccine against morphine (keyhole limpet hemocyanin-6-succinylmorphine; KLH-6-SM) administered to rats would produce antibodies and show specificity for morphine or other heroin metabolites. The functional effects of the vaccine were tested with antinociceptive and conditioned place preference (CPP) tests.

Spontaneous development of IgM anti-cocaine antibodies in habitual cocaine users: effect on IgG antibody responses to a cocaine cholera toxin B conjugate vaccine.

Background And Objectives: In cocaine vaccine studies, only a minority of subjects made strong antibody responses. To investigate this issue, IgG and IgM antibody responses to cocaine and to cholera toxin B (CTB-the carrier protein used to enhance immune responses to cocaine) were measured in sera from the 55 actively vaccinated subjects in a Phase IIb randomized double-blind placebo-controlled trial (TA-CD 109).

Methods: Isotype specific ELISAs were used to measure IgG and IgM anti-cocaine and anti-CTB antibody in serial samples collected prior to and at intervals after immunization.

A vaccine against methamphetamine attenuates its behavioral effects in mice.

Background: Vaccines have treatment potential for methamphetamine (MA) addiction. We tested whether a conjugate vaccine against MA (succinyl-methamphetamine-keyhole limpet hemocyanin carrier protein; SMA-KLH) would generate MA antibodies and alter MA-induced behaviors.

Methods: Mice were injected with SMA-KLH and received booster administrations 3 and 20 weeks later.

Dose-dependent changes in the locomotor responses to methamphetamine in BALB/c mice: low doses induce hypolocomotion.

The overall goal of the present study was to determine the effects of different doses of (+)-methamphetamine (meth) on locomotor activity of Balb/C mice. Four experiments were designed to test a wide range of meth doses in BALB/c female mice. In Experiment 1, we examined locomotor activity induced by an acute administration of low doses of meth (0.

Combined cocaine hydrolase gene transfer and anti-cocaine vaccine synergistically block cocaine-induced locomotion.

Mice and rats were tested for reduced sensitivity to cocaine-induced hyper-locomotion after pretreatment with anti-cocaine antibody or cocaine hydrolase (CocH) derived from human butyrylcholinesterase (BChE). In Balb/c mice, direct i.p.

Probing cocaine-antibody interactions in buffer and human serum.

Background: Despite progress in cocaine immunotherapy, the kinetic and thermodynamic properties of antibodies which bind to cocaine and its metabolites are not well understood. It is also not clear how the interactions between them differ in a complex matrix such as the serum present in the human body. In the present study, we have used microscale thermophoresis (MST), isothermal titration calorimetry (ITC), and surface plasmon resonance (SPR) we have evaluated the affinity properties of a representative mouse monoclonal (mAb08) as well as those of polyclonal antibodies purified from vaccinated mouse and human patient serum.

Anti-addiction vaccines.

Despite intensive efforts to eradicate it, addiction to both legal and illicit drugs continues to be a major worldwide medical and social problem. Anti-addiction vaccines can produce the antibodies to block the effects of these drugs on the brain, and have great potential to ameliorate the morbidity and mortality associated with illicit drug intoxications. This review provides a current overview of anti-addiction vaccines that are under clinical trial and pre-clinical research evaluation.

Anti-cocaine vaccine development.

Cocaine abuse is an ongoing and serious problem that has led to the growth of a brutal criminal enterprise, particularly in the Americas and Europe. At present, there are no effective pharmacological agents available to treat the addiction by blocking cocaine or reversing its effects. In order to help motivated addicts conquer their addiction, vaccines against cocaine are being developed and one has progressed to clinical trials.

Delayed diagnosis of hereditary angioedema.

Hereditary angioedema (HAE) is a rare and potentially fatal disease that is important to recognize early. It is usually associated with low levels or impaired function of C1 inhibitor, which is involved in several inflammatory pathways. The treatment of HAE is very different from other causes of angioedema, emphasizing the importance of early and accurate diagnosis.

Active immunotherapy for the Treatment of Cocaine Dependence.

Although cocaine is illegal in most countries of the world, addiction is common and increasing in many populations, and the effectiveness of current treatment options for those afflicted has been very limited. The availability of an anti-cocaine vaccine could offer help to those who wish to quit their addiction. A number of vaccines differing in their chemical nature have been developed, and one has advanced into clinical trials.

The concept of pharmacologic cocaine interception as a treatment for drug abuse.

Cocaine access to brain tissue and associated cocaine-induced behaviors are substantially reduced in rats and mice by significant plasma levels of an enzyme that rapidly metabolizes the drug. Similar results have been obtained in rodents and humans with therapeutic anti-cocaine antibodies, which sequester the drug and prevent its entry into the brain. We show that an efficient cocaine hydrolase can lead to rapid unloading of anti-cocaine antibodies saturated with cocaine, and we provide a theoretical basis for the hypothesis that dual therapy with antibody and hydrolase enzyme may be especially effective.

Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial.

Context: Cocaine dependence, which affects 2.5 million Americans annually, has no US Food and Drug Administration-approved pharmacotherapy.

Objectives: To evaluate the immunogenicity, safety, and efficacy of a novel cocaine vaccine to treat cocaine dependence.

Monocyte CD49e and 110-120 kDa fibronectin fragments: HIV prognostic indicators independent of viral load and CD4 T-cell counts.

Objective: To investigate the prognostic impact of chronic inflammation associated with HIV infections. Previously, we had observed that proteases, released in the course of HIV infections, cause 110-120 kDa fibronectin fragments (FNf) to appear in the blood of many patients. In vitro, at concentrations within the range found in patients' plasma, FNf stimulate monocytes to release proteolytic enzymes that remove CD49e from the cell surface and produce cytokines that suppress proliferation of activated T cells when stimulated by agents that crosslink their antigen receptors.

Anti-drug vaccines to treat substance abuse.

Substance abuse is a growing world-wide problem. The big four drugs of abuse that might lend themselves to immunotherapy are nicotine, cocaine, morphine/heroin and methamphetamine. Tobacco abuse has a well-known enormous impact on major chronic cardiovascular and pulmonary diseases, while the last three, aside from their neuropsychological effects, are illegal, leading to crime and incarceration as well as the transmission of viral diseases.

Vaccines for cocaine abuse.

Treatments for cocaine abuse have been disappointingly ineffective, especially in comparison with those for some other abused substances. A new approach, using vaccination to elicit specific antibodies to block the access of cocaine to the brain, has shown considerable promise in animal models, and more recently in human trials. The mechanism of action for the antibody effect on cocaine is very likely to be the straightforward and intuitive result of the binding of the drug in circulation by antibodies, thereby reducing its entry into the central nervous system and thus its pharmacological effects.

Substance abuse vaccines.

Conventional substance-abuse treatments have only had limited success for drugs such as cocaine, nicotine, methamphetamine, and phencyclidine. New approaches, including vaccination to block the effects of these drugs on the brain, are in advanced stages of development. Although several potential mechanisms for the effects of antidrug vaccines have been suggested, the most straightforward and intuitive mechanism involves binding of the drug by antibodies in the bloodstream, thereby blocking entry and/or reducing the rate of entry of the drug into the central nervous system.

The future of vaccines in the management of addictive disorders.

Conventional substance abuse treatments have had only limited success. As a result, new approaches, including vaccination to block the effects of drugs such as cocaine, nicotine, methamphetamine, and phencyclidine, are in development. Although a number of possible rationales for the effects of antidrug vaccines have been suggested, the most straightforward and intuitive mechanism would involve binding of the drug by antibodies in the bloodstream, thereby blocking entry or reducing the rate of entry of the drug into the central nervous system.

Protection against influenza infection by cytokine-enhanced aerosol genetic immunization.

Background: Conventional vaccine development for newly emerging pandemic influenza virus strains would likely take too long to prevent devastating global morbidity and mortality. If DNA vaccines can be distributed and delivered efficiently, genetic immunization could be an attractive solution to this problem, since plasmid DNA is stable, easily engineered to encode new protein antigens, and able to be quickly produced in large quantities.

Methods: We compared two novel genetic immunization methods in a mouse model of influenza to evaluate protective effects: aerosol delivery of polyethylenimine (PEI)-complexed hemagglutinin (HA)-expressing plasmid and intravenous (IV) delivery of the plasmid complexed with macroaggregated albumin/PEI.

Hepatocyte growth factor gene transfer to alveolar septa for effective suppression of lung fibrosis.

We examined therapeutic gene transfer of human hepatocyte growth factor (hHGF) to alveolar septa in mouse bleomycin-induced lung fibrosis using macroaggregated albumin-polyethylenimine complex (MAA-PEI). Intravenous administration of MAA-PEI along with 1 microg pCAG.hHGF to C57BL/6 mice increased the uptake of plasmids into alveolar capillary endothelial cells and epithelial cells, prolonged hHGF expression in the lung, and induced a level of hHGF expression equal to that seen with 10 microg of hHGF-expression plasmids alone.