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1.  A VACCINE AGAINST METHAMPHETAMINE ATTENUATES ITS BEHAVIORAL EFFECTS IN MICE 
Drug and alcohol dependence  2012;129(1-2):41-48.
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. Serum antibody titers reached peak levels by 4–6 weeks, remained at a modest level through 18-weeks, peaked again at 22-wks after the second boost, and were still elevated at 35-weeks. At 7 weeks, groups of vaccinated and non-vaccinated mice were administered one of three MA doses (1, 2, or 3 mg/kg) to assess locomotor activity.
RESULTS
Non-vaccinated mice showed dose-dependent effects of MA with hypolocomotion at the lowest dose and elevated activity levels at the highest dose. Both dose effects were reduced in SMA-KLH groups, particularly low dose-induced hypolocomotion at later times post MA administration. Separate groups of vaccinated and non-vaccinated mice were trained in MA place conditioning at 30-weeks with either 0 (vehicle) or 0.5 mg/kg MA. Although times spent in the MA-paired side did not differ between groups on Test vs. Baseline sessions, SMA-KLH mice conditioned with MA showed reduced conditioned approach behaviors and decreased conditioned activity levels compared to control groups.
CONCLUSION
These data suggest SMA-KLH attenuates the ability of MA to support place conditioning and reduces or delays its locomotor effects. Overall, results support SMA-KLH as a candidate MA vaccine.
doi:10.1016/j.drugalcdep.2012.09.007
PMCID: PMC3563850  PMID: 23022610
conjugate vaccine; keyhole limpet hemocyanin; monophosphoryl lipid A; serum antibody titers; locomotor activity; conditioned place preference
2.  Effects of anti-cocaine vaccine and viral gene transfer of cocaine hydrolase in mice on cocaine toxicity including motor strength and liver damage 
Chemico-biological interactions  2012;203(1):208-211.
In developing an vivo drug-interception therapy to treat cocaine abuse and hinder relapse into drug seeking provoked by re-encounter with cocaine, two promising agents are: 1) a cocaine hydrolase enzyme (CocH) derived from human butyrylcholinesterase and delivered by gene transfer: 2) an anti-cocaine antibody elicited by vaccination. Recent behavioral experiments showed that antibody and enzyme work in a complementary fashion to reduce cocaine-stimulated locomotor activity in rats and mice. Our present goal was to test protection against liver damage and muscle weakness in mice challenged with massive doses of cocaine at or near the LD50 level (100 to 120 mg/kg, i.p.). We found that, when the interceptor proteins were combined at doses that were only modestly protective in isolation (enzyme, 1 mg/kg; antibody, 8 mg/kg), they provided complete protection of liver tissue and motor function. When the enzyme levels were ~ 400-fold higher, after in vivo transduction by adeno-associated viral vector, similar protection was observed from CocH alone.
doi:10.1016/j.cbi.2012.08.006
PMCID: PMC3537841  PMID: 22935511
3.  Anti-cocaine antibody and butyrylcholinesterase-derived cocaine hydrolase exert cooperative effects on cocaine pharmacokinetics and cocaine-induced locomotor activity in mice 
Chemico-biological interactions  2012;203(1):212-216.
We are investigating treatments for cocaine abuse based on viral gene transfer of a cocaine hydrolase (CocH) derived from human butyrylcholinesterase, which can reduce cocaine-stimulated locomotion and cocaine-primed reinstatement of drug-seeking behavior in rats for many months. Here, in mice, we explored the possibility that anti-cocaine antibodies can complement the actions of CocH to reduce cocaine uptake in brain and block centrally-evoked locomotor stimulation. Direct injections of test proteins showed that CocH (0.3 or 1 mg/kg) was effective by itself in reducing drug levels in plasma and brain of mice given cocaine (10 mg/kg, s.c., or 20 mg/kg, i.p). Administration of cocaine antibody per se at a low dose (8 mg/kg, i.p.) exerted little effect on cocaine distribution. However, a higher dose of antibody (12 mg/kg) caused peripheral trapping (increased plasma drug levels), which led to increased cocaine metabolism by CocH, as evidenced by a 6-fold rise in plasma benzoic acid. Behavioral tests with small doses of CocH and antibody (1 and 8 mg/kg, respectively) showed that neither agent alone reduced mouse locomotor activity triggered by a very large cocaine dose (100 mg/kg, i.p.). However, dual treatment completely suppressed the locomotor stimulation. Altogether, we found cooperative and possibly synergistic actions that warrant further exploration of dual therapies for treatment of cocaine abuse.
doi:10.1016/j.cbi.2012.08.015
PMCID: PMC3572300  PMID: 22960160
4.  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 (0.01 and 0.03 mg/kg) in a 90-min session. Experiment 2 was conducted to test higher meth doses (0.3 – 10 mg/kg). In Experiment 3, separate sets of mice were pre-treated with various meth doses once or twice (one injection/week) prior to a locomotor challenge with a low meth dose. Finally, in Experiment 4, we tested whether locomotor activation would be affected by pretreatment with a low or moderate dose of meth one month prior to the low meth dose challenge. Results show that low doses of meth induce hypolocomotion whereas moderate to high doses induce hyperlocomotion. Prior exposure to either one moderate or high dose of meth or to two, low doses of meth attenuated the hypolocomotor effect of a low meth dose one week later. This effect was also attenuated in mice tested one month after administration of a moderate meth dose. These results show that low and high doses of meth can have opposing effects on locomotor activity. Further, prior exposure to the drug leads to tolerance, rather than sensitization, of the hypolocomotor response to low meth doses.
doi:10.1016/j.pbb.2012.08.013
PMCID: PMC3494772  PMID: 23010423
Methamphetamine; Mice; Hypolocomotion; Hyperlocomotion; Stereotypy
5.  Prospects, Promise and Problems on the Road to Effective Vaccines and Related Therapies for Substance Abuse 
Expert review of vaccines  2013;12(3):323-332.
EXECUTIVE SUMMARY
This review addresses potential new treatments for stimulant drugs of abuse, especially cocaine. Clinical trials of vaccines against cocaine and nicotine have been completed with the generally encouraging result that subjects showing high titers of anti-drug antibody experience a reduction in drug reward, which may aid in cessation. New vaccine technologies including gene transfer of highly optimized monoclonal antibodies are likely to improve such outcomes further. In the special case of cocaine abuse, a metabolic enzyme is emerging as an alternative or added therapeutic intervention, which would also involve gene transfer. Such approaches still require extensive studies of safety and efficacy, but they may eventually contribute to a robust form of in vivo drug interception that greatly reduces risks of addiction relapse.
doi:10.1586/erv.13.1
PMCID: PMC3738206  PMID: 23496671
cocaine abuse; vaccine; adenovirus gene transfer vector; metabolism-based therapies; monoclonal antibody; butyrylcholinesterase; cocaine hydrolase; Anti-drug immunoglobulin; clinical Trial
6.  Combined Cocaine Hydrolase Gene Transfer and Anti-Cocaine Vaccine Synergistically Block Cocaine-Induced Locomotion 
PLoS ONE  2012;7(8):e43536.
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. injection of CocH protein (1 mg/kg) had no effect on spontaneous locomotion, but it suppressed responses to i.p. cocaine up to 80 mg/kg. When CocH was injected i.p. along with a murine cocaine antiserum that also did not affect spontaneous locomotion, there was no response to any cocaine dose. This suppression of locomotor activity required active enzyme, as it was lost after pretreatment with iso-OMPA, a selective BChE inhibitor. Comparable results were obtained in rats that developed high levels of CocH by gene transfer with helper-dependent adenoviral vector, and/or high levels of anti-cocaine antibody by vaccination with norcocaine hapten conjugated to keyhole limpet hemocyanin (KLH). After these treatments, rats were subjected to a locomotor sensitization paradigm involving a “training phase" with an initial i.p. saline injection on day 1 followed by 8 days of repeated cocaine injections (10 mg/kg, i.p.). A 15-day rest period then ensued, followed by a final “challenge" cocaine injection. As in mice, the individual treatment interventions reduced cocaine-stimulated hyperactivity to a modest extent, while combined treatment produced a greater reduction during all phases of testing compared to control rats (with only saline pretreatment). Overall, the present results strongly support the view that anti-cocaine vaccine and cocaine hydrolase vector treatments together provide enhanced protection against the stimulatory actions of cocaine in rodents. A similar combination therapy in human cocaine users might provide a robust therapy to help maintain abstinence.
doi:10.1371/journal.pone.0043536
PMCID: PMC3422258  PMID: 22912888
7.  Probing Cocaine-Antibody Interactions in Buffer and Human Serum 
PLoS ONE  2012;7(7):e40518.
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.
Results
MST analysis of fluorescently tagged mAb08 binding to cocaine reveals an approximately 15 fold decrease in its equilibrium dissociation constant in 20–50% human serum compared with that in saline buffer. A similar trend was also found using enriched polyclonal antibodies purified from vaccinated mice and patient serum, for which we have used fluorescently tagged bovine serum albumin conjugated to succinyl norcocaine (BSA-SNC). This conjugate closely mimics both cocaine and the hapten used to raise these antibodies. The ITC data also revealed that cocaine has a moderate affinity of about 2 µM to 20% human serum and very little interaction with human serum albumin or nonspecific human IgG at that concentration range. In a SPR inhibition experiment, the binding of mAb08 to immobilized BSA-SNC was inhibited by cocaine and benzoylecgonine in a highly competitive manner, whereas the purified polyclonal antibodies from vaccinated humans and mice, revealed preferential selectivity to pharmacologically active cocaine but not to the inactive metabolite benzoylecgonine. We have also developed a simple binding model to simulate the challenges associated with cocaine immunotherapy using the variable quantitative and kinetic properties of the antibodies.
Conclusions
High sensitivity calorimetric determination of antibody binding to cocaine and its metabolites provide valuable information for characterization of their interactions and thermodynamic properties. In addition MST measurements of antibody affinity in the presence of biological fluids will provide a better opportunity to make reliable decisions and facilitate the design of cocaine vaccines and immunization conditions. The methods should be more widely adopted in characterization of antibody complexes.
doi:10.1371/journal.pone.0040518
PMCID: PMC3409241  PMID: 22859949
8.  Vaccines for Drug Abuse 
Current medications for drug abuse have had only limited success. Anti-addiction vaccines to elicit antibodies that block the pharmacological effects of drugs have great potential for treating drug abuse. We review the status for two vaccines that are undergoing clinical trials (cocaine and nicotine) and two that are still in pre-clinical development (methamphetamine and heroin). We also outline the challenges and ethical concerns for anti-addiction vaccine development and their use as future therapeutics.
doi:10.1038/clpt.2011.281
PMCID: PMC3345810  PMID: 22130115
9.  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. It also outlines the development challenges, ethical concerns, and likely future intervention for anti-addiction vaccines.
doi:10.3410/M3-20
PMCID: PMC3186043  PMID: 22003367
10.  The Concept of Pharmacologic Cocaine Interception as a Treatment for Drug Abuse 
Chemico-biological interactions  2010;187(1-3):421-424.
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.
doi:10.1016/j.cbi.2010.02.036
PMCID: PMC2895017  PMID: 20219449
11.  Anti-cocaine vaccine development 
Expert review of vaccines  2010;9(9):1109-1114.
Cocaine abuse is an ongoing and serious problem which has lead 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. This review will discuss the concept of anti-drug vaccines in general, the successes and limitations of the various anti-cocaine vaccine approaches, the results of the clinical trials with an anti-cocaine vaccine, and some new vaccine-mediated approaches to combat cocaine addiction.
doi:10.1586/erv.10.102
PMCID: PMC2936703  PMID: 20822352
Substance Abuse; Vaccination; Cocaine; Immunotherapy
12.  Active immunotherapy for the Treatment of Cocaine Dependence 
Drugs of the future  2010;35(4):301-306.
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. This review will discuss the successes and limitations of the various vaccines and the results of clinical trials of the vaccine using succinyl norcocaine conjugated to cholera toxin B. This latter vaccine shows considerable promise for those individuals whose antibody response is adequate..
doi:10.1358/dof.2010.035.04.1474292
PMCID: PMC3142961  PMID: 21796226
Substance Abuse; Vaccination; Cocaine; Immunotherapy
13.  Adult seafood allergy in the Texas Medical Center: A 13-year experience 
Allergy & Rhinology  2011;2(2):e71-e77.
There is a paucity of data regarding prevalence and characteristics of adult seafood allergy in United States cohorts. This study was designed to determine the characteristics of patient-reported seafood allergy in a large allergy referral adult population. Retrospective analysis was performed of laboratory and clinical characteristics of seafood-allergic patients in three allergy clinics in the Texas Medical Center between January 1, 1997 and January 30, 2010. Of 5162 patients seen in this adult allergy referral population, 159 had physician-diagnosed seafood allergy with an average age of diagnosis of 50.2 (18–81 years) years. Shellfish allergy (59.1%) was more frequent than fish allergy (13.8%). Crustacean allergy (82.6%) was more frequent than mollusk allergy (7.2%). Shrimp (72.5%), crab (34.8%), and lobster (17.4%) were the most common shellfish allergies and tuna (28.6%), catfish (23.8%), and salmon (23.8%) were the most common fish allergies. One-third of seafood-allergic patients reported reactions to more than one seafood. Shellfish-allergic adults were more likely to experience respiratory symptoms than fish-allergic adults (p < 0.05). The likelihood of having anaphylaxis (32%) was not statistically different between shellfish- and fish-allergic subjects. Severe reactions were 12.9 times more likely to occur within the 1st hour of ingestion compared with nonsevere reactions (p < 0.005). The percentage of seafood allergy in this adult allergy referral population was 3.08%.
doi:10.2500/ar.2011.2.0019
PMCID: PMC3390121  PMID: 22852122
Anaphylaxis; fish; food allergy; hypersensitivity; seafood; shrimp; urticaria
14.  Monocyte CD49e and 110–120 kDa fibronectin fragments: HIV prognostic indicators independent of viral load and CD4 T-cell counts 
AIDS (London, England)  2009;23(17):2247-2253.
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.
Design
A long-term observational study of patients whose plasma FNf and monocyte CD49e had been measured at 90-day intervals for 1.4 ± 0.5 years.
Methods
Plasma FNf was measured by a quantitative western blot assay and monocyte CD49e expression by flow cytometry. Patients were monitored clinically for up to 5 years after enrollment.
Results
All-cause mortality was significantly higher in patients who had at least 5 μg/ml FNf in more than 50% of plasma samples and/or persistent depletion of monocyte CD49e. Persistence of FNf and depletion of monocyte CD49e were not associated with changes in viral load or CD4 T-cell counts.
Conclusion
Persistently reduced expression of blood monocyte CD49e and/or the persistent presence of FNf in plasma are adverse prognostic markers in HIV-infected patients.
doi:10.1097/QAD.0b013e3283318ff4
PMCID: PMC2885978  PMID: 19710592
cell-binding 110; 120 kDa fibronectin fragments; inflammation; monocytes; patient survival; protease-antiprotease balance
15.  Cocaine Vaccine for the Treatment of Cocaine Dependence in Methadone Maintained Patients: A Randomized Double-Blind Placebo-Controlled Efficacy Trial 
Archives of general psychiatry  2009;66(10):1116-1123.
Context
Cocaine dependence, which affects 2.5 million Americans annually, has no FDA approved pharmacotherapy.
Objective
To evaluate the immunogenicity, safety, and efficacy of a novel cocaine vaccine to treat cocaine dependence.
Design
24 week Phase IIb randomized double-blind placebo-controlled trial with efficacy assessed during weeks 8 to 20 and follow-up to week 24.
Setting
Cocaine and opioid dependent persons recruited from 2003–2005 from greater New Haven, CT.
Participants
115 methadone maintained subjects (67% male, 87% Caucasian, aged 18–46) were randomized to vaccine or placebo and 82% completed the trial. Most smoked crack cocaine along with using marijuana (18%), alcohol (10%), and non-prescription opioids (44%).
Intervention
Over 12 weeks 109/115 subjects received five vaccinations of placebo or succinylnorcocaine linked to cholera B protein.
Main Outcome Measure
Semi-quantitative urinary cocaine metabolite levels measured thrice weekly with positive cutoff of 300 ng/ml.
Results
The 38% of vaccinated subjects who attained serum IgG anti-cocaine levels ≥ 43 µg/mL (high IgG) had significantly more cocaine-free urines than those with < 43 µg/mL (low IgG) and the placebo subjects during weeks 9 to 16 (45% vs 35%). The proportion of subjects having a 50% reduction in cocaine use was significantly greater in the high IgG than low IgG subjects (0.53 vs. 0.23) (P<0.04). The most common side effects were injection site induration and tenderness. There were no treatment related serious adverse events, withdrawals, or deaths.
Conclusions
Attaining high (≥ 43 µg/mL) IgG anti-cocaine antibody levels was associated with significantly reduced cocaine use, but only 38% of the vaccinated attained these IgG levels and they had only 2 months of adequate cocaine blockade. Thus, we need improved vaccines and boosters.
doi:10.1001/archgenpsychiatry.2009.128
PMCID: PMC2878137  PMID: 19805702
16.  Vaccines for Cocaine Abuse 
Human vaccines  2009;5(4):194-199.
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. The effectiveness of such antibodies on drug pharmacodynamics is a function of both the quantitative and the qualitative properties of the antibodies, and this combination will determine the success of the clinical applications of anti-cocaine vaccines in helping addicts discontinue cocaine abuse. This review will discuss these issues and present the current developmental status of cocaine conjugate vaccines.
PMCID: PMC2878138  PMID: 19276665
Substance Abuse; Vaccine; Cocaine; Immunization; Antibody; Conjugate
17.  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 anti-drug 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 benefits of such antibodies on drug pharmacodynamics will be influenced by both the quantitative and the qualitative properties of the antibodies. The sum of these effects will determine the success of the clinical applications of anti-drug vaccines in addiction medicine. This review will discuss these issues and present the current status of vaccine development for nicotine, cocaine, methamphetamine, phencyclidine, and morphine.
doi:10.1196/annals.1441.027
PMCID: PMC2587140  PMID: 18991962
Substance Abuse; Vaccination; Theory; Cocaine; Methamphetamine; Nicotine; Phencyclidine; Morphine

Results 1-17 (17)