Anti-Cocaine IgA Rather Than IgG Mediates Vaccine Protection from Cocaine Use.

In developing a vaccine for fentanyl use disorder, we observed that IgA was the best correlate of vaccine-mediated protection from injected drug challenge, rather than IgG or binding affinity. Recent evidence shows that IgA secreting cells line the blood−brain barrier that capture pathogens and could prevent drug antigens from penetrating the brain. We assayed IgA and IgG antibodies from an anti-cocaine vaccine clinical trial and categorized each subject's antibody levels using half-log cut-points for IgA: <1000, <5000, <10,000 and >10,000; and for IgG: <10,000 to >100,000. We compared these antibody groups on urine toxicology in 130 subjects at week 9 after 3 booster vaccinations. We also provided relevant data on benzoylecgonine (BE, cocaine metabolite) from this study's placebo patients. BE urine levels were lowest for the highest IgA category; however, levels did not differ across IgG groups. Our findings linking IgA to protection from cocaine and fentanyl in mice, rats and humans are novel and suggest an increasingly recognized role of IgA in vaccine efficacy.

A Clinical Trial of Entolimod a TLR-5 Adjuvant for Vaccines Using Diphtheria or Tetanus as Carrier Proteins.

Anti-drug vaccines previously failed clinical trials because they did not provide a sufficient titer or duration of antibodies (AB), but new adjuvants enhance both AB titers and efficacy duration. This clinical trial assessed AB titers after a single booster of commercial tetanus-diphtheria (Td) vaccine in 40 males randomized as 15 to Td alone and 25 to Td combined with the TLR5 adjuvant, Entolimod (Ent). Ent significantly increased ABs against diphtheria (DPT) (0.46 vs. 0.29 IU/mL increase; n = 40, p < 0.05), but against tetanus (TT) only if baseline TT AB was below 3 IU/mL (3.1 vs. 2.1 IU/mL; n = 20; p < 0.05). These 20 participants also showed a two-fold increase in anti-TT AB titer more often when given Ent than non-Ent (33% vs. 82%) (p < 0.03). Anti-Ent AB was low and appeared unlikely to reduce Ent efficacy after repeated Ent administration. Medical safety was excellent, and a TLR5 missense polymorphism reduced anti-DPT AB production, but Ent increased anti-DPT AB titers to levels induced in subjects with genetically "normal" TRL5 functioning. Further clinical testing of TLR5 adjuvants like Ent seems warranted for anti-drug vaccines.

Doxazosin treatment in cocaine use disorder: pharmacogenetic response based on an alpha-1 adrenoreceptor subtype D genetic variant.

Background: The α1 antagonist doxazosin reduces cocaine use in individuals with cocaine use disorder (CUD) through a functional polymorphism of the α1 adrenoreceptor. The regulatory role of the α1adrenoreceptor subtype D (ADRA1D) gene polymorphism in CUD is uncharacterized.Objectives: To study how the genetic variant of ADRA1D gene (T1848A, rs2236554) may affect the treatment efficacy of doxazosin in reducing cocaine use.Methods: This 12-week pilot trial included 76 participants with CUD with ADRA1D (T1848A, rs2236554) AA (N = 40) or AT/TT genotype (N = 36). Participants were randomized to doxazosin (8 mg/day, N = 47) or placebo (N = 29), and followed with thrice weekly urine toxicology and once weekly cognitive behavioral psychotherapy.Results: The AA and the AT/TT groups had comparable baseline rates of cocaine positive urines at weeks 1-2 (~ 76%). In the placebo group, an increase of cocaine positive urines in the AT/TT group was found as compared to the AA group (24% vs. 9%). In the doxazosin group, a greater decrease in cocaine positive urines was found in the AT/TT group relative to the AA group. The difference between the doxazosin and placebo groups in cocaine negative urines became evident at weeks 5-6 and peaked at weeks 9-10 (~35% difference). The AT/TT group demonstrated a significant medication and time by medication effect (p < .001), whereas the AA group did not.Conclusion: The T-allele carriers showed a greater reduction of cocaine use after treatment with doxazosin in participants with the ADRA1D gene polymorphism (T1848A), suggesting that this SNP may serve as a pharmacogenetic marker in pharmacotherapy of CUD.

Buprenorphine for the treatment of posttraumatic stress disorder.

BACKGROUND AND OBJECTIVES: The core pharmacological treatment of Post-Traumatic Stress Disorder (PTSD) is selective serotonin reuptake inhibitors (SSRIs), although remission is only around 30% with them. Many patients will self-treat with opioids and due to the opiate system involvement in dysphoric mood and anxiety/stress responses, it is likely that antagonism of the kappa opioid receptor (KOR) system represents a potential target for treatment of PTSD. The aim of this study is to compare response of PTSD symptoms when antagonizing KOR via buprenorphine/naloxone compared to SSRIs or opioid therapy. METHODS: A retrospective chart review of patients in the MEDVAMC between June 1, 2010 and June 30, 2016 was conducted. Inclusion criteria included patients with a documented diagnosis of PTSD with at least two documented PTSD scores (either PCLC or PC-PTSD). Exclusion criteria included patients not prescribed one of the study medications (ie, buprenorphine, SSRI, or opiate for chronic pain), and patients not on the study medication for at least 30 days. RESULTS: Buprenorphine patients exhibited the lowest final average PTSD score (2.47) and the largest change from baseline (-24.0%) compared to opioids (-16.1%) or SSRIs (1.16%). The average buprenorphine dose was 23.3 mg/day, and the average length of therapy was 860 days. CONCLUSIONS: Buprenorphine may help decrease PTSD symptoms more than SSRIs or opioids alone. Prospective studies are needed to determine whether these effects are reproducible. SCIENTIFIC SIGNIFICANCE: Pharmacotherapy advancements in PTSD treatment have been limited and the kappa opioid receptor system presents a new target that warrants further research. (Am J Addict 2019;XX:1-6).

Pharmacogenetics of Dopamine ß-Hydroxylase in cocaine dependence therapy with doxazosin.

The α1 -adrenergic antagonist, doxazosin, has improved cocaine use disorder (CUD) presumably by blocking norepinephrine (NE) stimulation and reward from cocaine-induced NE increases. If the NE levels for release were lower, then doxazosin might more readily block this NE stimulation and be more effective. The NE available for release can be lower through a genetic polymorphism in dopamine ß-hydroxylase (DBH) (C-1021T, rs1611115), which reduces DßH's conversion of dopamine to NE. We hypothesize that doxazosin would be more effective in CUD patients who have these genetically lower DßH levels. This 12-week, double-blind, randomized, placebo-controlled trial included 76 CUD patients: 49 with higher DßH levels from the DBH CC genotype and 27 with lower DßH levels from T-allele carriers (CT or TT). Patients were randomized to doxazosin (8 mg/day, N = 47) or placebo (N = 29) and followed with thrice weekly urine toxicology and once weekly cognitive behavioral psychotherapy. Cocaine use was reduced at a higher rate among patients in the doxazosin than in the placebo arm. We found significantly lower cocaine use rates among patients carrying the T-allele (CT/TT) than the CC genotype. The percentage of cocaine positive urines was reduced by 41 percent from baseline in the CT/TT group with low DßH and NE levels, as compared with no net reduction in the CC genotype group with normal DßH and NE levels. The DBH polymorphism appears play an important role in CUD patients' response to doxazosin treatment, supporting a pharmacogenetic association and potential application for personalized medicine.

Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy.

INTRODUCTION: Cocaine use is a global public health concern of significant magnitude, negatively impacting both the individual as well as larger society. Despite numerous trials, the discovery of an effective medication for treatment of cocaine use disorder remains elusive. AREAS COVERED: This article reviews the emerging pharmacotherapies for treatment of cocaine use disorder, focusing on those medications that are currently in Phase II or III human clinical trials. Articles reviewed were obtained through searches of PubMed, Ovid MEDLINE, Clinicaltrials.gov and the Pharmaprojects database. EXPERT OPINION: Research into cocaine pharmacotherapy must continue to show innovation. Given that medications targeting single neurotransmitter systems have demonstrated little efficacy in treatment of cocaine use disorder, the recent focus on pharmacotherapeutic agents with multiple neurobiochemical targets represents an exciting shift in trial design and approach. Additionally, consideration of pharmacogenetics may be helpful in identification of subpopulations of cocaine-dependent individuals who may preferentially respond to medications.

Vaccine for cocaine dependence: a randomized double-blind placebo-controlled efficacy trial.

AIMS: We evaluated the immunogenicity, efficacy, and safety of succinylnorcocaine conjugated to cholera toxin B protein as a vaccine for cocaine dependence. METHODS: This 6-site, 24 week Phase III randomized double-blind placebo-controlled trial assessed efficacy during weeks 8 to 16. We measured urine cocaine metabolites thrice weekly as the main outcome. RESULTS: The 300 subjects (76% male, 72% African-American, mean age 46 years) had smoked cocaine on average for 13 days monthly at baseline. We hypothesized that retention might be better and positive urines lower for subjects with anti-cocaine IgG levels of ≥42 µg/mL (high IgG), which was attained by 67% of the 130 vaccine subjects receiving five vaccinations. Almost 3-times fewer high than low IgG subjects dropped out (7% vs 20%). Although for the full 16 weeks cocaine positive urine rates showed no significant difference between the three groups (placebo, high, low IgG), after week 8, more vaccinated than placebo subjects attained abstinence for at least two weeks of the trial (24% vs 18%), and the high IgG group had the most cocaine-free urines for the last 2 weeks of treatment (OR=3.02), but neither were significant. Injection site reactions of induration and tenderness differed between placebo and active vaccine, and the 29 serious adverse events did not lead to treatment related withdrawals, or deaths. CONCLUSIONS: The vaccine was safe, but it only partially replicated the efficacy found in the previous study based on retention and attaining abstinence.

Can you vaccinate against substance abuse?

Vaccines are being developed against substance abuse and most progress has been made with anti-cocaine, nicotine and opiate vaccines, but new ones are being developed for methamphetamine and may be in humans within 18 - 24 months. These haptenated vaccines share a common problem in that only about one-third of those vaccinated get a sufficiently robust antibody titer to enable them to effectively block drug use. This problem is being addressed with better carrier proteins and new adjuvants beyond alum. This review provides details about these developing vaccines that act through pharmacokinetic rather than pharmacodynamics blockade. Due to this pharmacokinetic mechanism of keeping abused drugs in the bloodstream and not allowing them entry into the brain or other organs, these vaccines have very few side effects compared to other blockers used in addictions treatment.

DBH gene as predictor of response in a cocaine vaccine clinical trial.

We examined a pharmacogenetic association of the dopamine ß-hydroxylase (DBH) gene with a response to an anti-cocaine vaccine that was tested in a recent clinical trial. This gene is associated with cocaine-induced paranoia, which has a slower onset than the euphoria from cocaine. The vaccine reduced euphoria by slowing the entry of cocaine into the brain, but it may not reduce aversive symptoms like paranoia. A 16-week Phase IIb randomized double-blind placebo-controlled trial of 114 cocaine and opioid dependent subjects who received five vaccinations over the first 12 weeks was examined. We genotyped 71 subjects for the rs1611115 (-1021C>T) variant of the DBH gene and compared vaccine to placebo subjects on cocaine-free urines. Using repeated measures analysis of variance, corrected for population structure, vaccine pharmacotherapy reduced cocaine positive urines significantly based on DBH genotype. Patients with the low DßH level genotype dropped from 77% to 51% on vaccine (p=0.0001), while those with the normal DßH level genotype dropped from 83% to 72%. Placebo showed no effect on cocaine use overall or by genotype. This study indicates that a patient's DBH genotype could be used to identify a subset of individuals for whom vaccine treatment may be an effective pharmacotherapy for cocaine dependence.