RESUMO
The nearly insurmountable adversity that accompanies opioid use disorder (OUD) creates life-altering complications for opioid users. To worsen matters, existing small-molecule drugs continue to inadequately address OUD due to their engagement of the opioid receptor, which can leave the user to deal with side effects and financial hardships from their repeated use. An alternative therapeutic approach utilizes endogenously generated antibodies through active vaccination to reduce the effect of opioids without modulating the opioid receptor. Here, we explore different adjuvants and storage conditions to improve opioid vaccine efficacy and shelf life. Our results revealed that inulin-based formulations (Advax) containing a CpG oligodeoxynucleotide (ODN) acted as effective adjuvants when combined with a heroin conjugate: immunized mice showed excellent recovery from heroin-induced antinociception accompanied by high titer, high opioid affinity serum antibodies similar to the immunopotentiating properties of traditional alum-based adjuvants. Moreover, nonhuman primates vaccinated with a heroin/fentanyl combination vaccine demonstrated potent antibody responses against opioids when formulated with both inulin and alum adjuvants. Finally, storing a freeze-dried opioid vaccine formulation maintained efficacy for up 1 year at room temperature. The results from our studies represent an advance toward a clinically feasible opioid vaccine.
Assuntos
Adjuvantes Imunológicos/farmacologia , Adjuvantes Farmacêuticos/farmacologia , Fentanila/imunologia , Heroína/imunologia , Vacinas Conjugadas/imunologia , Analgésicos Opioides/imunologia , Animais , Imunização/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oligodesoxirribonucleotídeos/imunologia , Transtornos Relacionados ao Uso de Opioides/imunologia , Vacinação/métodosRESUMO
Opioid abuse in the United States has been declared a national crisis and is exacerbated by an inexpensive, readily available, and illicit supply of synthetic opioids. Specifically, fentanyl and related analogues such as carfentanil pose a significant danger to opioid users due to their high potency and rapid acting depression of respiration. In recent years these synthetic opioids have become the number one cause of drug-related deaths. In our research efforts to combat the public health threat posed by synthetic opioids, we have developed monoclonal antibodies (mAbs) against the fentanyl class of drugs. The mAbs were generated in hybridomas derived from mice vaccinated with a fentanyl conjugate vaccine. Guided by a surface plasmon resonance (SPR) binding assay, we selected six hybridomas that produced mAbs with 10-11 M binding affinity for fentanyl, yet broad cross-reactivity with related fentanyl analogues. In mouse antinociception models, our lead mAb (6A4) could blunt the effects of both fentanyl and carfentanil in a dose-responsive manner. Additionally, mice pretreated with 6A4 displayed enhanced survival when subjected to fentanyl above LD50 doses. Pharmacokinetic analysis revealed that the antibody sequesters large amounts of these drugs in the blood, thus reducing drug biodistribution to the brain and other tissue. Lastly, the 6A4 mAb could effectively reverse fentanyl/carfentanil-induced antinociception comparable to the opioid antagonist naloxone, the standard of care drug for treating opioid overdose. While naloxone is known for its short half-life, we found the half-life of 6A4 to be approximately 6 days in mice, thus monoclonal antibodies could theoretically be useful in preventing renarcotization events in which opioid intoxication recurs following quick metabolism of naloxone. Our results as a whole demonstrate that monoclonal antibodies could be a desirable treatment modality for synthetic opioid overdose and possibly opioid use disorder.
Assuntos
Analgésicos Opioides/antagonistas & inibidores , Anticorpos Monoclonais/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor Nociceptiva/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Analgésicos Opioides/administração & dosagem , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/química , Camundongos , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/química , Ressonância de Plasmônio de SuperfícieRESUMO
The leaves of the Mitragynine speciosia tree (also known as Kratom) have long been chewed, smoked, or brewed into a tea by people in Southeastern Asian countries, such as Malaysia and Thailand. Just this past year, the plant Kratom gained popularity in the United States as a "legal opioid" and scheduling it as a drug of abuse is currently pending. The primary alkaloid found in Kratom is a µ-opioid receptor agonist, mitragynine, whose structure contains a promising scaffold for immunopharmacological use. Although Kratom is regarded as a safe opioid alternative, here we report the LD50 values determined for its two main psychoactive alkaloids, mitragynine and 7-hydroxymitragynine, as comparable to heroin in mice when administered intravenously. Given Kratom's recent emergence in the U.S., there is currently no diagnostic test available for law enforcement or health professionals, so we sought to design such an assay. Mitragynine was used as a starting point for hapten design, resulting in a hapten with an ether linker extending from the C9 position of the alkaloid. Bacterial flagellin (FliC) was chosen as a carrier protein for active immunization in mice, yielding 32 potential monoclonal antibodies (mAbs) for assay development. Antimitragynine mAbs in the range of micro- to nanomolar affinities were uncovered and their utility in producing a convenient lateral flow detection assay of human fluid samples was examined. Antibodies were screened for binding to mitragynine, 7-hydroxymitragynine, and performance in lateral flow assays. Two monoclonal antibodies were subcloned and further purified with 93 and 362 nM affinity to mitragynine. Test strip assays were optimized with a detection cut off of 0.5 µg/mL for mitragynine in buffer and urine (reflecting projected clinically relevant levels of drug in urine), which could be beneficial to law enforcement agencies and health professionals as the opioid epidemic in America continues to evolve.
Assuntos
Mitragyna/química , Extratos Vegetais/análise , Folhas de Planta/química , Alcaloides de Triptamina e Secologanina/análise , Animais , Anticorpos Monoclonais/análise , Anticorpos Monoclonais/biossíntese , Injeções Intravenosas , Camundongos , Conformação Molecular , Extratos Vegetais/administração & dosagem , Extratos Vegetais/toxicidade , Alcaloides de Triptamina e Secologanina/administração & dosagem , Alcaloides de Triptamina e Secologanina/toxicidade , Ressonância de Plasmônio de SuperfícieRESUMO
Heroin is a highly abused opioid that has reached epidemic status within the United States. Yet, existing therapies to treat addiction are inadequate and frequently result into rates of high recidivism. Vaccination against heroin offers a promising alternative therapeutic option but requires further development to enhance the vaccine's performance. Hsp70 is a conserved protein with known immunomodulatory properties and is considered an excellent immunodominant antigen. Within an antidrug vaccine context, we envisioned Hsp70 as a potential dual carrier-adjuvant, wherein immunogenicity would be increased by co-localization of adjuvant and antigenic drug hapten. Recombinant Mycobacterium tuberculosis Hsp70 was appended with heroin haptens and the resulting immunoconjugate granted anti-heroin antibody production and blunted heroin-induced antinociception. Moreover, Hsp70 as a carrier protein surpassed our benchmark Her-KLH cocktail through antibody-mediated blockade of 6-acetylmorphine, the main mediator of heroin's psychoactivity. The work presents a new avenue for exploration in the use of hapten-Hsp70 conjugates to elicit anti-drug immune responses.
Assuntos
Analgésicos Opioides/imunologia , Proteínas de Choque Térmico HSP70/química , Haptenos/imunologia , Heroína/imunologia , Imunoconjugados/imunologia , Vacinas/imunologia , Adjuvantes Imunológicos/química , Compostos de Alúmen/química , Animais , Proteínas de Bactérias/química , Escherichia coli/genética , Haptenos/química , Imunoconjugados/química , Masculino , Camundongos , Mycobacterium tuberculosis/química , Proteínas Recombinantes/química , Vacinas/síntese química , Vacinas/químicaRESUMO
Background: Increased death due to the opioid epidemic in the United States has necessitated the development of new strategies to treat addiction. Monoclonal antibodies and antidrug vaccines provide a tool that both aids addiction management and reduces the potential for overdose. Dual drug vaccines formulated by successive conjugation or by mixture have certain drawbacks. The current study examines an approach for combatting the dangers of fentanyl-laced heroin, by using a hapten with one epitope that has domains for both fentanyl and heroin. Results: We evaluated a series of nine vaccines developed from chemically contiguous haptens composed of both heroin- and fentanyl-like domains. Analysis of the results obtained by SPR and ELISA revealed trends in antibody affinity and titers for heroin and fentanyl based on epitope size and linker location. In antinociception studies, the best performing vaccines offered comparable protection against heroin as our benchmark heroin vaccine, but exhibited attenuated protection against fentanyl compared to our fentanyl vaccine. Conclusion: After thorough investigation of this strategy, we have identified key considerations for the development of a chemically contiguous heroin-fentanyl vaccine. Importantly, this is the first report of such a strategy in the opioid-drug-vaccine field.
RESUMO
In recent years, drug conjugate vaccines have shown promise as therapeutics for substance use disorder. As a means to improve the efficacy of a heroin conjugate vaccine, we systematically explored 20 vaccine formulations with varying combinations of carrier proteins and adjuvants. In regard to adjuvants, we explored a Toll-like receptor 9 (TLR9) agonist and a TLR3 agonist in the presence of alum. The TLR9 agonist was cytosine-guanine oligodeoxynucleotide 1826 (CpG ODN 1826), while the TLR3 agonist was virus-derived genomic doubled-stranded RNA (dsRNA). The vaccine formulations containing TLR3 or TLR9 agonist alone elicited strong antiheroin antibody titers and blockade of heroin-induced antinociception when formulated with alum; however, a combination of TLR3 and TLR9 adjuvants did not result in improved efficacy. Investigation of month-long stability of the two lead formulations revealed that the TLR9 but not the TLR3 formulation was stable when stored as a lyophilized solid or as a liquid over 30 days. Furthermore, mice immunized with the TLR9 + alum heroin vaccine gained significant protection from lethal heroin doses, suggesting that this vaccine formulation is suitable for mitigating the harmful effects of heroin, even following month-long storage at room temperature.
Assuntos
Analgésicos Opioides/farmacologia , Overdose de Drogas/prevenção & controle , Dependência de Heroína/complicações , Heroína/farmacologia , Vacinas Conjugadas/farmacologia , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Analgésicos Opioides/química , Animais , Modelos Animais de Doenças , Overdose de Drogas/etiologia , Heroína/química , Humanos , Masculino , Camundongos , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/farmacologia , Receptor 3 Toll-Like/agonistas , Receptor Toll-Like 9/agonistas , Vacinação/métodos , Vacinas Conjugadas/químicaRESUMO
RNA polymerase II (pol II) utilizes a complex interaction network to select and incorporate correct nucleoside triphosphate (NTP) substrates with high efficiency and fidelity. Our previous 'synthetic nucleic acid substitution' strategy has been successfully applied in dissecting the function of nucleic acid moieties in pol II transcription. However, how the triphosphate moiety of substrate influences the rate of P-O bond cleavage and formation during nucleotide incorporation is still unclear. Here, by employing ß,γ-bridging atom-'substituted' NTPs, we elucidate how the methylene substitution in the pyrophosphate leaving group affects cognate and non-cognate nucleotide incorporation. Intriguingly, the effect of the ß,γ-methylene substitution on the non-cognate UTP/dT scaffold (â¼3-fold decrease in kpol) is significantly different from that of the cognate ATP/dT scaffold (â¼130-fold decrease in kpol). Removal of the wobble hydrogen bonds in U:dT recovers a strong response to methylene substitution of UTP. Our kinetic and modeling studies are consistent with a unique altered transition state for bond formation and cleavage for UTP/dT incorporation compared with ATP/dT incorporation. Collectively, our data reveals the functional interplay between NTP triphosphate moiety and base pair hydrogen bonding recognition during nucleotide incorporation.
Assuntos
Nucleotídeos/metabolismo , RNA Polimerase II/metabolismo , Pareamento de Bases , Domínio Catalítico , Ligação de Hidrogênio , Cinética , Modelos Moleculares , Nucleotídeos/química , Ligação Proteica , RNA/química , RNA/metabolismo , RNA Polimerase II/química , Uridina Monofosfato/metabolismoRESUMO
Jakeman et al. recently reported the inability to distinguish the diastereomers of uridine 5'-ß,γ-fluoromethylenetriphosphate (ß,γ-CHF-UTP, 1) by (19)F NMR under conditions we previously prescribed for the resolution of the corresponding ß,γ-CHF-dGTP spectra, stating further that 1 decomposed under these basic conditions. Here we show that the (19)F NMR spectra of 1 (~1:1 diastereomer mixture prepared by coupling of UMP-morpholidate with fluoromethylenebis(phosphonic acid)) in D2O at pH 10 are indeed readily distinguishable. 1 in this solution was stable for 24 h at rt.
Assuntos
Nucleotídeos de Desoxiguanina/química , Flúor/química , Nucleotídeos de Uracila/química , Uridina/química , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Modelos Moleculares , EstereoisomerismoRESUMO
Reduction of the first known halogen-containing substrate by nitrogenase (N2ase), 3,3-difluorocyclopropene (DFCP), was investigated. Reduction requires both N2ase proteins (MoFe and Fe protein), ATP, and an exogenous reductant (dithionite, DT), as with N2 and known alternative substrates of the enzyme. Two major products providing evidence for reductive C-F bond cleavage were confirmed, propene (P1, requiring 6e(-)/6H(+)) and 2-fluoropropene (P2, 4e(-)/4H(+)). Both were identified by GC-MS and NMR spectroscopy, and had the same Km constants (0.022 atm, 5.4 mM). Reduction of 1,2-dideuterated DFCP (d2-DFCP) further revealed that (i) in both P1 and P2, two deuterium atoms are retained, one on carbon-1 and one on carbon-3, indicating that CâC bond cleavage rather than C-C bond cleavage is involved during DFCP reduction at least to P2 (assuming no F migration); (ii) no selectivity was observed in formation of cis and trans isomers of 1,3-d2-2-fluoropropene, whereas cis-1,3-d2-propene is the predominant 1,3-d2-propene product, indicating that one of the bound reduction intermediates on the pathway to propene is constrained geometrically. A reduction mechanism, consistent with hydride transfer as a key step, is discussed. Reductive C-F bond cleavage is an ability of N2ase that further demonstrates the unique and remarkable scope of its catalytic prowess.
Assuntos
Ciclopropanos/metabolismo , Nitrogenase/metabolismo , Ciclopropanos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Nitrogenase/química , OxirreduçãoAssuntos
Analgésicos Opioides/efeitos adversos , Descoberta de Drogas/tendências , Epidemias/prevenção & controle , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Vacinas/administração & dosagem , Analgésicos Opioides/metabolismo , Animais , Descoberta de Drogas/métodos , Humanos , Transtornos Relacionados ao Uso de Opioides/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo , Vacinas/metabolismoRESUMO
Anti-drug vaccines have potential as new interventions against substance use disorder (SUD). However, given the challenges seen with inter-individual variability in SUD vaccine trials to date, new interventions should ensure a robust immune response and safety profile among a diverse population. This requires accounting for sex and heritable genetic differences in response to both abused substances as well as the vaccination itself. To test response variability to our heroin-tetanus toxoid (Her-TT) immunoconjugate vaccine, we vaccinated male and female mice from several mouse strains including Swiss Webster (SW), BALB/c, and Jackson diversity mice (J:DO). Previous studies with vaccinated male SW mice demonstrated a rare hypersensitivity resulting in mice rapidly expiring with exposure to a low dose of heroin. Our results indicate that this response is limited to only male SW mice, and not to any other strain or female SW mice. Our data suggest that this hypersensitivity is not the result of an overactive cytokine or IgE response. Vaccination was similarly effective among the sexes for each strain and against repeated heroin challenge. Inbred BALB/c and J:DO mice were found to have the best vaccine response against heroin in antinociception behavioral assay. These results highlight the importance of incorporating both male and female subjects, along with different strains to mimic diverse human populations, as new SUD vaccines are being tested.
Assuntos
Heroína/uso terapêutico , Toxoide Tetânico/uso terapêutico , Vacinas Conjugadas/uso terapêutico , Animais , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fatores Sexuais , Vacinação/métodosRESUMO
Growing nonmedical use of prescription opioids is a global problem, motivating research on ways to reduce use and combat addiction. Medical cannabis ("medical marijuana") legalization has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of opioids in animal models. This study was conducted to determine if Δ9-tetrahydrocannabinol (THC) enhances the behavioral effects of oxycodone. Male rats were trained to intravenously self-administer (IVSA) oxycodone (0.15â¯mg/kg/infusion) during 1â¯h, 4â¯h or 8â¯h sessions. Following acquisition rats were exposed to THC by vapor inhalation (1â¯h and 8â¯h groups) or injection (0-10â¯mg/kg, i.p.; all groups) prior to IVSA sessions. Fewer oxycodone infusions were obtained by rats following vaporized or injected THC compared with vehicle treatment prior to the session. Follow-up studies demonstrated parallel dose-dependent effects of THC, i.p., on self-administration of different per-infusion doses of oxycodone and a preserved loading dose early in the session. These patterns are inconsistent with behavioral suppression. Additional groups of male and female Wistar rats were assessed for nociception following inhalation of vaporized THC (50â¯mg/mL), oxycodone (100â¯mg/mL) or the combination. Tail withdrawal latency was increased more by the THC/oxycodone combination compared to either drug alone. Similar additive antinociceptive effects were produced by injection of THC (5.0â¯mg/kg, i.p.) and oxycodone (2.0â¯mg/kg, s.c.). Together these data demonstrate additive effects of THC and oxycodone and suggest the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids.
Assuntos
Analgésicos Opioides/administração & dosagem , Canabinoides/farmacologia , Dronabinol/farmacologia , Nociceptividade/efeitos dos fármacos , Oxicodona/administração & dosagem , Animais , Feminino , Masculino , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , AutoadministraçãoRESUMO
The current opioid crisis remains a significant public health issue and there is a critical need for biomedical research to develop effective and easily deployable candidate treatments. One emerging treatment strategy for opioid use disorder includes immunopharmacotherapies or opioid-targeted vaccines. The present study determined the effectiveness of a fentanyl-tetanus toxoid conjugate vaccine to alter fentanyl self-administration using a fentanyl-vs.-food choice procedure in male and female rats under three experimental conditions. For comparison, continuous 7-day naltrexone (0.01-0.1 mg/kg/h) and 7-day clonidine (3.2-10 µg/kg/h) treatment effects were also determined on fentanyl-vs.-food choice. Male and female rats responded for concurrently available 18% diluted Ensure® (liquid food) and fentanyl (0-10 µg/kg/infusion) infusions during daily sessions. Under baseline and saline treatment conditions, fentanyl maintained a dose-dependent increase in fentanyl-vs.-food choice. First, fentanyl vaccine administration significantly blunted fentanyl reinforcement and increased food reinforcement for 15 weeks in non-opioid dependent rats. Second, surmountability experiments by increasing the unit fentanyl dose available during the self-administration session 10-fold empirically determined that the fentanyl vaccine produced an approximate 22-fold potency shift in fentanyl-vs.-food choice that was as effective as the clinically approved treatment naltrexone. Clonidine treatment significantly increased fentanyl-vs.-food choice. Lastly, fentanyl vaccine administration prevented the expression of withdrawal-associated increases in fentanyl-vs.-food choice following introduction of extended 12 h fentanyl access sessions. Overall, these results support the potential and further consideration of immunopharmacotherapies as candidate treatments to address the current opioid crisis.
Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/imunologia , Comportamento Animal/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Fentanila/administração & dosagem , Fentanila/imunologia , Vacinas Conjugadas/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Clonidina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Feminino , Alimentos , Masculino , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides , Ratos , Reforço Psicológico , Autoadministração , Síndrome de Abstinência a Substâncias/fisiopatologia , Toxoide TetânicoRESUMO
One proposed factor contributing to the increased frequency of opioid overdose deaths is the emergence of novel synthetic opioids, including illicit fentanyl and fentanyl analogues. A treatment strategy currently under development to address the ongoing opioid crisis is immunopharmacotherapies or opioid-targeted vaccines. The present study determined the effectiveness and selectivity of a fentanyl-tetanus toxoid conjugate vaccine to alter the behavioral effects of fentanyl and a structurally dissimilar mu-opioid agonist oxycodone in male rhesus monkeys (nâ¯=â¯3-4). Fentanyl and oxycodone produced dose-dependent suppression of behavior in an assay of schedule-controlled responding and antinociception in an assay of thermal nociception (50⯰C). Acute naltrexone (0.032â¯mg/kg) produced an approximate 10-fold potency shift for fentanyl to decrease operant responding. The fentanyl vaccine was administered at weeks 0, 2, 4, 9, 19, and 44 and fentanyl or oxycodone potencies in both behavioral assays were redetermined over the course of 49 weeks. The vaccine significantly and selectively shifted fentanyl potency at least 10-fold in both assays at several time points over the entire experimental period. Mid-point titer levels correlated with fentanyl antinociceptive potency shifts. Antibody affinity for fentanyl as measured by a competitive binding assay improved over time to approximately 3-4â¯nM. The fentanyl vaccine also increased fentanyl plasma levels approximately 6-fold consistent with the hypothesis that the vaccine sequesters fentanyl in the blood. Overall, these results support the continued development and evaluation of this fentanyl vaccine in humans to address the ongoing opioid crisis.
Assuntos
Analgésicos Opioides/imunologia , Fentanila/imunologia , Oxicodona/farmacologia , Toxoide Tetânico/imunologia , Vacinas Conjugadas/imunologia , Analgésicos Opioides/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fentanila/farmacologia , Macaca mulatta , Masculino , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Nociceptividade/efeitos dos fármacos , Receptores Opioides mu , Toxoide Tetânico/farmacologia , Vacinas/imunologia , Vacinas/farmacologia , Vacinas Conjugadas/farmacologiaRESUMO
Abuse of prescription opioids is a growing public health crisis in the United States, with drug overdose deaths increasing dramatically over the past 15 years. Few preclinical studies exist on the reinforcing effects of oxycodone or on the development of therapies for oxycodone abuse. This study was conducted to determine if immunopharmacotherapy directed against oxycodone would be capable of altering oxycodone-induced antinociception and intravenous self-administration. Male Wistar rats were administered a small-molecule immunoconjugate vaccine (Oxy-TT) or the control carrier protein, tetanus toxoid (TT), and trained to intravenously self-administer oxycodone (0.06 or 0.15â¯mg/kg/infusion). Brain oxycodone concentrations were 50% lower in Oxy-TT rats compared to TT rats 30â¯min after injection (1â¯mg/kg, s.c.) whereas plasma oxycodone was 15-fold higher from drug sequestration by circulating antibodies. Oxy-TT rats were also less sensitive to 1-2â¯mg/kg, s.c. oxycodone on a hot water nociception assay. Half of the Oxy-TT rats failed to acquire intravenous self-administration under the 0.06â¯mg/kg/infusion training dose. Oxycodone self-administration of Oxy-TT rats trained on 0.15â¯mg/kg/infusion was higher than controls; however under progressive ratio (PR) conditions the Oxy-TT rats decreased their oxycodone intake, unlike TT controls. These data demonstrate that active vaccination provides protection against the reinforcing effects of oxycodone. Anti-oxycodone vaccines may entirely prevent repeated use in some individuals who otherwise would become addicted. Vaccination may also reduce dependence in those who become addicted and therefore facilitate the effects of other therapeutic interventions which either increase the difficulty of drug use or incentivize other behaviors.
Assuntos
Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Vacinação , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento de Procura de Droga , Imunoconjugados , Masculino , Motivação , Nociceptividade/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides/metabolismo , Oxicodona/administração & dosagem , Oxicodona/metabolismo , Ratos Wistar , AutoadministraçãoRESUMO
Fentanyl and its derivatives have become pervasive contaminants in the U.S. heroin supply. Previously, we reported a proof-of-concept vaccine designed to combat against heroin contaminated with fentanyl. Herein, we optimized the admixture vaccine and found that it surpassed the individual vaccines in every antinociceptive test, including a 10% fentanyl to heroin formulation. It is anticipated that other co-occurring drug abuse disorders may also be examined with admixture vaccines.
RESUMO
The sharp increase in overdose deaths involving illicit opioid use has been declared a national crisis in the United States. This growing number of overdose deaths can in part be attributed to the increased frequency of fentanyl contamination in the United States heroin supply. To combat this growing trend, we designed a vaccine containing a mixture of heroin and fentanyl hapten-conjugates as a proof-of-concept immunotherapy targeting a combination of these drugs. Rodents immunized with the admixture vaccine showed drug retention in serum and reduced distribution in the brain after administration of an intravenous bolus of heroin coadministered with fentanyl (10% w/w). Moreover, the admixture vaccine performed as well as or better than individual immunoconjugate vaccines in antinociception behavioral models and recognized six other fentanyl analogues with nanomolar affinity. Taken together, these data highlight the potential of an admixture vaccine against heroin contaminated with fentanyl.
Assuntos
Fentanila/imunologia , Heroína/imunologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Vacinas/uso terapêutico , Analgésicos Opioides/efeitos adversos , Animais , Overdose de Drogas/prevenção & controle , Feminino , Camundongos Endogâmicos BALB CRESUMO
The first preparation of the individual ß,γ-CHF-ATP stereoisomers 12a and 12b is reported. Configurationally differing solely by the orientation of the C-F fluorine, 12a and 12b have discrete (31)P (202 MHz, pH 10.9, ΔδPα 6 Hz, ΔδPß 4 Hz) and (19)F NMR (470 MHz, pH 9.8, ΔδF 25 Hz) spectral signatures and exhibit a 6-fold difference in IC50 values for c-Src kinase, attributed to a unique interaction of the (S)-fluorine of bound 12b with R388 in the active site.