Thesis (Ph. D.)--University of Texas at Austin, 2002. / Vita. Includes bibliographical references. Available also from UMI Company.

Thesis (Ph. D.)--Virginia Commonwealth University, 2006. / Prepared for: Dept. of Pharmaceutics. Bibliography: leaves 163-178. Also available online.

This diploma thesis deals with preparation of modified ligands of mu, delta and kappa opioid receptors, following up on the author's bachelor's thesis.1 The main goal of the submitted thesis is ligand tethering at an appropriate position using oligoethylene glycol linkers, to enable their use in the innovative iBodies concept.2 Ligands chosen for modifications were: naltrexone (μ-opioid receptor), naltrindole (δ-opioid receptor) and nalfurafine (κ-opioid receptor). Naltrexone was modified, according to the bachelor's thesis results, at the C-6 position with linker attachment via ether and amide. At the same time, the influence of the configuration at the newly formed C-6 stereogenic center on biological activity was studied. In case of naltrindole, access through indole nitrogen was chosen based on the information in literature.3-5 Nalfurafine was modified on the furane fragment. Series of fluorescently labeled ligands were prepared. Attachment of the fluorescent tag allowed us to study the affinity and selectivity of these modified ligands. Based on the results, ligands for development of DIANA method and for preparation of synthetic iBodies were synthesised.6 Key words: naltrexone, receptor, conjugate, opioid receptor 1 M. Hadzima. Fluorescenčně značené ligandy μ-opioidních receptorů, 2016. 2 P....

This study examined the state of the literature on the effectiveness of medication assisted treatment (MAT; methadone, buprenorphine, naltrexone) delivered in prisons and jails on community substance use treatment engagement, opioid use, recidivism, and health risk behaviors following release from incarceration. Randomized controlled trials (RCTs) and quasi-experimental studies published through December 2017 that examined induction to or maintenance on methadone (n = 18 studies), buprenorphine (n = 3 studies), or naltrexone (n = 3 studies) in correctional settings were identified from PsycINFO and PubMed databases. There were a sufficient number of methadone RCTs to meta-analyze; there were too few buprenorphine or naltrexone studies. All quasi-experimental studies were systematically reviewed. Data from RCTs involving 807 inmates (treatment n = 407, control n = 400) showed that methadone provided during incarceration increased community treatment engagement (n = 3 studies; OR = 8.69, 95% CI = 2.46; 30.75), reduced illicit opioid use (n = 4 studies; OR = 0.22, 95% CI = 0.15; 0.32) and injection drug use (n = 3 studies; OR = 0.26, 95% CI = 0.12; 0.56), but did not reduce recidivism (n = 4 studies; OR = 0.93, 95% CI = 0.51; 1.68). Data from observational studies of methadone showed consistent findings. Individual review of buprenorphine and naltrexone studies showed these medications were either superior to methadone or to placebo, or were as effective as methadone in reducing illicit opioid use post-release. Results provide the first meta-analytic summary of MATs delivered in correctional settings and support the use of MATs, especially with regard to community substance use treatment engagement and opioid use; additional work is needed to understand the reduction of recidivism and other health risk behaviors.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Microneedles are a minimally invasive method for delivering drugs through the impermeable skin layers, and have been used to deliver a variety of compounds including macromolecules, vaccines, and naltrexone. Microneedles can be applied to the skin once, creating micropores that allow for drug delivery into the underlying circulation from a drug formulation. The utility of this technique, however, is blunted by rapid micropore closure. This research project sought to: 1) characterize micropore lifetime and re-sealing kinetics, and 2) prolong micropore lifetime via inhibition of the skin’s barrier restoration processes. Impedance spectroscopy was used as a surrogate technique in animals and humans to measure micropore formation and lifetime. A proof of concept study in humans, using impedance spectroscopy, demonstrated that diclofenac (a topical anti-inflammatory) applied to microporated skin resulted in slower re-sealing kinetics compared to placebo, in agreement with previous animal studies. The clinical feasibility of prolonging micropore lifetime with diclofenac was confirmed via 7-day delivery of naltrexone through microneedle treated skin in humans (compared to 72 hour delivery with placebo). Lastly, naltrexone gels with calcium salts were applied to microneedle treated skin (hairless guinea pigs) to restore the altered epidermal calcium gradient; this method did not significantly extend micropore lifetime.

Microneedle (MN) enhanced drug delivery is a safe, effective and efficient enhancement method for delivery of drug molecules across the skin. The “poke (press) and patch” approach employs solid stainless steel MN to permeablize the skin prior to application of a regular drug patch over the treated area. It has been previously shown that MN can be used to deliver naltrexone (NTX) at a rate that provides plasma concentrations in the lower end of the therapeutic range in humans. The drug delivery potential of this technique is, however, limited by the re-sealing of the micropores in a 48-72h timeframe. The goal of the current research was to optimize the formulation for a 7 day MN enhanced delivery system for NTX either by adding a second active pharmacological moiety or by optimizing formulation characteristics alone. Three different formulation strategies were explored: formulation pH optimization with NTX; a codrug approach with NTX and a nonspecific cyclooxygenase inhibitor, diclofenac (DIC); and a topical/transdermal approach with NTX and an enzyme inhibitor of the cholesterol synthesis pathway, fluvastatin (FLU). The results indicated that formulation pH cannot be used to extend micropore lifetime, although formulation optimization leads to enhanced transport and thus drug delivery across MN treated skin. The codrug approach was successful in extending the micropore lifetime and further screening of codrug structures and formulation optimization helped in selection of a codrug candidate suitable for evaluation in animal pharmacokinetic studies. Local treatment with FLU helped to keep the micropores open and enabled delivery of NTX for an extended period. The pores re-sealed on removal of treatment within a 30-45 minute timeframe, indicating that infection/irritation should not be a major issue, as in the case of other topical chemical enhancers. Thus, overall it can be concluded that different formulation strategies can be utilized to extend micropore lifetime and enhance delivery of drug molecules across the skin.

Drug self-administration has proven to be an adequate model for assessing variables that contribute to the maintenance of drug taking. The present experiment was concerned with the persistence of drug self-administration, a defining characteristic of drug dependence and abuse. Findings from studies of the resistance to change of food-maintained responding may contribute to a better understanding of the persistence of drug abuse and dependence. Using an animal model of alcohol self-administration, this study evaluated the effects of rate of reinforcement on the persistence of ethanol self-administration in rats in the face of behavioral (i.e., extinction) and pharmacological (i.e., naltrexone) disruptors. Four experimentally naive Long Evans rats were trained to respond for a 10% (vol/vol) ethanol solution on a multiple variable-interval (VI) 15-s VI 45-s schedule of reinforcement. Baseline response rates were higher in the component that provided higher rates of ethanol delivery. Consistent with behavioral momentum theory, responding was more resistant to extinction in the component with higher rates of ethanol delivery. Conversely, disruption with naltrexone (1.0, 3.0, 10.0 mg/kg, s.c.), injected one hour before the session, resulted in no differential resistance to change of responding. The results are interpreted in terms of the effect of naltrexone on the incentive-motivational properties of the stimulus context.

Opioid dependence is a complex and persistent disorder with a high mortality rate and severe impact on health and social situation. It is associated with much harm, including the transmission of blood-borne bacterial and viral infections, self-harm, traumatic injury and drug overdose. All of these harms carry a risk of death, and accordingly, mortality rates in opioid-dependent people are many times higher than those in the general population of the same age and sex. One of the more commonly used strategies for reducing the risks of opioid dependence is the provision of maintenance treatment. In Australia, available maintenance treatments include methadone, buprenorphine, oral naltrexone, and the unregistered sustained-release formulation of naltrexone, naltrexone implants. This thesis reports on a range of data collections and study designs to investigate the levels, predictors and causes of mortality in opioid-dependent persons entering methadone, buprenorphine and naltrexone maintenance treatment in Australia. The studies used data linkage to examine mortality rates and causes of death in a longitudinal cohort of the early entrants to the NSW methadone program, examined the predictors of mortality (particularly the impact of methadone and buprenorphine treatment) using survival analysis in a longitudinal cohort study, compared national mortality rates between methadone, buprenorphine and naltrexone maintenance treatments in a cross-sectional analytic study, and used a small case series of coronial cases to examine whether death from opioid overdose was possible in a recipient of a naltrexone implant. This thesis demonstrates that mortality rates as a whole and from particular causes of death are many times higher in Australian opioid-dependent subjects than the general population, exposure to methadone or buprenorphine maintenance treatment significantly reduced mortality in a sample of opioid-dependent subjects, naltrexone treatment appears to have higher mortality than both methadone and buprenorphine maintenance treatments, and fatal opioid overdose while in receipt of sustained-release naltrexone treatment is possible. These results support longer retention in and repeated access to methadone and buprenorphine maintenance treatments in order to reduce mortality in opioid-dependent people, and greater regulation of the access to and more rigorous monitoring of the mortality associated with oral and sustained-release naltrexone maintenance treatments.

Opioid dependence is a complex and persistent disorder with a high mortality rate and severe impact on health and social situation. It is associated with much harm, including the transmission of blood-borne bacterial and viral infections, self-harm, traumatic injury and drug overdose. All of these harms carry a risk of death, and accordingly, mortality rates in opioid-dependent people are many times higher than those in the general population of the same age and sex. One of the more commonly used strategies for reducing the risks of opioid dependence is the provision of maintenance treatment. In Australia, available maintenance treatments include methadone, buprenorphine, oral naltrexone, and the unregistered sustained-release formulation of naltrexone, naltrexone implants. This thesis reports on a range of data collections and study designs to investigate the levels, predictors and causes of mortality in opioid-dependent persons entering methadone, buprenorphine and naltrexone maintenance treatment in Australia. The studies used data linkage to examine mortality rates and causes of death in a longitudinal cohort of the early entrants to the NSW methadone program, examined the predictors of mortality (particularly the impact of methadone and buprenorphine treatment) using survival analysis in a longitudinal cohort study, compared national mortality rates between methadone, buprenorphine and naltrexone maintenance treatments in a cross-sectional analytic study, and used a small case series of coronial cases to examine whether death from opioid overdose was possible in a recipient of a naltrexone implant. This thesis demonstrates that mortality rates as a whole and from particular causes of death are many times higher in Australian opioid-dependent subjects than the general population, exposure to methadone or buprenorphine maintenance treatment significantly reduced mortality in a sample of opioid-dependent subjects, naltrexone treatment appears to have higher mortality than both methadone and buprenorphine maintenance treatments, and fatal opioid overdose while in receipt of sustained-release naltrexone treatment is possible. These results support longer retention in and repeated access to methadone and buprenorphine maintenance treatments in order to reduce mortality in opioid-dependent people, and greater regulation of the access to and more rigorous monitoring of the mortality associated with oral and sustained-release naltrexone maintenance treatments.