Existem vArias evidências exPerimentais e clinicas de que os Opióides Endógenos exercem um papel importante no controle cardiovascular. Com o objetivo de avaliaa influência destes peptideos, liberados durante o exercicio, sobre as respostas cardiovasculares, metabólicas e da percepção do esforco ao exercicio sub-màximo, foi administrado um antagonista opióide: Naloxone (14 mg), de maneira duplo-cega e, á 10 jovens normais, não treinados. Os individuas pedalaram durante 60 minutos, divididos em três estàgios de 20 minutos sob cargas que atingiram . (médias ± DP) 48 ± 7, 62 ± 4 e 83 ± 5% da frequência cardiaca màxima, aferida em teste màximo prévio. A avaliacâo da funcâo ventricular foi realizada por estudo eco-Dopplercardiogràfico obtido nos cinco minutos finais de cada estAgio. Durante os testes submàximos, ocorreu aumento significativo da pressão arterial sistólica, da frequência cardiaca. da percepção do esforco e do lactato sanguineo. A percepcâo do esforco. aferida através da escala de Borg, não foi diferente quando da administracâo de Naloxone A funcâo sistólica do ventriculo esquerdo, avaliada pelo volume sistólico e pela fracâo de encurtamento estimados pela ecocardiografia mono-dimensional, apresentou aumento significativo com o exercicio. Não houve correlacâo significativa entre a integral total do fluxo trans-mitral, calculada por planimetria, e o volume sistólico. Houve uma diminuição progressiva dos diâmetros diast6licos e dos diâmetros sistõlicos ventricular esquerdo do repouso em relação aos 60 minutos de esforco. A funcâo diastolica do ventriculo esquerdo, avaliada pela velocidade màxima de enchimento (pico "E") do fluxo trans-mitral e a taxa de enchimento màximo normalizada para o volume sistólico, aumentou progressivamente durante o exercicio. A curva bifàsica do fluxo trans-mitral tornou-se monofàsica com a diminuicâo do periodo diastolico. A administração de Naloxone não alterou as respostas das variàveis estudadas ao exercicio (ANOVA). Portanto, o presente estudo demonstra que o Naloxone , mesmo em altas doses, nâo modifica as respostas hemodinãmicas, metabõlicas e de Percepção do esforco em jovens normais submetidos a este protocolo de exercicio.

Opioid addiction is a serious national crisis impacting public health. Naloxone is a potent opioid antagonist administered to reverse the effects of opioid overdose. It is currently administered as an intravenous, intramuscular, subcutaneous injection and intranasal spray. The short duration of action of naloxone results in requirement of frequent re-dosing, especially in cases of larger overdoses, which may impact successful outcomes, especially when drug administration is provided by non-medical personnel as in case of intranasal sprays. These weaknesses necessitate the development of a non-injectable dosage form that has a rapid onset and extended duration of action. Delivery of drugs via skin is an attractive alternative that provides these benefits. Our study aimed to assess the effect of microneedles on the amount and lag time of permeation of naloxone across skin. In vitro permeation studies were performed to assess the delivery of naloxone through dermatomed porcine ear skin using Franz Diffusion cells. The donor and receptor chamber of the cells contained the drug solution and phosphate buffered saline, respectively. The receptor was sampled until 6 h and analyzed using HPLC. The permeation of naloxone across intact (passive) and microneedle-treated (Dr. Pen™ Ultima A6) skin was evaluated. Two microporation conditions with donor concentration of 10 mg/mL were investigated: needle lengths (500 µm and 250 µm) for 1 minute and 500 µm needle length for different durations (1 and 2 minutes). Further, the effect of application of different naloxone concentrations (10 and 20 mg/mL) on skin treated with 500 µm microneedles for 2 minutes was also tested. One-way ANOVA was applied to ascertain statistical difference between the different test groups. The amount of passive permeation after 6 h and lag time for naloxone was observed to be 8.251.06 µg/cm2 and88.58 ± 3.05 min, respectively. One minute treatment with 500 µm needles significantly enhanced the permeation to 463.24 ± 30.21 µg/cm2 and reduced the lag time to 15.90 ± 1.63 min (p0.05). Microneedles were found to enhance the permeation of naloxone across skin. The observation of quick onset of drug permeation in the in vitro settings is very encouraging and future studies would focus on developing a microneedle patch for quick onset and extended drug release.

E-rosette formation by human lymphocytes incubated with sheep red blood cells (sRBC) is inhibited by morphine. We studied the ability of the opiate antagonists naloxone and Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) to block this action. Active E-rosette formation by lymphocytes incubated with morphine was reduced from the control of 35.7±1.7% to 23.7±1.5% (p<0.001). Similarly, total E-rosette formation was reduced by morphine from the control of 65.8±1.3% to 53.2±2.9% (p<0.001). These effects were blocked by co-incubation of the lymphocytes with either Tyr-MIF-1 or naloxone (p<0.05). Tyr-MIF-1 was active (p<0.05) at concentrations as dilute as 10-13M. These results indicate that the neuropeptide Tyr-MIF-1 exerts an antiopiate effect at the human T-lymphocyte.

Naloxone (NAL) is administered parenterally or intranasally for treating opioid overdose. The short duration of action of NAL calls for frequent re-dosing which may be eliminated by the development of a transdermal system. This study aimed to assess the effect of microneedles on improving the skin permeation of NAL hydrochloride. In vitro permeation of NAL across intact and microneedle-treated (Dr. Pen™ Ultima A6) porcine skin was evaluated. The effect of microneedle length and application duration, and donor concentration on NAL permeation were investigated. In-vitro in-vivo correlation of the permeation results was done to predict the plasma concentration kinetics of NAL in patients. In vitro passive permeation of NAL after 6 h was observed to be 8.25±1.06 µg/cm2. A 56- and 37-fold enhancement was observed with 500 and 250 µm needles applied for 1 min, respectively. Application of 500 µm MNs for 2 min significantly reduced the lag time to ~ 8 min and increasing the donor concentration for the same treatment group doubled the permeation (p < 0.05). Modeling simulations demonstrated the attainment of pharmacokinetic profile of NAL comparable to those obtained with the FDA-approved intramuscular and intranasal devices. Microneedle-mediated transdermal delivery holds potential for rapid and sustained NAL delivery for opioid overdose treatment.

Indiana University-Purdue University Indianapolis (IUPUI) / Deaths due to prescription painkillers and heroin have quickly become national, state, and local public health concerns. Studies using data from Medical Examiners or Coroner Offices throughout the United States have been conducted and are contributing to the understanding of this epidemic. However, the analysis of these fatalities are specific to the communities where the study was conducted and cannot be assumed that the decedents in one community are similar to decedents in another community. Many local governments and agencies throughout the U.S. are aware that this problem exists in their communities, but are not prepared to adequately respond to and intervene in these fatalities as an analysis of those who have died has rarely been conducted. This dissertation is a replication study of longitudinal epidemiological analyses of opiate related fatalities that was implemented in a location where an analysis of opiate-related fatalities had not been conducted, Marion County, Indiana. The purpose of the dissertation was twofold: (1) to describe the demographic characteristics of the decedents using publicly available data from the Marion County Coroner’s Office to be used in informing future preventative efforts to decrease opiate-related fatalities in Marion County and (2) to inform other communities on how to conduct a similar analysis in their own community. This dissertation describes the methods of the replication study, provides descriptive results of the people who died from opiate-related overdoses, and: (a) Report the types of opiates identified in blood toxicology reports and (b) Present the histories of opiate-related decedents as reported in the Deputy Coroner Field Officer’s Reports (DCFOR). Additionally, analysis was conducted to determine if decedent characteristics deferred depending on the type of opiate fatality based on the toxicology in 1) heroin alone, 2) painkillers alone, and 3) heroin and painkillers combined.

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Because endorphin receptor activation alters the function of the central noradrenergic system, opiates may change the regenerative sprouting of neurons in response to adrenergic neurotoxins. To test this hypothesis, newborn rats were treated with several opioids and 6-hydroxydopa (6-OHDOPA) and the development of the noradrenergic system was evaluated. In combination with 6-OHDOPA morphine and naloxone potentiated the development of norepinephrine (NE) levels in the pons-medulla and cerebellum by four weeks of age. β-Endorphin, Leu- and Met-enkephalin and d-Ala2-enkephalinamide produced a similar effect in the pons-medulla. The effect of morphine was partially attenuated by naloxone. Increased cerebellar noradrenergic histofluorescent staining was observed with the morphine + 6-OHDOPA and naloxone + 6-OHDOPA treatments. Both naloxone and morphine decreased NE levels in the pons-medulla of adult rats treated with 6-OHDOPA. These results suggest that opiates and endorphins may enhance sprouting of noradrenergic neurons following neonatal treatment with 6-OHDOPA, by increasing the toxicity of this neurotoxin.

Four experiments were conducted to investigate the effect of naloxone, an opioid receptor antagonist, on pituitary LH secretion in Holstein cows during two periods after parturition and two phases of the estrous cycle. In experiment 1, 24 cows (12 primiparous; 12 multiparous) received either saline (n = 12) or 1 mg/kg naloxone (n = 12) i. v. at 14 1 days postpartum. Blood samples were collected at 15-minute intervals for 2 hours before and 2.5 hours after naloxone or saline. Serum LH concentrations increased (P < .05) in response to naloxone injection in both primi- and multiparous cows. Saline injection did not affect LH concentrations. In experiment 2, 27 cows (13 primiparous; 14 multiparous) received either saline (n=14) or 1 mg/kg naloxone (n=13) i. v. at 28 ± 1 days postpartum. Blood samples were collected as in the previous experiment. Naloxone did not affect serum LH concentrations in either primi- or multi-parous cows at 28 days postpartum. In experiment 3, estrous cycles were synchronized via prostaglandin administration (25 mg) in 22 cows (10 primiparous; 12 multiparous). Cows received either saline (n=11) or 1 mg/kg naloxone (n=11) Lv. during the luteal phase of the estrous cycle. Blood samples were collected as in the previous experiments. Luteinizing hormone concentrations were not affected by naloxone in either primi- or multi-parous cows during the luteal phase of the estrous cycle. In experiment 4, the same cows used in experiment 3 received a second dose of prostaglandin (25 mg). Thirty-six hours later, during the follicular phase of the estrous cycle, the cows received either saline (n =9) or 1 mg/kg naloxone (n = 11) i. v. Naloxone increased (P < .05) serum LH concentrations in both primi- and multi-parous cows in the follicular phase. These results suggest that LH release in the early postpartum dairy cow is regulated, at least in part, by endogenous opioid pep tides , and the ability of naloxone to affect LH secretion may change as days postpartum increases, perhaps due to changes in degree of inhibition by endogenous opioid peptides, and (or) changes in serum progesterone concentration due to onset of ovarian activity during postpartum period. It appears that the modulation of LH secretion may be mediated via opioids during the follicular phase of the estrous cycle. However, an opioid-mediated mechanism for modulation of LH secretion was absent or overridden by progesterone feedback during the luteal phase of the estrous cycle. / Master of Science

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