The use and abuse of fentanyl has risen drastically over the last several decades. The abuse of this substance has created a hazardous situation for law enforcement and first responders because they could arrive at locations and not necessarily know that they will encounter fentanyl or a fentanly analog. Fentanyl analogs are substances that have a similar structure to fentanyl, and while the analogs may have additional or altered groups on the molecule, the backbone structure remains the similar. This work focuses on the electrochemical characterization of fentanyl as a stepping stone for the detection of both fentanyl and later fentanyl analogs by electrochemistry. The metabolic reaction of fentanyl is an N-dealkylation to norfentanyl, occurring in the liver, and can be mimicked by electrochemistry through the irreversible oxidation of fentanyl. This electrochemical reaction is hypothesized to generate electroactive metabolites in solution. The combination of the visualization of both the irreversible oxidation with the development of the additional metabolic redox peaks would constitute a unique electrochemical signiture for fentanyl and fentanyl analogs towards a universal rapid screening assay. The electrochemical behavior of fentanyl was characterized in depth using multiple electrochemical techniques such as cyclic voltammetry (CV), square wave voltammetry (SWV), and differential pulse voltammetry (DPV). The optimization of the supporting electrolyte, the potential range, and methods to decrease the background current were explored with CV. To work toward a more portable system, screen printed electrodes were used. The observation of the metabolic peaks remained challenging, and different methods were attempted to achieve it. The quantification of fentanyl was successfully demonstrated using the different electrochemical systems proposed in this work. The electrochemical characterization of fentanyl and the optimization of multiple experimental parameters were the first step in developing a universal, rapid, electrochemical sensing method for the detection of fentanyl and fentanyl analogs. <br>

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The opioid epidemic in Philadelphia has evolved into a complex polysubstance crisis with the emergence of xylazine alongside fentanyl, reshaping substance use dynamics. Xylazine's rising prevalence introduces unique health risks due to its sedative properties, compounded when combined with fentanyl, leading to heightened potency and toxicity. This combination contributes to severe medical complications, notably injection-related infections driving hospitalizations. Ethical care for individuals with substance use disorder necessitates prioritizing patient autonomy in healthcare decision-making. Critical discussions on care goals with hospitalized drug users are imperative, encompassing pain management, withdrawal mitigation, and medication for opioid use disorder, aligning with patient preferences. Open and transparent communication fosters trust, enabling healthcare providers to effectively support substance use disorder patients and enhance their overall quality of life. / Urban Bioethics

Fentanyl has historically been used to reduce inhalant anesthetic requirements in the dog, with the end goal of reducing detrimental cardiovascular effects seen with their use. While fentanyl has been investigated in this context with the older agent enflurane, this agent is no longer in common use. In the current literature, no studies exist that compare the effects of low and high doses of fentanyl on cardiovascular function in dogs anesthetized with isoflurane. In previous literature, a high dose of fentanyl improved cardiovascular function in enflurane anesthetized dogs only following correction of bradycardia associated with its use. The objective of this study was to evaluate the effect of two doses of fentanyl on isoflurane requirement in the dog, followed by an evaluation of cardiovascular function in the isoflurane-anesthetized dog at equivalent depth of anesthesia. The hypothesis was that fentanyl would reduce inhalant requirements in a dose dependent fashion, and that cardiovascular function would increase with fentanyl administration only following correction of bradycardia. A total of 8 healthy adult male beagle dogs were enrolled in this study, which was performed in a randomized cross-over design. Minimum Alveolar Concentration (MAC) was determined in these dogs via a 30 mA electric stimulation both before and after administration of a low (loading dose 30 µg/kg, continuous rate infusion (CRI) of 0.2 µg/kg/minute) or high (loading dose 90 µg/kg, CRI 0.8 µg/kg/min) dose of fentanyl. A 7-day washout was observed between experimental days. Following MAC determination, in a subsequent anesthetic episode animals were placed at a MAC multiple of 1.3 and cardiovascular and blood gas parameters were evaluated before and after each fentanyl dose in the presence and absence of bradycardia. Fentanyl decreased MAC in a dose-dependent fashion (p < 0.001), with the low dose reducing MAC by about 42% and the high dose by about 77%. MAC reduction, however, did not translate into improvement in cardiovascular function, with a significant reduction in cardiac index and oxygen delivery noted with both doses (p < 0.01) that was not different between treatments. Normal mean arterial pressures were maintained with both treatments despite these effects. Only with the high dose, however, correction of bradycardia caused an increase in both cardiac index and oxygen delivery (p < 0.02) when compared to isoflurane alone. In clinically healthy dogs, administration of a high dose of fentanyl increased cardiac function following correction of bradycardia, but a decrease was observed when bradycardia went uncorrected. Further studies are needed in order to evaluate these effects in clinical patients. / Master of Science / Fentanyl, a potent opioid painkiller, has historically been used to reduce inhalant anesthetic requirements in the dog, with the end goal of reducing detrimental effects on the heart and blood vessels seen with their use. While fentanyl has been investigated in this context with the older agent enflurane, this agent is no longer in common use. In the current literature, no studies exist that compare the effects of low and high doses of fentanyl on heart function in dogs anesthetized with isoflurane. In previous literature, a high dose of fentanyl improved blood flow in enflurane anesthetized dogs only following correction of the low heart rate associated with its use. The objective of this study was to evaluate the effect of two doses of fentanyl on isoflurane requirement in the dog, followed by an evaluation of heart function and blood flow in the isoflurane-anesthetized dog at equivalent depth of anesthesia. The hypothesis was that fentanyl would reduce isoflurane requirements in a dose dependent fashion, and that heart function would increase with fentanyl administration only following correction of low heart rate. A total of 8 healthy adult male beagle dogs were enrolled in this study, which was performed in a randomized cross-over design. Inhalant anesthetic requirement was assessed with an electric stimulation both before and after administration of a low or high dose of fentanyl. A 7-day washout was observed between experimental days. In a subsequent anesthetic episode animals were placed at a surgical anesthetic depth and cardiac and blood gas parameters were evaluated before and after each fentanyl dose in the presence and absence of low heart rate. Fentanyl decreased inhalant requirements in a dose-dependent fashion. This did not translate into improvement in cardiovascular function, with a significant reduction in blood flow and oxygen delivery noted with both doses that was not different between treatments. Normal blood pressure was maintained with both treatments despite these effects. Only with the high dose, however, correction of low heart rate caused an increase in both blood flow and oxygen delivery when compared to isoflurane alone. In clinically healthy dogs, administration of a high dose of fentanyl increased heart function following correction of low heart rate, but a decrease was observed when the low rate went uncorrected. Further studies are needed in order to evaluate these effects in clinical patients.

Submitted by Johnny Rodrigues (johnnyrodrigues@ufcg.edu.br) on 2018-04-11T15:06:17Z No. of bitstreams: 1 LEONARDO FALCÃO FEITOSA - DISSERTAÇÃO PPG-CEMat 2014..pdf: 2258061 bytes, checksum: cdc233909fd365937aacd1ef5fa7c2cd (MD5) / Made available in DSpace on 2018-04-11T15:06:17Z (GMT). No. of bitstreams: 1 LEONARDO FALCÃO FEITOSA - DISSERTAÇÃO PPG-CEMat 2014..pdf: 2258061 bytes, checksum: cdc233909fd365937aacd1ef5fa7c2cd (MD5) Previous issue date: 2014-12-29 / Na terapia medicamentosa convencional o fármaco é administrado através de uma forma farmacêutica e produz um nível tecidual do fármaco que não se mantêm dentro da faixa terapêutica por um período prolongado de tempo. Desta forma, o êxito do tratamento vai depender de vários fatores como dosagens precisas e frequentes em horários específicos pré-determinados e adesão do paciente à terapêutica de modo que, a não obediência ao esquema terapêutico, pode resultar em utilização do fármaco em faixa não efetiva ou em níveis tóxicos Devido a grande problemática da manutenção de níveis séricos de fármacos no organismo humano, principalmente quando se tratam se fármacos relacionados ao tratamento de dores de moderadas a intensa, este trabalho propõe o desenvolvimento de membranas porosas a base de quitosana, que é um polímero natural biocompatível, capazes de promover a liberação controlada de fentanil. As matrizes obtidas foram caracterizadas por: MO, MEV, EDS, FTIR, DRX, Ensaio de Intumescimento, Ensaio de Biodegradação e Ensaio de Citotoxicidade. Por MO e MEV verificou-se uma superfície com poros aparentemente interconectados. A partir da análise por EDS pode-se verificar os elementos componentes da quitosana e do fármaco. Por FTIR e DRX notou-se a não alteração dos grupos funcionais e cristalinidade, respectivamente, do material devido a incorporação do fármaco. Baseado nos ensaios de intumescimentos e biodegradação verificou-se a capacidade de controlar as variáveis: razão de intumescimento e taxa de degradação exclusivamente pela variação da concentração de quitosana na membrana porosa. Verificou-se no ensaio de citotoxicidade que as membranas, mesmo com a incorporação do fármaco, não apresentaram citotoxicidade. Baseado nos resultados obtidos pôde-se concluir que é possível sintetizar uma matriz polimérica com promissoras propriedades para carrear fármaco e para testes in vivo. / In conventional medical therapy the drug is administered via a dosage form and produces a tissue level of the drug that is not maintained within the therapeutic range over an extended period of time. Thus, the success of the treatment will depend on several factors such as accurate and frequent dosing at predetermined specific times and patient adherence to therapy so that the non-compliance to the treatment regimen can result in use of the drug in not effective range or toxic levels Due to the great problem of maintaining serum levels of drugs in the human body, especially in the case if drugs related to the treatment of moderate to severe pain, this paper proposes the development of porous membranes chitosan base, which is a biocompatible natural polymer, capable of promoting the controlled release of fentanyl. The matrices obtained were characterized by: OM, SEM, EDS, FTIR, XRD, Swelling test, biodegradation test and Cytotoxicity Assay. For OM and SEM there was apparently a surface with interconnected pores. From the EDS analysis can verify the elements of chitosan and drug. FTIR and XRD noted not to change functional groups of crystallinity and, respectively, of the material due to the incorporation of the drug. Based on swellings and biodegradation tests verified the ability to control the following variables: swelling ratio and degradation rate solely by varying the concentration of the chitosan porous membrane. It was found that the cytotoxicity assay the membranes, even with the incorporation of the drug did not show cytotoxicity. Based on the results obtained it was concluded that it is possible to synthesize a polymer matrix with promising properties to adduce drug and in vivo tests.

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Os opióides, como o fentanil e o sufentanil, embora amplamente utilizados em cães são raramente empregados pela via epidural nesta espécie. O presente estudo teve como objetivo avaliar comparativamente os efeitos cardiovasculares e sistêmicos bem como a analgesia no período pós-operatório imediato e tardio da anestesia epidural realizada com fentanil ou sufentanil associados a bupivacaína ou desta sozinha em cadelas, sedados com infusão contínua de propofol. Para tanto foram utilizadas 30 fêmeas da espécie canina, submetidas a ovariosalpingohisterectomia eletiva, distribuídas aleatoriamente em 3 grupos de 10 animais cada. Todos os animais deste estudo receberam acepromazina (0,1 mg/kg), e infusão contínua de propofol para sedação. Os animais do grupo I foram então tratados com o fentanil (2 &micro;g/kg) e bupivacaína (1,0 mg/kg), os do grupo II com sufentanil (1&micro;g/kg) e bupivacaína (1,0 mg/kg), e os do grupo III com bupivacaína (1,0 mg/kg). Os agentes foram administrados pela via epidural, no espaço lombo-sacral, e diluídos em solução salina para um volume total de 0,36 ml/kg. A freqüência cardíaca, freqüência respiratória, e pressões arterial sistólica, média e diastólica foram mensuradas bem como pH e gases sangüíneos. Para avaliação de parâmetros sistêmicos relacionados á qualidade da analgesia no trans e pós-operatório foram analisados grau de analgesia e sedação e catecolaminas. A avaliação da extensão do bloqueio foi realizada através do teste do panículo. Para avaliação da latência e duração de ação motora e sensitiva dos fármacos foi realizado o pinçamento do espaço interdigital de membros pélvicos e da região perianal. O período total de avaliação foi de 6 horas após a realização da anestesia epidural. Não foram verificadas diferenças significativas quanto a alterações no sistema cardiovascular e respiratório, nem quanto a alterações na avaliação da sedação. Pode-se observar que o grupo tratado com bupivacaína e sufentanil obteve menores escores de dor no período pós-operatório, mas os demais grupos obtiveram valores satisfatórios em relação a este parâmetro. Pelos resultados obtidos, pode-se concluir que todos os protocolos permitiram a realização do procedimento cirúrgico, e produziram analgesia adequada, nos animais estudados, com modulação da resposta neuroendócrina à dor e mínimos efeitos adversos. / Potent opioids such as fentanyl and sufentanil, althought largely used in dogs, are rarely employed at the epidural space on this species. The aim of the present study was to compare the cardiovascular and systemics effects, as well as the analgesic action on the post operative period of epidural anaesthesia performed with bupivacaine alone or associated with fentanyl and sufentanil, in bitches sedated with continuous infusion of propofol. Thirty female dogs, submitted to ovariosalpingohisterectomy, allocated in three groups of ten animals each were used. All the animals received acepromazine (0,1 mg/kg), and continuous infusion of propofol for sedation. The animals of group I received fentanyl (2&micro;g/kg) and bupivacaine (1 mg/kg), animals of group II received sufentanil (1&micro;g/kg) and bupivacaine (1 mg/kg) and those of group III received bupivacaine (1mg/kg). The agentes were administered at the lumbosacral space, and diluted in saline soluction to a total volume of 0,36 ml/kg. Cardiac and respiratory rate, arterial blood pressure were evaluated, as well as pH and blood gases. Analgesia and sedation levels, and plasmatic cathecolamines were measured for the evaluation of systemic parameters. The evaluation of blook extension was performed by the panniculus test. Pinprick performed at the interdigital space and at perineum region were utilized to evaluate onset time of sensitive and motor blockage. All parameters were evaluated during a total time of 6 hours. No significant changes related to the cardiovascular, respiratory and sedation parameters were observed during the study. The degree of analgesia observed at the post operative period were higher in the sufentanil group. However both fentanyl and bupivacaine groups also obtained a sufficient level of analgesia. Based on the results obtained, the authors concluded that the surgical procedure could be performed by means of the three anesthetic techniques employed producing sufficient analgesia and an acceptable neuroendocrine modulation of pain with minimal adverse effects.

Os equinos são comumente anestesiados com agentes voláteis em procedimentos cirúrgicos acima de 60 minutos, resultando em depressão cardiovascular dosedependente, contribuindo para uma alta taxa de mortalidade. Sendo assim, este estudo objetivou determinar se o fentanil, em infusão contínua, seria capaz de diminuir a fração expirada de isoflurano, promovendo estabilidade cardiovascular transoperatória e uma melhor recuperação após cirurgia de artroscopia, em comparação à infusão de lidocaína ou quetamina, durante a manutenção da anestesia com isoflurano. Para tanto foram utilizados 20 equinos de 3 a 8 anos e pesando 350 a 500kg, submetidos a cirurgia de artroscopia em decúbito dorsal. Os animais foram divididos aleatoriamente em 4 grupos: GL (1,5 mg/kg em bolus e infusão de 0,15mg/kg/min) ; GQ (2mg/kg em bolus e infusão de 0,2mg/kg/min); GF (7&micro;g/kg em bolus e infusão de 0,7&micro;g/kg/min) e GI que não recebeu infusão de nenhum fármaco adjuvante. Foram avaliados os parâmetros cardiovasculares (FC, PAM, PAS e PAD), ventilatórios e de oxigenação (PaO2, PaCO2, Compl e Rva), fração expirada de isoflurano [ISSO](Fexp%), e qualidade de recuperação. Em relação à [ISSO] (Fexp%) as maiores quedas foram observadas no momento 30bolus em todos os grupos, que utilizaram adjuvantes, comparados ao momento basal sendo, GL (1,50 para 0,90%) GQ (1,44 para 0,96%) e GF (1,32 para 0,96%). Observou-se que após 15 minutos da interrupção da infusão contínua de fentanil e lidocaína a fração expirada de isoflurano foi aumentada GL 25% e GF 45%. Apesar de não ter havido diferença estatística, o GF apresentou escore de recuperação menor 16,8 pontos, GL 24,6; GQ 30,0 e GI 31,8 pontos. Conclui-se então que o uso do fentanil foi capaz de reduzir a fração expirada de isoflurano em até 43%, não observando qualquer efeito colateral no momento da recuperação após re-sedação com xilazina 0,5mg/kg. / Volatile anesthetics are commonly used in horse anesthesia in surgical procedures over 60 minutes, resulting in a dose-dependent cardiovascular depression, contributing to a high mortality rate. Thus, the aimed this study was determine whether fentanyl continuous rate infusion would be able to reduce end tidal isoflurane, promoting intraoperative cardiovascular stability and a better recovery after arthroscopic surgery, when compared to lidocaine or ketamine infusion during maintenance of anesthesia with isoflurane. Therefore, 20 horses aging 3-8 years and weighing 350 to 500 kg underwent arthroscopic surgery in dorsal recumbence. The animals were randomly divided into four groups: GL (1.5 mg/kg bolus and 0.15 mg/kg/min infusion rate of lidocaine), GQ (2 mg/kg bolus and 0.2 mg/kg/min infusion of ketamine); GF (7&micro;g/kg bolus and 0.7 mg/kg/min infusion rate of fentanyl) and GI did not receive any adjuvant infusion. Cardiovascular parameters (HR, MBP, SBP and DBP), ventilatory and oxygenation (PaO2, PaCO2, Cst and Rva), end tidal isoflurano [ISO] (Fexp%), and quality of recovery were evaluated. Regarding [ISO] (Fexp%) the highest decreases were observed at the time 30bolus in all groups with adjuvants, in comparison to base line -GL (1.50 to 0.90%) GQ (1.44 to 0.96 %) and GF (1.32 to 0.96%). At 15 minutes after the end of continuous rate infusion of fentanyl and lidocaine, expired fraction of isoflurane was increased 25% for GL and 45% for GF. Although there was no statistical difference, GF showed lower recovery score - 16.8 points, while 24.6 for GL, 30.0 for GQ and 31.8 points for GI. In conclusion, fentanyl was able to reduce end tidal isoflurane to 43%, with no side effects at recovery time after re-sedation with xylazine 0.5 mg / kg.

During my research career in Prof. V.J.Hruby's laboratory I worked on two different projects. The first project, which was initiated by the author, was planned to serve the need of our laboratory for a novel method of peptide cyclization. This method was planned to use recent advances in Pd0-catalyzed asymmetric synthesis combined with the structural richness offered by the Baylis-Hillman chemistry which could open new ways to diverse areas of drug design, molecular immunology and chemotherapy. This approach would provide cyclic peptides featuring N-alkylated amino acids that would confer high resistance to degradation by proteases. Because of numerous synthetic problems imposed, this strategy was not of considerable current use in peptide synthesis, especially on solid supports. However, despite a substantial amount of effort invested, this method faced serious drawbacks such as multistep synthesis and side reactions when applied to solid supports. Moreover, recent introduction of microwave technology which has helped to solve a great number of problems has led to a renaissance in the classical lactam and thioester bond cyclizations which overshadowed our quest for a novel methodology. The second project was focused on application of 4-anilidopiperidines for the synthesis of chimeric bioactive peptides. It was an effort towards the development of novel analgesics with reduced toxicity and enhanced potency. This project linked small molecule and multimeric ligand designs that were ongoing in our laboratory at the time. Major accomplishments in this project were made possible by successful resolution of several research challenges. I was able to find a straightforward, convenient and economical approach for the synthesis of novel analogues on a solid support. These developments led to novel compounds which showed substantial increases in their binding affinity relative to corresponding opioid analogues. To illustrate, compounds PET25, 26, 27, 29, 30, 31, and 32 showed high bioactivity and sub-nanomolar binding affinity to opioid receptors. Most of the peptides generated in the second project are still being investigated for their biological activities by our colleagues at the Department of Pharmacology, but the results to date indicate that some highly potent novel compounds have been made.