RESUMO
BACKGROUND: The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response. METHODS: In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three separate occasions. On each occasion, isohypercapnic hypoxic ventilatory responses were measured during a fixed sequence of placebo, followed by low- and high-dose propofol infusion. The authors conducted a population pharmacokinetic/pharmacodynamic analysis that included oxygen and carbon dioxide kinetics. RESULTS: Twelve subjects completed the three sessions; no serious adverse events occurred. The propofol concentrations were 0.6 and 2.0 µg/ml at low and high dose, respectively. The ENA-001 concentrations were 0.6 and 1.0 µg/ml at low and high dose, respectively. The propofol concentration that reduced the hypoxic ventilatory response by 50% was 1.47 ± 0.20 µg/ml. The steady state ENA-001 concentration to increase the depressed ventilatory response by 50% was 0.51 ± 0.04 µg/ml. A concentration of 1 µg/ml ENA-001 was required for full reversal of the propofol effect at the propofol concentration that reduced the hypoxic ventilatory response by 50%. CONCLUSIONS: In this pilot study, the authors demonstrated that ENA-001 restored the hypoxic ventilatory response impaired by propofol. This finding is not only of clinical importance but also provides mechanistic insights into the peripheral stimulation of breathing with ENA-001 overcoming central depression by propofol.
Assuntos
Anestésicos Intravenosos , Estudos Cross-Over , Hipóxia , Propofol , Humanos , Propofol/farmacologia , Propofol/administração & dosagem , Masculino , Método Duplo-Cego , Feminino , Adulto , Hipóxia/fisiopatologia , Anestésicos Intravenosos/farmacologia , Adulto Jovem , Relação Dose-Resposta a DrogaRESUMO
Opioids are commonly used for the management of severe chronic cancer pain. Their well-known pharmacological effects on the gastrointestinal system, particularly opioid-induced constipation (OIC), are the most common limiting factors in the optimization of analgesia, and have led to the wide use of laxatives and/or peripherally acting mu-opioid receptor antagonists (PAMORAs). A growing interest has been recently recorded in the possible effects of opioid treatment on the gut microbiota. Preclinical and clinical data, as presented in this review, showed that alterations of the gut microbiota play a role in modulating opioid-mediated analgesia and tolerability, including constipation. Moreover, due to the bidirectional crosstalk between gut bacteria and the central nervous system, gut dysbiosis may be crucial in modulating opioid reward and addictive behavior. The microbiota may also modulate pain regulation and tolerance, by activating microglial cells and inducing the release of inflammatory cytokines and chemokines, which sustain neuroinflammation. In the subset of cancer patients, the clinical meaning of opioid-induced gut dysbiosis, particularly its possible interference with the efficacy of chemotherapy and immunotherapy, is still unclear. Gut dysbiosis could be a new target for treatment in cancer patients. Restoring the physiological amount of specific gut bacteria may represent a promising therapeutic option for managing gastrointestinal symptoms and optimizing analgesia for cancer patients using opioids.
Assuntos
Analgésicos Opioides , Dor do Câncer , Disbiose , Microbioma Gastrointestinal , Humanos , Disbiose/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Dor do Câncer/tratamento farmacológico , Dor do Câncer/etiologia , Animais , Neoplasias/complicações , Neoplasias/tratamento farmacológicoRESUMO
WHAT IS KNOWN AND OBJECTIVE: Many premature infants less than 37 weeks gestational age (GA), and almost all infants less than 28 weeks GA, will experience apnoea of prematurity (AOP)-a cessation of respiration for 20 or more seconds (or less than 20 s if accompanied by other signs). Because the treatment options for AOP are so limited, we explore its epidemiology, with the ultimate hope of learning how to decrease its incidence. COMMENT: Although AOP usually resolves with maturation of the respiratory system, many short- and long-term negative effects are correlated statistically with AOP (although direct causality has not been established). The primary risk factor for AOP is preterm birth, but delivery technique, genetics, socioeconomic status, racial disparities and other influences are suspected to be involved. Anaemia, asthma and gastric reflux have also been associated with preterm birth, but the relationship with AOP is unclear. The postulated associations and the strength of the evidence are briefly reviewed and discussed. WHAT IS NEW AND CONCLUSION: Attempts to elucidate the epidemiology of apnoea of prematurity have been challenging. Studies of AOP are hampered in part by challenges in monitoring the condition, the interplay of multiple comorbidities in preterm neonates and lack of expert consensus definitions. However, since the primary risk factor is preterm birth, efforts to decrease the prevalence of preterm birth would have a positive secondary effect on the prevalence of AOP. Until then, better pharmacotherapeutic options are needed.
Assuntos
Doenças do Prematuro , Nascimento Prematuro , Apneia/tratamento farmacológico , Apneia/epidemiologia , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/epidemiologia , Doenças do Prematuro/etiologia , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologiaRESUMO
WHAT IS KNOWN AND OBJECTIVE: About 10% of all infants are born prematurely. Almost all of those of gestational age less than about 30 weeks, and about half of those of gestational age up to about 35 weeks, are subject to unpredictable interruptions of breathing-known as "apnoea of prematurity" (AOP). We present a synopsis of the problem and point out the limited management options. COMMENT: A basal rate for spontaneous breathing is normally maintained by integrated action of generator cells in the brainstem and feedback from central and peripheral chemosensors. In AOP, there are intermittent periods (seconds) lacking spontaneous firing, which results in hypoxia and hypercapnia. The long-term consequences of these interruptions in oxygen supply to tissues are not known. Although many treatment modalities are used, including drug therapy, nonpharmacologic care and mechanical intervention, there is no universally effective first-line management for AOP. Caffeine citrate is generally the most frequently used pharmacotherapeutic agent, but its side effect profile narrows with higher doses and the upper limit is still being investigated to discern the greatest benefit-to-risk ratio; thus, most infants do not achieve complete resolution of apnoeas. WHAT IS NEW AND CONCLUSION: Given the widespread and serious nature of the problem of AOP, there is a surprising lack of treatment options. A more consistent and effective treatment, alone or as adjunct, would be welcome.
Assuntos
Apneia , Doenças do Prematuro , Apneia/tratamento farmacológico , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/tratamento farmacológicoRESUMO
PURPOSE OF REVIEW: While ketamine's analgesia has mostly been attributed to antagonism of N-methyl-D-aspartate receptors, evidence suggests multiple other pathways are involved in its antidepressant and possibly analgesic activity. These mechanisms and ketamine's role in the nociplastic pain paradigm are discussed. Animal studies demonstrating ketamine's neurotoxicity have unclear human translatability and findings from key rodent and human studies are presented. RECENT FINDINGS: Ketamine's metabolites, and (2R,6R)-hydroxynorketamine in particular, may play a greater role in its clinical activity than previously believed. The activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and the mammalian target of rapamycin by ketamine are mechanisms that are still being elucidated. Ketamine might work best in nociplastic pain, which involves altered pain processing. While much is known about ketamine, new studies will continue to define its role in clinical medicine. Evidence supporting ketamine's neurotoxicity in humans is lacking and should not impede future ketamine clinical trials.
Assuntos
Ketamina , Animais , Previsões , Humanos , Ketamina/metabolismo , Ketamina/farmacologia , Ketamina/toxicidade , Dor/tratamento farmacológicoRESUMO
WHAT IS KNOWN AND OBJECTIVE: Deaths due to opioid-induced respiratory depression (OIRD) continue to rise despite intense regulatory and professional actions. COVID-19 has only worsened this situation.1 An opioid receptor antagonist (ORA) such as naloxone is the most common intervention for OIRD. However, with increasing overdose from highly potent illicit opioids and polysubstance abuse, appraisal of the adequacy of ORA seems warranted and timely. COMMENT: OIRD results from the binding of an excess number of agonist molecules to opioid receptors. Mechanistically, it makes sense to reverse this by displacing agonist molecules by administering an ORA. But realistically, the trend to higher-potency agonists and polysubstance abuse diminishes the effectiveness of this approach. We are left facing a crisis without a solution. WHAT IS NEW AND CONCLUSION: For the increasingly common OIRD from highly potent illicit agonists and polysubstance overdose, ORAs are correspondingly less effective. Alternatives are needed-soon.
Assuntos
Overdose de Drogas/etiologia , Drogas Ilícitas/intoxicação , Antagonistas de Entorpecentes/uso terapêutico , Overdose de Drogas/tratamento farmacológico , Humanos , Overdose de Opiáceos/tratamento farmacológicoRESUMO
WHAT IS KNOWN AND OBJECTIVE: Food and Drug Administration (FDA) risk evaluation and mitigation strategies (REMs) encourage emergency responders, paramedics, law enforcement agents, and even laypeople to be trained in the administration of naloxone with the intent of rescuing individuals from a known or suspected opioid overdose. COMMENT: Although naloxone is generally safe and effective at reversing respiratory depression caused by a conventional opioid such as morphine or heroin by competing with the opioid and displacing it from the µ-opioid receptor, questions increasingly are arising as to whether naloxone can adequately reverse opioid overdoses that may involve the potent opioids fentanyl and its analogues (F/FAs). In other words, as more and more opioid overdoses involve F/FAs, can naloxone keep up? WHAT IS NEW AND CONCLUSION: As a competitive antagonist at µ-opioid receptors, naloxone is often a life-saving agent in cases of overdose caused by conventional opioids, but it may not be versatile or powerful enough to combat the rising tide of overdoses due to fentanyl and its illicit analogues, or in cases of overdose involving combinations of opioids and non-opioids.
Assuntos
Fentanila/toxicidade , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Overdose de Opiáceos/tratamento farmacológico , Diafragma/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fentanila/farmacologia , Heroína/toxicidade , Humanos , Laringismo/induzido quimicamente , Rigidez Muscular/induzido quimicamente , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides mu/efeitos dos fármacos , Parede Torácica/efeitos dos fármacosRESUMO
WHAT IS KNOWN AND OBJECTIVE: Treating an opioid overdose using an opioid receptor antagonist (such as naloxone) makes mechanistic sense and can be effective. Unfortunately, the majority of current drug overdose deaths involve polysubstance use (i.e., an opioid plus a non-opioid). COMMENT: Respiratory depression induced by opioids results from excessive opioid molecules binding to opioid receptors. This effect can be reversed by an opioid receptor antagonist. However, the respiratory depression induced by non-opioid drugs is not due to action at opioid receptors; thus, an opioid receptor antagonist is ineffective in many of these cases. For respiratory depression induced by non-opioids, receptor antagonists are either not available (e.g., for propofol overdose) or there may be attendant risks with their use (e.g., seizures with flumazenil). This gives rise to a need for more effective ways to treat polysubstance overdose. WHAT IS NEW AND CONCLUSION: A new approach to treating opioid-induced respiratory depression due to drug overdose focuses on agents that stimulate respiratory drive rather than competing for opioid receptors. Such an approach is "agnostic" to the cause of the respiratory depression, so might be a potential way to treat polysubstance overdose.
Assuntos
Analgésicos Opioides/toxicidade , Overdose de Drogas/tratamento farmacológico , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/farmacologia , Antagonistas de Entorpecentes/uso terapêutico , Insuficiência Respiratória/tratamento farmacológico , Corpo Carotídeo/efeitos dos fármacos , Corpo Carotídeo/metabolismo , Overdose de Drogas/fisiopatologia , Humanos , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Assistência PerioperatóriaRESUMO
WHAT IS KNOWN AND OBJECTIVE: Postsurgical recovery is influenced by multiple pre-, intra- and perioperative pharmacotherapeutic interventions, including the administration of medications that can induce respiratory depression postoperatively. We present a succinct overview of the topic, including the nature and magnitude of the problem, contributing factors, current limited options, and potential novel therapeutic approach. COMMENT: Pre-, intra- and perioperative medications are commonly administered for anxiety, anaesthesia, muscle relaxation and pain relief among other reasons. Several of the medications alone or in joint-action can be additive or synergistic producing respiratory depression. Given the large number of surgical procedures that are performed each year, even a small percentage of postoperative respiratory complications translates into a large number of affected patients. WHAT IS NEW AND CONCLUSION: Due to the large number of surgeries performed each year, and the variety of medications used before, during, and after surgery, the occurrence of postoperative respiratory depression is surprisingly common. It is a significant medical problem and burden on hospital resources. There is a need for new strategies to prevent and treat the acute and collateral problems associated with postoperative respiratory depression.
Assuntos
Complicações Pós-Operatórias/prevenção & controle , Insuficiência Respiratória/prevenção & controle , Analgésicos/efeitos adversos , Comorbidade , Falha da Terapia de Resgate , Humanos , Hipnóticos e Sedativos/efeitos adversos , Bloqueio Neuromuscular/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Insuficiência Respiratória/induzido quimicamente , Medicamentos para o Sistema Respiratório/uso terapêutico , Medição de Risco , Albumina Sérica/análiseRESUMO
WHAT IS KNOWN AND OBJECTIVE: In response to rapid spread of coronavirus (SARS-CoV-2) and lack of vaccine or effective treatment for COVID-19 disease, governments imposed measures that resulted in a shift from work and school to isolation at home. Studies from three countries (China, Belgium and the United States) report the consequences on traumatic bone fractures. COMMENT: The coronavirus pandemic has resulted in a widespread change to a relative sedentary lifestyle and decreased exposure to light (vitamin D). A consequence of the stay-at-home policies is a negative change in bone-health and environmental surroundings that has led to age-related changes in the number of traumatic bone fractures. WHAT IS NEW AND CONCLUSION: A consequence of stay-at-home policies has been a decline in bone fractures for young and middle-aged adults; but an increase for the elderly. The trends are predicted to reverse, and present new problems, when isolation restrictions are removed.
Assuntos
COVID-19 , Controle de Doenças Transmissíveis/métodos , Fraturas Ósseas , Distanciamento Físico , Fatores Etários , Idoso , Bélgica/epidemiologia , Densidade Óssea , COVID-19/epidemiologia , COVID-19/prevenção & controle , Criança , China/epidemiologia , Feminino , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/metabolismo , Fraturas Ósseas/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Comportamento Sedentário , Estados Unidos/epidemiologia , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/epidemiologiaRESUMO
WHAT IS KNOWN AND OBJECTIVE: The United States Food and Drug Administration (FDA) recently issued a Drug Safety Communication requiring Boxed Warning updating and other changes in order to improve the safe use of the benzodiazepine drug class. These changes were prompted because 'The current prescribing information for benzodiazepines does not provide adequate warnings about [the] serious risks and harms associated with these medicines so they may be prescribed and used inappropriately'. COMMENT: The FDA Communication points out that benzodiazepines can be an important option for treating disorders for which these drugs are indicated. However, the acknowledged problems of these drugs, which historically were considered an acceptable trade-off against their benefits, need to be reassessed in light of their widespread (over?) prescribing (for example, in 2019 an estimated 92 million benzodiazepine prescriptions were dispensed from US retail and mail-order pharmacies). WHAT IS NEW AND CONCLUSION: The FDA Communication can be viewed as an important step in reminding healthcare providers of the 'serious risks and harms associated with these medicines', and validation of such reports by patients. Importantly, the FDA Communication includes an often-neglected aspect of benzodiazepine prescribing, namely how to discontinue use, and the perplexing protracted withdrawal syndrome experienced by some patients. The Communication advises to providers: 'No standard benzodiazepine tapering schedule is suitable for all patients; therefore, create a patient-specific plan to gradually reduce the dosage, and ensure ongoing monitoring and support as needed to avoid serious withdrawal symptoms or worsening of the patient's medical condition'.
Assuntos
Benzodiazepinas/administração & dosagem , Rotulagem de Medicamentos/normas , Segurança do Paciente/normas , United States Food and Drug Administration/normas , Benzodiazepinas/efeitos adversos , Humanos , Prescrição Inadequada/prevenção & controle , Educação de Pacientes como Assunto , Participação do Paciente , Padrões de Prática Médica , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , Estados UnidosRESUMO
WHAT IS KNOWN AND OBJECTIVE: A large percentage of opioid overdose fatalities involve fentanyl or one of its legal or illegal analogs (F/FAs). Is there something about the pharmacology of these drugs that make them unusually dangerous in an overdose? COMMENT: Some of the reasons for the dangers of overdose of F/FAs is their high potency and low cost (that leads to wide distribution). But it is rarely asked if the basic pharmacology of F/FAs differ in some fundamental way from conventional opioids such as morphine and heroin. In addition to centrally mediated respiratory depression via opioid receptors, F/FAs cause rigidity in the key respiratory muscles of the chest, upper airway and diaphragm ("wooden chest syndrome," WCS) by a non-opioid mechanism. WHAT IS NEW AND CONCLUSION: WCS is an atypical pharmacology of F/FAs. Because of its rapid onset and non-opioid mechanism, WCS makes F/FA overdose particularly dangerous.
Assuntos
Fentanila/toxicidade , Overdose de Opiáceos/fisiopatologia , Diafragma/fisiopatologia , Heroína/toxicidade , Humanos , Laringismo/fisiopatologia , Rigidez Muscular/induzido quimicamente , Síndrome , Parede Torácica/efeitos dos fármacosRESUMO
WHAT IS KNOWN AND OBJECTIVE: Opioid use in the United States has reached unprecedented-some would even say crisis-levels. Although many individuals use opioid drugs as part of legitimate pain management plans, a significant number misuse prescription or illicit opioids. With regular opioid use, individuals develop tolerance and physical dependence; both are predictable, physiologic responses to repeated opioid exposure. However, a substantial number of individuals who misuse opioids will develop opioid use disorder (OUD), a complex, primary, chronic, neurobiological disease rooted in genetic, environmental and psychosocial factors. This article discusses OUD, opioid receptor physiology, and opioid withdrawal symptomatology and pathophysiology, as well as current treatment options available to reduce opioid withdrawal symptoms in individuals with physical dependence and/or OUD. METHODS: The research articles regarding OUD and its management have been reviewed thoroughly based on a PubMed literature search using keywords related to opioid dependence, its pathophysiology and current treatment strategies. RESULTS AND DISCUSSION: Tolerance/physical dependence and the behavioural characteristics associated with OUD reflect complex neurobiologic adaptations in several major systems of the brain, including the locus ceruleus and mesolimbic systems. Physical dependence is responsible for the distressing withdrawal symptoms individuals experience upon abrupt cessation or rapid dose reduction of exogenous opioids. Opioid withdrawal symptoms are a key driver behind continued opioid use, and a barrier to opioid discontinuation. Several opioid-based medications are available to treat patients with OUD; these treatments can diminish opioid withdrawal symptoms and cravings as well as block opioid effects in the event of relapse. Additionally, non-opioid drugs may be used during acute detoxification to help alleviate opioid withdrawal symptoms. WHAT IS NEW AND CONCLUSION: The opioid crisis has produced many challenges for physicians, one being the need to determine which patients would benefit most from maintenance therapy and which may be candidates for opioid discontinuation. In addition to summarizing current understanding of OUD, we provide a new algorithm for determining the need for continued opioid use as well as examples of situations where management of opioid withdrawal symptoms is indicated.
Assuntos
Analgésicos Opioides/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/complicações , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Algoritmos , Analgésicos Opioides/administração & dosagem , Animais , Humanos , Epidemia de Opioides , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Dor/tratamento farmacológico , Uso Indevido de Medicamentos sob Prescrição/efeitos adversos , Síndrome de Abstinência a Substâncias/fisiopatologia , Estados Unidos/epidemiologiaRESUMO
Concern about coronavirus 2019 (COVID-19) morbidity and mortality has drawn attention to the potential role of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) because the SARS-CoV-2 uses the ACE2 receptor as its point of entry into the body. It is not clear if and to what degree the SARS-CoV-2 virus affects the renin-angoiotensin system. Early studies from China which speculated on the role of ACE inhibition and ARBs did not evaluate the drug regimens. A vast body of evidence supports the use of ACE inhibitors and ARBs in hypertensive patients and patients with heart failure, and very little evidence has been acquired about their role in COVID-19. There is good evidence in support of the use of ACE inhibitors and ARBs in indicated patients with hypertension and heart failure, and clinicians should be reticent about abruptly withdrawing these drugs based on a paucity of evidence.
Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Tratamento Farmacológico da COVID-19 , Insuficiência Cardíaca/tratamento farmacológico , Hipertensão/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/administração & dosagem , Enzima de Conversão de Angiotensina 2/genética , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , COVID-19/virologia , Insuficiência Cardíaca/metabolismo , Humanos , Hipertensão/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , SARS-CoV-2RESUMO
BACKGROUND: Prescribing opioids for chronic noncancer pain (CNCP) has been strictly regulated in Taiwan. This study was undertaken to survey pain and non-pain related physicians' knowledge, attitudes, and practices regarding prescribing opioids for CNCP. METHODS: A questionnaire survey was conducted in this comparison study. All 66 physicians who were treating officially registered CNCP outpatients were visited and completed anonymous questionnaires. The other physicians (anesthesiologists, oncologists, and non-pain physicians) were surveyed by a mailed questionnaire. RESULTS: A total of 266 (75%) questionnaires were received from 355 board-certified physicians. More CNCP physicians (81.8%) and anesthesiologists (69.7%) had received prior CNCP-related training courses than had oncologists (21.2%) and non-pain physicians (10.3%). Varied proportions of physicians by type were unfamiliar with the Taiwan opioid regulations (16.7-86.8%) and would accordingly skip or reduce dosage of opioid prescriptions (27.3-73.5%). In addition, non-pain physicians had a significantly lower knowledge level, more negative attitudes, and greater hesitation about prescribing opioids compared to the pain-related physicians (P < 0.001). CNCP physicians who had received CNCP-related training courses had a higher knowledge score than did those not receiving training (P = 0.002). Overall, the leading barriers for prescribing opioids were inadequate knowledge of pain management (76%), physician reluctance (73%), and family reluctance (78%). CONCLUSION: There are substantial knowledge gaps, negative attitudes, and hesitation toward prescribing long-term opioids for CNCP patients by physicians in Taiwan, suggesting that efforts are needed to improve postgraduate education regarding adequate opioid management for CNCP.
Assuntos
Analgésicos Opioides/uso terapêutico , Atitude do Pessoal de Saúde , Dor Crônica/tratamento farmacológico , Competência Clínica , Padrões de Prática Médica/estatística & dados numéricos , Anestesiologistas , Controle de Medicamentos e Entorpecentes/legislação & jurisprudência , Feminino , Humanos , Masculino , Oncologistas , Oftalmologistas , Otorrinolaringologistas , Manejo da Dor , Pediatras , Inquéritos e Questionários , TaiwanRESUMO
WHAT IS KNOWN AND OBJECTIVE: When patients fail other treatment regimens and still suffer from pain sufficiently severe, opioid analgesics are appropriate and required. Unfortunately, constipation is a common adverse effect of opioids. Opioid-induced constipation (OIC) can be treated with one of the new peripherally acting µ-opioid receptor antagonist (PAMORA) agents. We summarize the mechanism of action of these drugs, with an emphasis on comparison of their potential for metabolic drug interactions. METHODS: Internet sources were searched for English-language abstracts related to the topic. Emphasis was placed on the mechanism of the PAMORAs, their metabolic pathways, drugs co-administered with opioids and potential drug-drug interactions (particularly at the level of CYP450 isozyme drug metabolism). Each source was evaluated and synthesized into the review. RESULTS AND DISCUSSION: PAMORAs dose-dependently antagonize the access of agonist molecules to opioid receptors, thereby directly eliminating or reducing OIC. But they differ from other opioid antagonists in that they are restricted to the periphery. Hence, they block constipation, but leave central opioid receptor-mediated pain relief undiminished. The PAMORAs have similar efficacy and safety profiles, but many pain patients have comorbidities and thus are taking other medications, which increases the potential for metabolic drug interactions. WHAT IS NEW AND CONCLUSION: Managing OIC in patients who have failed OTC or other therapies can be accomplished using a PAMORA, but healthcare providers must make prudent decisions that avoid or at least mitigate the potential for metabolic drug interactions in those patients with other comorbidities being managed medically by rational polypharmacy strategies.
Assuntos
Analgésicos Opioides/efeitos adversos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Sistema Enzimático do Citocromo P-450 , Interações Medicamentosas , Humanos , Antagonistas de Entorpecentes/uso terapêutico , Dor/tratamento farmacológico , Receptores Opioides/metabolismoRESUMO
WHAT IS KNOWN AND OBJECTIVE: Hawaii will ban two major ingredients of sunscreens. This article reviews the reasons and future directions. Hawaii recently enacted legislation that will ban the use of two major ingredients of the majority of commonly used sunscreens. The reason for the ban is the ingredients' putative deleterious impact on marine ecosystems, particularly coral reefs. But sunscreens also save lives by decreasing the risk of UV-induced skin cancers. We review both sides of the issue and potential implications for the healthcare system. COMMENT: Coral reefs consist of organisms in delicate equilibria that are susceptible to small changes in their surroundings. Recent natural and man-made disruptions, direct or indirect, such as changes in ocean temperature and chemistry, ingress of invasive species, pathogens, pollution and deleterious fishing practices, have been blamed for the poor health, or even the outright destruction, of some coral reefs. The most popular sunscreen products contain two ingredients-oxybenzone and octinoxate-that have also been implicated in coral toxicity and will be banned. This creates a healthcare dilemma: Will the protection of coral reefs result in an increase in human skin cancers? WHAT IS NEW AND CONCLUSION: Concentration estimates and mechanism studies support an association-direct or indirect (via promotion of viral infection)-of sunscreens with bleaching of coral reefs. A ban on the two most common sunscreen ingredients goes into effect in Hawaii on January 1, 2021. Proponents suggest that this is a trend, just the first of many such bans worldwide; opponents warn of a dire increase in human skin cancers. As a result, alternative sunscreen compounds are being sought.
Assuntos
Antozoários/efeitos dos fármacos , Benzofenonas/toxicidade , Cinamatos/toxicidade , Protetores Solares/toxicidade , Animais , Benzofenonas/administração & dosagem , Cinamatos/administração & dosagem , Qualidade de Produtos para o Consumidor/legislação & jurisprudência , Recifes de Corais , Havaí , Humanos , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/prevenção & controle , Protetores Solares/administração & dosagem , Protetores Solares/químicaRESUMO
WHAT IS KNOWN AND OBJECTIVE: The double-helical conformation of human DNA (hDNA) is so axiomatic that it is called the "canonical" form. Recently, though, intrastrand folds ("I-motifs" and "G-quadruplexes") have been identified in hDNA. These could be targets for novel drug discovery. COMMENT: Any interruption of the canonical form of hDNA fundamentally impacts the normal progression of transduction and translation. In particular, the synthesis of receptors and cognate protein ligands would be affected, as well as their affinity for-and signal transduction of-pharmacotherapeutic agents. Recent studies have identified normally occurring, folded structures superimposed on the usual double-helix motif of hDNA. WHAT IS NEW AND CONCLUSION: The newly identified "folded DNA" structures ("I-motifs" and "G-quadruplexes") could represent novel drug-discovery targets, most likely for cancer.
Assuntos
Antineoplásicos/farmacologia , DNA/química , Descoberta de Drogas/métodos , Quadruplex G , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
WHAT IS KNOWN AND OBJECTIVE: Electronic nicotine delivery systems (ENDS) are battery-powered devices that allow nicotine and/or other substances to be inhaled in aerosolized form. e-Cigarettes (electronic cigarettes), the most commonly used ENDS, have been proposed to be smoking cessation aids. However, despite the rapid surge in their popularity, little is known about long-term health consequences of e-cigarette usage. We assess published data to see if they deliver what they promise. COMMENT: e-Cigarettes may contain uncertain quantities of various ingredients, and evidence of adulteration has been identified. Flavouring agents can alter the pharmacokinetics of nicotine and have uncertain impact on the nature of e-cigarette use (eg ab initio use vs smoking cessation). WHAT IS NEW AND CONCLUSION: Although e-cigarettes have been proposed to be a safe approach to encouraging smoking cessation, there are inconsistencies in available data. And further data are needed regarding long-term implications of primary and secondary exposure to e-cigarette products.
Assuntos
Fumar/efeitos adversos , Dispositivos para o Abandono do Uso de Tabaco/efeitos adversos , Adulto , Idoso , Sistemas Eletrônicos de Liberação de Nicotina , Aromatizantes/efeitos adversos , Humanos , Pessoa de Meia-Idade , Nicotina/efeitos adversos , Nicotina/farmacocinética , Fumar/metabolismo , Abandono do Hábito de Fumar , Adulto JovemRESUMO
The role of the patient-provider agreement (PPA) is to set forth respective roles and responsibilities for opioid therapy with the goal of improving outcomes, reducing risks, and improving patient education. The Food and Drug Administration (FDA) Safe Use Initiative Opioid PPA Working Group convened to develop a PPA and test it for acceptability as an educational and shared decision-making tool in opioid therapy. This multicentre study evaluated the utility of the PPA, how readily patients understood it, its ability to educate patients in an unbiased way about opioid treatment and the feasibility of incorporating a PPA in clinical practice. A total of 117 patients and 14 providers at urban centres were included (mean patient age: 56 years) with 85% of patients treated for pain for >3 months. Most patients reported the PPA to be 'somewhat helpful' or 'very helpful' in deciding a course of treatment (96%) and 'easy to understand' (97%). Both patients and prescribers (89% and 92%, respectively) found the PPA was neutral in terms of presenting opioid therapy. Most centres found the PPA could be administered in ≤10 min and 72% of prescribers said this PPA could be readily incorporated into their practice. This PPA was perceived by both patients and prescribers as helpful in deciding a course of treatment and unbiased in terms of presentation of the risks and benefits of opioid therapy.