RESUMO
PURPOSE: An oral docetaxel formulation boosted by the Cytochrome P450 (CYP) 3 A inhibitor ritonavir, ModraDoc006/r, is currently under clinical investigation. Based on clinical data, the incidence of grade 1-2 diarrhea is increased with this oral docetaxel formulation compared to the conventional intravenous administration. Loperamide, a frequently used diarrhea inhibitor, could be added to the regimen as symptomatic treatment. However, loperamide is also a substrate of the CYP3A enzyme, which could result in competition between ritonavir and loperamide for this protein. Therefore, we were interested in the impact of coadministered loperamide on the pharmacokinetics of ritonavir-boosted oral docetaxel. METHODS: We administered loperamide simultaneously or with an 8-hour delay to humanized CYP3A4 mice (with expression in liver and intestine) receiving oral ritonavir and docetaxel. Concentrations of docetaxel, ritonavir, loperamide and two of its active metabolites were measured. RESULTS: The plasma exposure (AUC and Cmax) of docetaxel was not altered during loperamide treatment, nor were the ritonavir plasma pharmacokinetics. However, the hepatic and intestinal dispositions of ritonavir were somewhat changed in the simultaneous, but not 8-hour loperamide treatment groups, possibly due to loperamide-induced delayed drug absorption. The pharmacokinetics of loperamide itself did not seem to be influenced by ritonavir. CONCLUSION: These results suggest that delayed loperamide administration can be added to ritonavir-boosted oral docetaxel treatment, without affecting the overall systemic exposure of docetaxel.
Assuntos
Citocromo P-450 CYP3A , Docetaxel , Interações Medicamentosas , Loperamida , Ritonavir , Taxoides , Ritonavir/administração & dosagem , Ritonavir/farmacocinética , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Loperamida/administração & dosagem , Loperamida/farmacocinética , Animais , Camundongos , Citocromo P-450 CYP3A/metabolismo , Administração Oral , Taxoides/farmacocinética , Taxoides/administração & dosagem , Humanos , Distribuição Tecidual , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacologia , Área Sob a Curva , Antidiarreicos/administração & dosagem , Antidiarreicos/farmacocinética , Camundongos TransgênicosRESUMO
Novel combinations of specific opioid agonists like loperamide and oxymorphindole targeting the µ- and δ-opioid receptors, respectively, have shown increased potency with minimized opioid-associated risks. However, whether their interaction is pharmacokinetic or pharmacodynamic in nature has not been determined. This study quantitatively determined whether these drugs have a pharmacokinetic interaction that alters systemic disposition or central nervous system (CNS) distribution. We performed intravenous and oral in vivo pharmacokinetic assessments of both drugs after discrete dosing and administration in combination to determine whether the combination had any effect on systemic pharmacokinetic parameters or CNS exposure. Drugs were administered at 5 or 10 mg/kg i.v. or 30 mg/kg orally to institute for cancer research (ICR) mice and 5 mg/kg i.v. to Friend leukemia virus strain B mice of the following genotypes: wild-type, breast cancer resistance protein (Bcrp-/- ) (Bcrp knockout), Mdr1a/b-/- [P-glycoprotein (P-gp) knockout], and Bcrp-/- Mdr1a/b-/- (triple knockout). In the combination, clearance of oxymorphindole (OMI) was reduced by approximately half, and the plasma area under the concentration-time curve (AUC) increased. Consequently, brain and spinal cord AUCs for OMI in the combination also increased proportionately. Both loperamide and OMI are P-gp substrates, but administration of the two drugs in combination does not alter efflux transport at the CNS barriers. Because OMI alone shows appreciable brain penetration but little therapeutic efficacy on its own, and because loperamide's CNS distribution is unchanged in the combination, the mechanism of action for the increased potency of the combination is most likely pharmacodynamic and most likely occurs at receptors in the peripheral nervous system. This combination has favorable characteristics for future development. SIGNIFICANCE STATEMENT: Opioids have yet to be replaced as the most effective treatments for moderate-to-severe pain and chronic pain, but their side effects are dangerous. Combinations of opioids with peripheral activity, such as loperamide and oxymorphindole, would be valuable in that they are effective at much lower doses and have reduced risks for dangerous side effects because the µ-opioid receptor agonist is largely excluded from the CNS.
Assuntos
Sistema Nervoso Central/metabolismo , Loperamida/farmacocinética , Morfolinas/farmacocinética , Receptores Opioides/agonistas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Genótipo , Loperamida/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos ICR , Morfolinas/administração & dosagem , Distribuição TecidualRESUMO
BACKGROUND: Ion channels have been proposed as therapeutic targets for different types of malignancies. One of the most studied ion channels in cancer is the voltage-gated potassium channel ether-à-go-go 1 or Kv10.1. Various studies have shown that Kv10.1 expression induces the proliferation of several cancer cell lines and in vivo tumor models, while blocking or silencing inhibits proliferation. Kv10.1 is a promising target for drug discovery modulators that could be used in cancer treatment. This work aimed to screen for new Kv10.1 channel modulators using a thallium influx-based assay. METHODS: Pharmacological effects of small molecules on Kv10.1 channel activity were studied using a thallium-based fluorescent assay and patch-clamp electrophysiological recordings, both performed in HEK293 stably expressing the human Kv10.1 potassium channel. RESULTS: In thallium-sensitive fluorescent assays, we found that the small molecules loperamide and amitriptyline exert a potent inhibition on the activity of the oncogenic potassium channel Kv10.1. These results were confirmed by electrophysiological recordings, which showed that loperamide and amitriptyline decreased the amplitude of Kv10.1 currents in a dose-dependent manner. Both drugs could be promising tools for further studies. CONCLUSIONS: Thallium-sensitive fluorescent assay represents a reliable methodological tool for the primary screening of different molecules with potential activity on Kv10.1 channels or other K+ channels.
Assuntos
Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Loperamida/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Relação Dose-Resposta a Droga , Fluorescência , Células HEK293 , Humanos , Loperamida/administração & dosagem , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/administração & dosagem , Reprodutibilidade dos Testes , Tálio/metabolismoRESUMO
In recent years, there has been an emergence of numerous novel drugs. Such toxicity may occur in both adolescents and adults. This article discusses the opioid epidemic and several emerging opioids, including buprenorphine, loperamide, fentanyl, fentanyl derivatives, and others. Kratom, a plant occasionally used for opiate detoxification, along with the sedatives etizolam and phenibut, will be discussed. Lastly, this article discusses the phenethylamines and marijuana.
Assuntos
Drogas Desenhadas/efeitos adversos , Drogas Ilícitas/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/complicações , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Buprenorfina/administração & dosagem , Buprenorfina/efeitos adversos , Canabinoides/efeitos adversos , Drogas Desenhadas/administração & dosagem , Overdose de Drogas/tratamento farmacológico , Fentanila/administração & dosagem , Fentanila/efeitos adversos , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Loperamida/administração & dosagem , Loperamida/efeitos adversos , Mitragyna/efeitos adversos , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Fenetilaminas/efeitos adversosRESUMO
BACKGROUND: Irritable bowel syndrome with diarrhea (IBS-D) is a chronic disorder of gut-brain interaction that negatively affects work productivity and health-related quality of life (HRQOL). IBS-D therapeutic options are limited and include loperamide, an over-the-counter µ-opioid receptor agonist commonly used as an antidiarrheal agent, and eluxadoline, a mixed µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist approved in the United States for the treatment of IBS-D in adults. OBJECTIVE: To characterize the effect of eluxadoline on work productivity and HRQOL in patients with IBS-D with previous inadequate response to loperamide. METHODS: The Work Productivity and Activity Impairment Questionnaire for IBS-D (WPAI:IBS-D), Centers for Disease Control and Prevention Healthy Days Core Module (CDC HRQOL-4), and EuroQoL-5 Dimension (EQ-5D) instruments were administered at baseline and week 12 of a phase 4 clinical trial (RELIEF), assessing the efficacy and safety of eluxadoline treatment in adults with IBS-D reporting previous inadequate response to loperamide. Changes from baseline to week 12 for each assessment were evaluated using an analysis of covariance model. Indirect costs were calculated by converting overall work productivity losses into monetary values. RESULTS: A total of 346 patients were randomized to either eluxadoline (n = 172) or placebo (n = 174). From baseline to week 12, compared with placebo, twice-daily treatment with eluxadoline resulted in significantly greater reductions in absenteeism (2.6%; P = 0.046). Numerically greater decreases in presenteeism, overall work productivity loss, and daily activity impairment were also observed in patients receiving eluxadoline compared with those receiving placebo (P = not significant for each). Numerical reductions in overall work productivity loss from baseline to week 12 translate to approximately 2.4 hours per patient per week (123 hours annually) and correspond to an avoided overall work loss of $4,503 annually for an employee with IBS-D treated with eluxadoline. In addition, from baseline to week 12, treatment with eluxadoline led to a significantly greater reduction in the number of unhealthy days experienced (-1.7 days; P = 0.042), as well as numerical improvements in EQ-5D measures in comparison with placebo (P = not significant for each). CONCLUSIONS: In patients with IBS-D reporting inadequate response to loperamide, eluxadoline treatment was associated with significant reductions in absenteeism and the number of unhealthy days experienced. Eluxadoline treatment of IBS-D may lead to significant cost savings via mitigation of losses in work productivity. DISCLOSURES: This study was sponsored by Allergan plc (before acquisition by AbbVie, Inc.). Allergan plc and/or AbbVie, Inc., was involved in the study design, collection, analysis, interpretation of the data, writing of the report, and the decision to submit the report for publication. Abel and Burslem are employees of AbbVie, Inc., and own stock/stock options. Brenner has served as a consultant, speaker, and/or advisor for Allergan plc (before acquisition by AbbVie, Inc.), Alnylam, Alpha Sigma, Arena, Bayer, Ironwood Pharmaceuticals, Salix Pharmaceuticals, Shire, Synergy, and Takeda Pharmaceuticals. He is also supported in research by an unrestricted gift from the Irene D. Pritzker Foundation. Sayuk has served as a consultant and speaker for Allergan plc (before acquisition by AbbVie, Inc.), Gi Health Foundation, Ironwood Pharmaceuticals, Salix Pharmaceuticals, and Synergy. Portions of the current work were presented at AMCP Nexus; October 22-25, 2018; Orlando, FL.
Assuntos
Absenteísmo , Fármacos Gastrointestinais/uso terapêutico , Imidazóis/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Loperamida/uso terapêutico , Fenilalanina/análogos & derivados , Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diarreia/tratamento farmacológico , Diarreia/psicologia , Feminino , Fármacos Gastrointestinais/administração & dosagem , Humanos , Imidazóis/administração & dosagem , Síndrome do Intestino Irritável/psicologia , Loperamida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fenilalanina/administração & dosagem , Fenilalanina/uso terapêutico , Inquéritos e Questionários , Estados Unidos , Adulto JovemRESUMO
Loperamide is a µ-opioid agonist with poor gastrointestinal absorption, mainly because of its modest aqueous solubility and being a P-glycoprotein (Pgp) efflux substrate. Nevertheless, studies associated with therapeutic effects strongly suggest that loperamide holds potential pharmacological advantages over traditional µ-opioid agonists commonly used for analgesia. Thus, in this Communication, we assessed in MDCK-hMDR1 cell lines the effects over loperamide uptake and efflux ratio, when loaded into Eudragit RS (ERS) nanocarriers coated with poloxamer 188 (P188). ERS was chosen for enhancing loperamide aqueous dispersibility and P188 as a potential negative Pgp modulator. In uptake assays, it was observed that Pgp limited the accumulation of loperamide into cells and that preincubation with P188, but not coincubation, led to increasing loperamide uptake at a similar extent of Pgp pharmacological inhibition. On the other hand, the efflux ratio displayed no alterations when Pgp was pharmacologically inhibited, whereas ERS/P188 nanocarriers effectively enhanced loperamide uptake and absorptive transepithelial transport. The latter suggests that loperamide transport across cells is significantly influenced by the presence of the unstirred water layer (UWL), which could hinder the visualization of Pgp-efflux effects during transport assays. Thus, results in this work highlight that formulating loperamide into this nanocarrier enhances its uptake and transport permeability.
Assuntos
Antidiarreicos/administração & dosagem , Portadores de Fármacos/química , Loperamida/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Resinas Acrílicas/química , Administração Oral , Animais , Antidiarreicos/farmacocinética , Disponibilidade Biológica , Cães , Humanos , Absorção Intestinal , Mucosa Intestinal/metabolismo , Loperamida/farmacocinética , Células Madin Darby de Rim Canino , Metacrilatos/química , Nanopartículas/química , Permeabilidade , Poloxâmero/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , SolubilidadeRESUMO
Patients on dialysis are frequently administered high doses of potassium binders such as calcium polystyrene sulfonate (CPS) and sodium polystyrene sulfonate (SPS), which exacerbate constipation. Here, we compare the degree of constipation induced by CPS and SPS using a loperamide-induced constipation model to identify the safer potassium binder. Constipation model was created by twice-daily intraperitoneal administration (ip) of loperamide hydrochloride (Lop; 1 mg/kg body weight) in rats for 3 days. Rats were assigned to a control group, Lop group, Lop + CPS group or Lop + SPS group, and a crossover comparative study was performed. Defecation status (number of feces, feces wet weight, fecal water content and gastrointestinal transit time (GTT)) was evaluated. In the Lop + CPS group, GTT was significantly longer, and fecal water content was reduced. In the Lop + SPS group-although the fecal water content and GTT were unaffected-the number of fecal pellets and the fecal wet weight improved. Thus, SPS was less likely to cause constipation exacerbation than CPS. Considering the high frequency of constipation in dialysis patients with hyperkalemia, preferentially administering SPS over CPS may prevent constipation exacerbation.
Assuntos
Antidiarreicos/efeitos adversos , Constipação Intestinal/induzido quimicamente , Loperamida/efeitos adversos , Poliestirenos/administração & dosagem , Potássio/metabolismo , Animais , Antidiarreicos/administração & dosagem , Defecação/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Injeções Intraperitoneais , Loperamida/administração & dosagem , Masculino , Poliestirenos/farmacologia , Ratos , Diálise Renal/efeitos adversosRESUMO
BACKGROUND: Insulin-like peptide 5 (INSL5) is a hormone stored in colonic enteroendocrine cells that also contain the unrelated hormones, GLP-1 and PYY. It acts at the relaxin family peptide 4, RXFP4, receptor. RXFP4 is expressed by enteric neurons in the colon, and it has been speculated that INSL5, through its action on enteric neurons, might be involved in the control of colonic contractions. Similar to insulin and relaxin, INSL5 consists of A and B peptide chains linked by three disulfide bonds, two between the chains and one intrinsic to the A chain. Because of its complex structure, it is difficult to synthesize and to prepare peptide analogues to investigate its roles. We have recently developed a potent simplified peptide analogue, INSL5-A13 (INSL5 analogue 13). METHODS: In the present work, we have investigated the actions of INSL5-A13 in mice. We investigated the ability of INSL5-A13 to increase the speed of emptying of a bead from the colon, after expulsion had been slowed by the peripherally restricted opioid agonist, loperamide (1 mg/kg). KEY RESULTS: INSL5-A13 was a full agonist at the mouse RXFP4 expressed in HEK cells, with an EC50 of ~9 nmol/L. INSL5-A13 caused an acceleration of colorectal bead propulsion in mice constipated by loperamide in the dose range 0.2 to 60 µg/kg, with an EC50 of ~6 µg/kg in vivo. It also accelerated bead propulsion in untreated mice. Bead expulsion was not accelerated in RXFP4-/- mice. CONCLUSION AND INFERENCES: Our data suggest that RXFP4 agonists could be useful in the treatment of constipation.
Assuntos
Colo/efeitos dos fármacos , Colo/fisiologia , Constipação Intestinal/fisiopatologia , Motilidade Gastrointestinal/efeitos dos fármacos , Hormônios Peptídicos/química , Receptores Acoplados a Proteínas G/agonistas , Animais , Antidiarreicos/administração & dosagem , Constipação Intestinal/induzido quimicamente , Motilidade Gastrointestinal/fisiologia , Células HEK293 , Humanos , Loperamida/administração & dosagem , Masculino , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Loperamide is a mu-opioid receptor agonist that is available as an over-the-counter anti-motility agent in the US and UK; recommended maximum doses of 12-16 mg/day. Anecdotal reports of non-medical use (NMU) have increased over the past decade with supra-therapeutic doses (70-800 mg/day) associated with cardiotoxicity. Little data exists on the prevalence of loperamide NMU. AIM: The aim of this study was to determine the prevalence of loperamide NMU in the UK and US and to describe characteristics of non-medical loperamide users. DESIGN: The Researched, Abuse, Diversion and Addiction Related Surveillance (RADARS® ) Survey of Nonmedical Use of Prescription Drugs (NMURx) was utilized to study NMU of loperamide among the adult population in the UK and US in 2017. The RADARS® NMURx is anonymous and self-administered online. METHODS: A total of 40,029 completed surveys were included (10,019 from the UK and 30,010 from the US). Respondents were asked questions about medical and NMU of loperamide, frequency of and reasons for NMU, route of use problematic drug use markers, and demographics. RESULTS: Prevalence of lifetime loperamide use (95% CI) and lifetime NMU of loperamide were: UK 28.5% (27.67-29.4), and 0.66% (0.5-0.8), respectively; US 33.7% (33.1-34.2), and 5.19% (4.9-5.5), respectively. Problematic drug use markers were elevated in those who reported NMU of loperamide in both the UK and US, however high-risk use was more prevalent in the UK than in the US. CONCLUSION: NMU of loperamide is common. In the current international environment of opioid addiction involving both therapeutic and illicit opioids, awareness of the NMU of loperamide is important.
Assuntos
Antidiarreicos/administração & dosagem , Loperamida/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Uso Indevido de Medicamentos sob Prescrição/estatística & dados numéricos , Medicamentos sob Prescrição , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Drogas Ilícitas , Masculino , Pessoa de Meia-Idade , Prevalência , Inquéritos e Questionários , Reino Unido/epidemiologia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Acute noninfectious diarrhea is a common phenomenon in intensive care unit patients. Multiple treatments are suggested but the most effective management is unknown. A working group of the Eastern Association for the Surgery of Trauma, aimed to evaluate the effectiveness of loperamide, diphenoxylate/atropine, and elemental diet on acute noninfectious diarrhea in critically ill adults and to develop recommendations applicable to daily clinical practice. METHODS: The literature search identified 11 randomized controlled trials (RCT) appropriate for inclusion. The Grading of Recommendations Assessment, Development, and Evaluation methodology was applied to evaluate the effect of loperamide, diphenoxylate/atropine, and elemental diet on the resolution of noninfectious diarrhea in critically ill adults based on selected outcomes: improvement in clinical diarrhea, fecal frequency, time to the diarrhea resolution, and hospital length of stay. RESULTS: The level of evidence was assessed as very low. Analyses of 10 RCTs showed that loperamide facilitates resolution of diarrhea. Diphenoxylate/atropine was evaluated in three RCTs and was as effective as loperamide and more effective than placebo. No studies evaluating elemental diet as an intervention in patients with diarrhea were found. CONCLUSION: Loperamide and diphenoxylate/atropine are conditionally recommended to be used in critically ill patients with acute noninfectious diarrhea. LEVEL OF EVIDENCE: Systematic Review/Guidelines, level III.
Assuntos
Estado Terminal/terapia , Diarreia/etiologia , Diarreia/terapia , Dietoterapia/métodos , Difenoxilato/administração & dosagem , Loperamida/administração & dosagem , Adulto , Antidiarreicos/administração & dosagem , Diarreia/fisiopatologia , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the effects of multiple doses of loperamide on the pharmacokinetics and safety of a single oral dose of neratinib. METHODS: This was an open-label, two-period, fixed-sequence study. Twenty healthy adult subjects received an oral dose of neratinib 240 mg daily on Days 1-4 of Period 1 followed by a 7-day washout. In Period 2, oral neratinib 240 mg was administered with loperamide 4 mg followed by two further doses of loperamide 2 mg 8 and 16 h later on Days 1-4. Pharmacokinetic sampling was performed for 72 h following each neratinib dose. Safety was monitored throughout the study. RESULTS: A median tmax of ~ 6 h was observed for neratinib during both periods. Apparent clearance and volume of distribution were similar for Periods 1 and 2: mean CLss/F 308.2 and 322.1 L/h; mean Vzτ/F 7995 and 10,318 L, respectively. The half-life of neratinib increased in the presence of loperamide from 18.0 to 22.2 h. Mean exposure was within the same range without and with loperamide administration: Cmax 61.2 ng/mL and 49.5 ng/mL; AUClast 1086 ng h/mL and 1153 ng h/mL, and AUCtau 779 ng h/mL and 745 ng h/mL, respectively. Treatment-emergent adverse events were mainly mild in intensity, with the most frequent events being diarrhea (45%) and constipation (35%). CONCLUSIONS: Neratinib administered alone and concomitantly with multiple oral doses of loperamide is generally safe and well tolerated. Loperamide has minimal effects on neratinib pharmacokinetic parameters.
Assuntos
Antidiarreicos/administração & dosagem , Loperamida/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/administração & dosagem , Administração Oral , Adulto , Antidiarreicos/farmacologia , Área Sob a Curva , Esquema de Medicação , Interações Medicamentosas , Feminino , Meia-Vida , Humanos , Loperamida/farmacologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/efeitos adversos , Quinolinas/farmacocinética , Distribuição Tecidual , Adulto JovemAssuntos
Buprenorfina/uso terapêutico , Loperamida , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Formulações de Dissuasão de Abuso , Adulto , Analgésicos Opioides/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Loperamida/administração & dosagemRESUMO
The opioid epidemic has left its toll on the United States with millions suffering from an opioid use disorder and tens of thousands dying from overdoses each year. With intentions to combat the crisis, health providers have been prescribing less opioids, which resulted in an unintentional increase in the abuse of other opioid-like substances. Three emerging drugs of abuse have been noted in the literature as having increased abuse potential in light of recent trends. Kratom, an herbal supplement, gabapentin, a prescription nerve pain and anticonvulsant medication, and loperamide, an over-the-counter antidiarrheal medication. These have all displayed opioid-like properties at high doses and used to alleviate opioid withdrawal. Healthcare clinicians and patients might not be aware of the potential risks involved with misusing or abusing these opioid substitutes. This article discusses the increased usage of kratom, gabapentin, and loperamide, the abuse potential, adverse effects and withdrawal symptoms of each drug, and nursing implications that impact inpatient safety and management.
Assuntos
Tratamento de Substituição de Opiáceos/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Antidiarreicos/administração & dosagem , Antidiarreicos/efeitos adversos , Gabapentina/administração & dosagem , Gabapentina/efeitos adversos , Humanos , Loperamida/administração & dosagem , Loperamida/efeitos adversos , Mitragyna/efeitos adversos , Síndrome de Abstinência a Substâncias , Estados UnidosRESUMO
BACKGROUND: Loperamide is a potent mu opioid receptor agonist available over the counter to treat diarrhea. Although at therapeutic doses loperamide is devoid of central effects, it may exert them if used at high doses or combined with drugs that increase its systemic and/or central bioavailability. Recently, public health and scientific interest on loperamide has increased due to a growing trend of misuse and abuse, and consequent reports on its toxicity. Our aim was to evaluate in the rat the effects of increasing loperamide doses, with increasing likelihood to induce central effects, on gastrointestinal motor function (including gastric dysmotility and nausea-like behavior). METHODS: Male Wistar rats received an intraperitoneal injection of vehicle or loperamide (0.1, 1, or 10 mg kg-1 ). Three sets of experiments were performed to evaluate: (a) central effects (somatic nociceptive thresholds, immobility time, core temperature, spontaneous locomotor activity); (b) general gastrointestinal motility (serial X-rays were taken 0-8 hours after intragastric barium administration and analyzed semiquantitatively, morphometrically, and densitometrically); and (c) bedding intake (a rodent indirect marker of nausea). Animals from sets 1 and 3 were used to evaluate gastric dysmotility ex vivo at 2 and 4 hours after administration, respectively. KEY RESULTS: Loperamide significantly induced antinociception, hypothermia, and hypolocomotion (but not catalepsy) at high doses and dose-dependently reduced gastrointestinal motor function, with the intestine exhibiting higher sensitivity than the stomach. Whereas bedding intake occurred early and transiently, gastric dysmotility was much more persistent. CONCLUSIONS AND INFERENCES: Our results suggest that loperamide-induced nausea and gastric dysmotility might be temporally dissociated.
Assuntos
Antidiarreicos/toxicidade , Motilidade Gastrointestinal/efeitos dos fármacos , Loperamida/toxicidade , Animais , Relação Dose-Resposta a Droga , Hipotermia/induzido quimicamente , Locomoção/efeitos dos fármacos , Loperamida/administração & dosagem , Masculino , Náusea/induzido quimicamente , Nociceptividade/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Upper gastrointestinal (GI) motility is affected by various drugs and diseases. However, changes in upper GI motility during these conditions are not well understood, as there are few quantitative in vivo methods that assess small intestinal motility in mice. Ultrasonography is a noninvasive method for imaging and evaluating the condition of the abdominal organs. The aim of the present study was to establish a novel method for evaluating small intestinal motility by using ultrasonography in mice. We measured GI motility with and without loperamide, an antidiarrheal medication, by intestinal transit using an orally administered dye, a 13C-octanoic acid breath test, and ultrasonography. Locomotion activity of the duodenal wall was used for quantifying the GI motility observed via ultrasonography. Our results showed that upper GI transit was significantly delayed by loperamide. The 13C-octanoic acid breath test revealed decreased gastric emptying in loperamide-treated mice. Through ultrasonography, large peristaltic movements were observed in the duodenum of the control mice. In contrast, after treatment with loperamide, these peristaltic movements were suppressed, and the duodenal lumen was enlarged, suggesting decreased duodenal motility. In accordance with these results, quantifiable locomotion activity was also significantly decreased. In conclusion, ultrasonography is an effective in vivo method to quantify small intestinal motility in mice.
Assuntos
Antidiarreicos/administração & dosagem , Motilidade Gastrointestinal/fisiologia , Intestino Delgado/fisiologia , Loperamida/administração & dosagem , Camundongos/fisiologia , Ultrassonografia/métodos , Animais , Feminino , Camundongos Endogâmicos C57BL , Modelos AnimaisRESUMO
BACKGROUND: The use of regional and other opioid-sparing forms of anesthesia has been associated with a decrease in the recurrence of certain malignancies. Direct suppression of human natural killer cells by opioids has been postulated to explain this observation. However, the effect of different classes of opioids on suppression of natural killer cell cytotoxicity has not been systematically characterized. METHODS: After confirming that freshly isolated natural killer cells from peripheral human blood express opioid receptors, cells were incubated with increasing concentrations of clinically used or receptor-specific opioid agonists. We also evaluated the effect of pretreatment with receptor-specific antagonists or naloxone. Treated natural killer cells were then coincubated with a carboxyfluorescein succinimidyl ester-labeled target tumor cell line, K562. Annexin V staining was used to compare the percent of tumor cell apoptosis in the presence of opioid-pretreated and untreated natural killer cells. Treated samples were compared to untreated samples using Kruskal-Wallis tests with a post hoc Dunn correction. RESULTS: Morphine, methadone, buprenorphine, loperamide, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, and U-50488 significantly decreased natural killer cell cytotoxicity. When natural killer cells were pretreated with naloxone, cyprodime, and nor-binaltorphimine before exposure to morphine, there was no difference in natural killer cytotoxicity, compared to the amount observed by untreated natural killer cells. Fentanyl, O-desmethyltramadol, and [D-Pen2,D-Pen5] enkephalin did not change natural killer cell cytotoxicity compare to untreated natural killer cells. CONCLUSIONS: Incubation of isolated natural killer cells with certain opioids causes a decrease in activity that is not observed after naloxone pretreatment. Suppression of natural killer cell cytotoxicity was observed with µ- and κ-receptor agonists but not δ-receptor agonists. These data suggest that the effect is mediated by µ- and κ-receptor agonism and that suppression is similar with many clinically used opioids.
Assuntos
Analgésicos Opioides/administração & dosagem , Células Matadoras Naturais/efeitos dos fármacos , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/administração & dosagem , Anestesia , Buprenorfina/administração & dosagem , D-Penicilina (2,5)-Encefalina/administração & dosagem , Fentanila/administração & dosagem , Fluoresceínas/administração & dosagem , Humanos , Terapia de Imunossupressão , Células K562 , Loperamida/administração & dosagem , Metadona/administração & dosagem , Morfinanos/administração & dosagem , Morfina/administração & dosagem , Naloxona/administração & dosagem , Naltrexona/administração & dosagem , Naltrexona/análogos & derivados , Succinimidas/administração & dosagem , Receptor 4 Toll-Like/metabolismo , Tramadol/administração & dosagem , Tramadol/análogos & derivadosAssuntos
Caesalpinia/toxicidade , Intoxicação por Plantas , Plantas Tóxicas , Adulto , Antidiarreicos/administração & dosagem , Antidiarreicos/uso terapêutico , Antieméticos/administração & dosagem , Antieméticos/uso terapêutico , Criança , Feminino , Humanos , Loperamida/administração & dosagem , Loperamida/uso terapêutico , Masculino , Ondansetron/administração & dosagem , Ondansetron/uso terapêuticoRESUMO
INTRODUCTION: Loperamide is a readily accessible nonprescription medication that is increasingly being used surreptitiously as an opioid substitute to alleviate the symptoms of acute opioid withdrawal. The objective of this study was to determine the clinical characteristics of patients with loperamide misuse and toxicity. METHODS: The ToxIC registry, a nationwide, prospectively collected cohort of patients evaluated by medical toxicologists was searched from November 2011-December 2016 for patients with loperamide exposure. Each record was reviewed to determine the circumstances, dose, clinical presentations, treatment, and outcomes associated with loperamide use. RESULTS: Twenty-six cases were identified, and both the absolute number and relative proportion of overall cases in the ToxIC registry increased annually. The median age was 27 and 54% were male. Of cases with known intent (n = 18), 12(67%) were misuse/abuse, 3(17%) were self-harm/suicide, and 3(17%) were pediatric exploratory ingestions. Circumstances for misuse included taking higher doses than labeled (n =7), avoiding withdrawal (n = 6), and gaining a pleasurable sensation (n =4). The dose was reported in nine cases and ranged from 4 mg to 400 mg. In patients seeking to avoid withdrawal doses were 160-400 mg/day; the most common reported dose was 200 mg. Reported ECG abnormalities included 10 cases of prolonged QTc (>500 ms), which consisted of misuse/abuse (n =6) and self-harm (n =1) exposures; six prolonged QRS (>120 ms); two first degree AV block; seven ventricular dysrhythmias, five of which were single-agent exposures. All but one ECG demonstrated prolonged QTc with a range of 566-749 ms. All patients with dysrhythmias in which dose were reported ingested ≥200 mg. CONCLUSIONS: The majority of patients had loperamide toxicity due to misuse/abuse, in-line with national trends. In patients avoiding withdrawal, doses >100 mg were observed. When taken in large doses (>200 mg), loperamide may cause significant cardiovascular effects, including QTc-prolongation and ventricular dysrhythmias.
Assuntos
Antidiarreicos/efeitos adversos , Loperamida/efeitos adversos , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antidiarreicos/administração & dosagem , Antidiarreicos/uso terapêutico , Arritmias Cardíacas/induzido quimicamente , Bloqueio Atrioventricular/induzido quimicamente , Criança , Pré-Escolar , Estudos de Coortes , Eletrocardiografia , Feminino , Humanos , Síndrome do QT Longo/induzido quimicamente , Loperamida/administração & dosagem , Loperamida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
: This case report describes a patient with opioid use disorder who developed cardiac toxicity secondary to non-medical use of loperamide. At recommended doses, loperamide remains in the periphery to treat diarrhea. At high doses, loperamide causes central nervous system (CNS) opioid agonism. Complications of high-dose loperamide have been documented, including cardiotoxicity, and death. This is particularly important in light of the ongoing opioid epidemic. This case presents a patient with sequela of high-dose loperamide as an illicit opioid replacement and the subsequent loperamide toxicity, including significant QTc prolongation. Abrupt cessation of his high-dose loperamide use resulted in opioid withdrawal symptoms, which were treated with buprenorphine. Buprenorphine was selected to avoid possible worsening of QTc secondary to an additional medication, such as methadone. To our knowledge, this is the first description of the use of buprenorphine for treatment of loperamide-associated opioid use disorder. Non-medical use of loperamide requires increased recognition by the health care community, including both physicians and pharmacists, because it can result in marked and life-threatening toxicity.