RESUMO
Urinary incontinence due to urethral sphincter mechanism incompetence (USMI) affects up to 20% of bitches that undergo spaying surgery. Amitriptyline is a tricyclic antidepressant whose urinary retention is a reported side effect. This study aimed to assess the efficacy and safety of amitriptyline when compared to estriol orally. Fifteen bitches with a clinical diagnosis of post-spaying UI were evaluated during 60 days in a non-blinded randomized clinical trial. All patients were enrolled after clinical evaluation consisting of anamnesis, physical examination, and complementary exams (complete blood count, biochemical parameters, urinalysis, and abdominal ultrasound). The amitriptyline (AMT) group consisted of 8 bitches, which received the initial dose of 1 mg/kg every 12 h, whereas the estriol (EST) group consisted of 7 bitches which were initially treated with 1 mg/animal every 24 h. Patients underwent clinical evaluation at 7 days, and then at 21 and 60 days of treatment to assess safety and efficacy, as well as adjustments of dose when necessary. A urinary incontinence scale was used to assess the level of incontinence and therapeutic response to treatment. During the period of the study, estriol was fully effective in 71% of cases and amitriptyline in 62%. Both drugs proved safe in the medical treatment of USMI, with adverse effects such as somnolence (AMT, n = 5/8) and male attraction (EST, n = 1/7). The results support the amitriptyline recommendation as a substitute for estriol in USMI treatment.
Assuntos
Doenças do Cão , Enurese , Incontinência Urinária , Feminino , Masculino , Animais , Cães , Amitriptilina/uso terapêutico , Ovariectomia/veterinária , Doenças do Cão/diagnóstico , Incontinência Urinária/tratamento farmacológico , Incontinência Urinária/veterinária , Incontinência Urinária/diagnóstico , Enurese/etiologia , Enurese/veterináriaRESUMO
Clomipramine, a tricyclic antidepressant used to treat depression and obsessive-compulsive disorder, has been linked to a few cases of acute hepatotoxicity. It is also recognized as a compound that hinders the functioning of mitochondria. Hence, the effects of clomipramine on mitochondria should endanger processes that are somewhat connected to energy metabolism in the liver. For this reason, the primary aim of this study was to examine how the effects of clomipramine on mitochondrial functions manifest in the intact liver. For this purpose, we used the isolated perfused rat liver, but also isolated hepatocytes and isolated mitochondria as experimental systems. According to the findings, clomipramine harmed metabolic processes and the cellular structure of the liver, especially the membrane structure. The considerable decrease in oxygen consumption in perfused livers strongly suggested that the mechanism of clomipramine toxicity involves the disruption of mitochondrial functions. Coherently, it could be observed that clomipramine inhibited both gluconeogenesis and ureagenesis, two processes that rely on ATP production within the mitochondria. Half-maximal inhibitory concentrations for gluconeogenesis and ureagenesis ranged from 36.87 µM to 59.64 µM. The levels of ATP as well as the ATP/ADP and ATP/AMP ratios were reduced, but distinctly, between the livers of fasted and fed rats. The results obtained from experiments conducted on isolated hepatocytes and isolated mitochondria unambiguously confirmed previous propositions about the effects of clomipramine on mitochondrial functions. These findings revealed at least three distinct mechanisms of action, including uncoupling of oxidative phosphorylation, inhibition of the FoF1-ATP synthase complex, and inhibition of mitochondrial electron flow. The elevation in activity of cytosolic and mitochondrial enzymes detected in the effluent perfusate from perfused livers, coupled with the increase in aminotransferase release and trypan blue uptake observed in isolated hepatocytes, provided further evidence of the hepatotoxicity of clomipramine. It can be concluded that impaired mitochondrial bioenergetics and cellular damage are important factors underlying the hepatotoxicity of clomipramine and that taking excessive amounts of clomipramine can lead to several risks including decreased ATP production, severe hypoglycemia, and potentially fatal outcomes.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Clomipramina , Ratos , Animais , Clomipramina/toxicidade , Clomipramina/metabolismo , Metabolismo Energético , Fígado/metabolismo , Mitocôndrias/metabolismo , Trifosfato de Adenosina/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Mitocôndrias Hepáticas/metabolismoRESUMO
BACKGROUND: Rat isolated vas deferens releases 6-nitrodopamine (6-ND), and the spasmogenic activity of this novel catecholamine is significantly reduced by tricyclic compounds such as amitriptyline, desipramine, and carbamazepine and by antagonists of the α1 -adrenergic receptors such as doxazosin, tamsulosin, and prazosin. OBJECTIVES: To investigate the liberation of 6-ND by human epididymal vas deferens (HEVDs) and its pharmacological actions. METHODS: The in vitro liberation of 6-ND, dopamine, noradrenaline, and adrenaline from human vas deferens was evaluated by LC-MS/MS. The contractile effect of the catecholamines in HEVDs was investigated in vitro. The action of tricyclic antidepressants was evaluated on the spasmogenic activity ellicited by the catecholamines and by the electric-field stimulation (EFS). The tissue was also incubated with the inhibitor of nitric oxide (NO) synthase L-NAME and the release of catecholamines and the contractile response to EFS were assessed. RESULTS: 6-ND is the major catecholamine released from human vas deferens and its synthesis/release is inhibited by NO inhibition. The spasmogenic activity elicited by EFS in the human vas deferens was blocked by tricyclic antidepressants only at concentrations that selectively antagonize 6-ND induced contractions of the human vas deferens, without affecting the spasmogenic activity induced by dopamine, noradrenaline, and adrenaline in this tissue. Incubation of the vas deferens with L-NAME reduced both the 6-ND release and the contractions induced by EFS. DISCUSSION AND CONCLUSION: 6-ND should be considered a major endogenous modulator of human vas deferens contractility and possibly plays a pivotal role in the emission process of ejaculation. It offers a novel and shared mechanism of action for tricyclic antidepressants and α1 -adrenergic receptor antagonists.
Assuntos
Dopamina , Ducto Deferente , Antagonistas Adrenérgicos/farmacologia , Amitriptilina/farmacologia , Animais , Antidepressivos Tricíclicos/farmacologia , Carbamazepina/farmacologia , Cromatografia Líquida , Desipramina/farmacologia , Dopamina/análogos & derivados , Dopamina/farmacologia , Doxazossina/farmacologia , Epinefrina/farmacologia , Humanos , Masculino , Contração Muscular , Músculo Liso , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico , Norepinefrina/farmacologia , Prazosina/farmacologia , Ratos , Receptores Adrenérgicos , Tansulosina/farmacologia , Espectrometria de Massas em TandemRESUMO
Behavioral disorders, including noise phobia, have a great impact on small animals internal medicine, impairing their quality of life as well as their life expectancy. The objective of this work is to report the case of a male dog who suffered from noise phobia and panic attacks triggered by thunderstorms and fireworks, and did not respond to previous training and treatment. After clinical and laboratory evaluations, he was treated with 2mg/kg clomipramine twice daily for 90 days associated with 0.06mg/kg alprazolam as needed on those days of intense fear. During the first week of treatment, a significant improvement could already be observed, with reduction in destructive behaviors, which lingered on for up to eight months of follow-up. The treatment stabilized the clinical condition and improved the patients quality of life.(AU)
Os distúrbios de comportamento, entre eles o medo de ruídos, apresentam um grande impacto na clínica de peque-nos animais, acarretando em decréscimo na qualidade e expectativa de vida. O objetivo deste trabalho é relatar o caso de um cão, macho, com histórico de medo de ruídos, que apresentava quadros de pânico desencadeados por trovões e fogos de arti-fício, sendo refratário a tentativas prévias de adestramento e tratamento medicamentoso. Após avaliação clínica e laboratorial, instituiu-se tratamento com clomipramina 2mg/kg BID durante 90 dias associada à administração de alprazolam 0,06mg/kg conforme necessário nos dias de medo intensificado. Na primeira semana de tratamento observou-se melhora significativa, com redução dos comportamentos destrutivos, se estendendo até 8 meses de acompanhamento. O tratamento realizado proporcio-nou estabilização do quadro clínico e incremento na qualidade de vida do paciente. informação a ser inserida pelos autores.(AU)
Assuntos
Animais , Cães , Cães , Clomipramina/uso terapêutico , Alprazolam/uso terapêutico , Receptores de GABA-A , Monitoramento do RuídoRESUMO
Behavioral disorders, including noise phobia, have a great impact on small animals internal medicine, impairing their quality of life as well as their life expectancy. The objective of this work is to report the case of a male dog who suffered from noise phobia and panic attacks triggered by thunderstorms and fireworks, and did not respond to previous training and treatment. After clinical and laboratory evaluations, he was treated with 2mg/kg clomipramine twice daily for 90 days associated with 0.06mg/kg alprazolam as needed on those days of intense fear. During the first week of treatment, a significant improvement could already be observed, with reduction in destructive behaviors, which lingered on for up to eight months of follow-up. The treatment stabilized the clinical condition and improved the patients quality of life.
Os distúrbios de comportamento, entre eles o medo de ruídos, apresentam um grande impacto na clínica de peque-nos animais, acarretando em decréscimo na qualidade e expectativa de vida. O objetivo deste trabalho é relatar o caso de um cão, macho, com histórico de medo de ruídos, que apresentava quadros de pânico desencadeados por trovões e fogos de arti-fício, sendo refratário a tentativas prévias de adestramento e tratamento medicamentoso. Após avaliação clínica e laboratorial, instituiu-se tratamento com clomipramina 2mg/kg BID durante 90 dias associada à administração de alprazolam 0,06mg/kg conforme necessário nos dias de medo intensificado. Na primeira semana de tratamento observou-se melhora significativa, com redução dos comportamentos destrutivos, se estendendo até 8 meses de acompanhamento. O tratamento realizado proporcio-nou estabilização do quadro clínico e incremento na qualidade de vida do paciente. informação a ser inserida pelos autores.
Assuntos
Animais , Cães , Alprazolam/uso terapêutico , Clomipramina/uso terapêutico , Cães , Receptores de GABA-A , Monitoramento do RuídoRESUMO
In this work, for the first time, chromatographic paper was used for a multiphase extraction assisted by an electric field (MPEF) and directly coupled to paper spray mass spectrometry (PS-MS). Using this approach, five tricyclic antidepressants (TCAs) were determined in oral fluid. Firstly, the MPEF conditions were optimized using liquid chromatography-mass spectrometry (LC-MS/MS). The effects of the chromatographic paper and the types of electrolyte used in the acceptor phase, the organic solvent type and the amount used in the donor phase, the extraction time, and the applied electric potential were all investigated. After optimization, the analytes were extracted from the donor solution (sample and acetonitrile 1:1 (v/v)) over a period of 10 min at 300 V, crossing the free liquid membrane (1-octanol) and reaching the acceptor phase (chromatographic paper wetted with 400 mmol L-1 acetic acid). The method using LC-MS/MS was validated, demonstrating a linear range from 2 to 12 ng mL-1, with detection and quantification limits of 0.13-0.25 and 0.44-0.84 ng mL-1, respectively, an intraday precision of less than 20%, and no matrix effect observed. The optimized MPEF conditions were then applied to determine TCAs by PS-MS and for this analysis cyclobenzaprine was used as an internal standard. The easy, fast and direct approach of coupling MPEF with PS-MS analysis, as well as the pre-concentration and the low standard deviation of replicates (less than 20%), demonstrates that this method can be useful for screening in clinical and toxicological analysis.
Assuntos
Antidepressivos Tricíclicos , Espectrometria de Massas em Tandem , Cromatografia Líquida , Reprodutibilidade dos Testes , SolventesRESUMO
This work describes a novel methodology to analyze four tricyclic antidepressants (amitriptyline, doxepin, imipramine and, nortriptyline) in urine samples by combining supramolecular microextraction and paper spray ionization mass spectrometry (PS-MS). The proposed method uses a supramolecular solvent in which reverse micelles of 1-decanol are dispersed in tetrahydrofuran (THF)/water. The extraction of the tricyclic antidepressants at pH 9.0 requires a sample volume of 10.0 mL, short extraction time (1.0 min of extraction and 5 min of centrifugation), low amounts of organic solvent (50 µL of 1-decanol and 200 µL of THF), and provides high preconcentration factors: 96.9 to amitriptyline, 93.6 to doxepin, 71.3 to imipramine, and 146.9 to nortriptyline. The quantification by PS-MS is fast and straightforward because chromatographic separation is not required and all analytes were determined simultaneously. The limits of detection (LOD), quantification (LOQ), and the precision (RSD, %) of the developed method ranged between 5.2 and 8.6 µg L-1, 17.4-28.7 µg L-1 and 1.3-12.9%, respectively. Urine samples of five individuals (three males and two females) were used for accuracy evaluation. The accuracy obtained in these spiked urine samples at µg L-1 levels varied from 95.3 to 112.0%. The method also provided clean mass spectra with a high signal-to-noise ratio, which demonstrates the analytical appeal combination of supramolecular microextraction with determination by paper spray mass spectrometry.
Assuntos
Antidepressivos Tricíclicos/urina , Microextração em Fase Líquida , Papel , Amitriptilina/urina , Doxepina/urina , Humanos , Imipramina/urina , Substâncias Macromoleculares/química , Espectrometria de Massas , Estrutura Molecular , Nortriptilina/urinaRESUMO
OBJECTIVE: To analyse the use, indications and potential risks of tricyclic antidepressants (TCAs), using a technological system of clinical alerts at the time of prescription. METHODS: Observational, descriptive, retrospective study on a population covered by a Colombian health insurance plan with an average of 2,333,582 members/month. The information was generated in the PBM (Pharmacy Benefit Management) MC21 Colombia technological platform. RESULTS: Of the total members, 368,298 (16%) patients/month on average were prescribed medicines; 3,640 (1%) were prescribed TCAs: 2,573 amitriptyline (70%) and 1.062 imipramine (29%); 817 (22.5%) were over 65 years of age. The median daily dose of amitriptyline and imipramine was 25 mg. A total of 17,153 alerts were reported: 8,685 (51%) for drug-drug interactions, 7,354 (43%) for drug-age interactions and 543 (3%) for duplicate therapy. CONCLUSIONS: Risks were identified in the prescription of tricyclic antidepressants, especially in the over-65 population, where these drugs are used in particular for the management of neuropathic pain. The clinical alert system at the time of medicinal product formulation can make an important contribution to the prevention of potential adverse events associated with the use of medicinal products.
Assuntos
Antidepressivos Tricíclicos/administração & dosagem , Sistemas de Registro de Ordens Médicas , Padrões de Prática Médica/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Idoso , Amitriptilina/administração & dosagem , Antidepressivos Tricíclicos/efeitos adversos , Criança , Pré-Escolar , Colômbia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Imipramina/administração & dosagem , Lactente , Internet , Pessoa de Meia-Idade , Neuralgia/tratamento farmacológico , Padrões de Prática Médica/normas , Estudos Retrospectivos , Adulto JovemRESUMO
Pharmacogenomics (PGx) has emerged as an encouraging tool in chronic pain therapy. Genetic variations associated with drug effectiveness or adverse reactions (amitriptyline/nortriptyline/codeine/oxycodone/tramadol-CYP2D6, amitriptyline-CYP2C19, carbamazepine-HLA-A, carbamazepine/oxcarbazepine-HLA-B) can be used to guide chronic pain management. Despite this evidence, many obstacles still need to be overcome for the effective clinical implementation of PGx. To translate the pharmacogenetic testing into actionable clinical decisions, the Clinical Pharmacogenetics Implementation Consortium has been developing guidelines for several drug-gene pairs. This review will show the applicability of PGx in chronic pain from disease to treatment; report the drug-gene pairs with strongest evidences in the clinic; and the challenges for the clinical implementation of PGx.
Assuntos
Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Humanos , Manejo da Dor/métodos , Farmacogenética/métodos , Polimorfismo Genético/efeitos dos fármacos , Polimorfismo Genético/genéticaRESUMO
El uso de antidepresivos en el perioperatorio es muy frecuente, y la práctica clínica indica que los pacientes usuarios de antidepresivos que son sometidos a cirugía tienen un riesgo perioperatorio aumentado. No existen en la actualidad guías clínicas basadas en la evidencia que orienten el manejo de este tipo de pacientes, por lo que las recomendaciones se basan en las escasas revisiones sistemáticas y metaanálisis disponibles, reportes de casos y opinión de expertos, que en muchos casos resultan controversiales. La decisión de mantener o suspender la medicación antidepresiva implica considerar los riesgos tanto desde el punto de vista fisiológico (características generales del paciente, riesgos asociados al antidepresivo utilizado, la cirugía propiamente como tal, la interacción con fármacos frecuentemente utilizados en el perioperatorio, entre otros) como desde el punto de vista psiquiátrico (riesgo de síndrome de retirada, recaída de la enfermedad psiquiátrica, intentos suicidas), por lo que la decisión debe ser tomada idealmente de forma multidisciplinaria entre cirujanos, anestesiólogos y psiquiatras, con la idea de confeccionar un plan quirúrgico, anestésico y de manejo perioperatorio seguro para el paciente.
Antidepressant use in the perioperative is a common practice, and clinical evidence shows that surgical patients using antidepressants have an increased perioperative risk. There are not evidence-based guidelines for the perioperative management of these patients, and recommendations are based on few systematic reviews and meta-analysis, case reports and expert opinion, which in many cases are controversial. The decision to continue or discontinue the medication involves considering general patient characteristics, risks associated with the antidepressant used, type of surgery, interaction with drugs commonly used in the perioperative, risk of withdrawal symptoms, relapse of psychiatric disease and suicide risk, so decision should be made between surgeons, anesthesiologists and psychiatrists, in order to design a safe management plan for the patient who undergo surgery.