Applying children's enuresis treatment with amitriptyline for canine post-spaying urinary incontinence: A pilot estriol-controlled randomized clinical trial.

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.

The harmful acute effects of clomipramine in the rat liver: Impairments in mitochondrial bioenergetics.

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.

Intoxicación por antidepresivos tricíclicos / Tricyclic antidepressant poisoning

Introducción: el paciente intoxicado sigue siendo un desafío para el personal de salud. La intoxicación por antidepresivos tricíclicos (ATC) es un diagnóstico frecuente y una patología que puede llegar a ser muy grave. A pesar de que ha cambiado el objetivo terapéutico de estos fármacos a lo largo de los años, la alta disponibilidad de estos hace que su uso para intento de autolisis siga presentándose. Su presentación clínica es variada y dado el riesgo de mortalidad asociada, es importante que esta patología sea rápidamente reconocida por los médicos que los reciben para iniciar un manejo oportuno y eficaz. Objetivo: presentar el enfrentamiento inicial y manejo terapéutico de la intoxicación por ATC desde la perspectiva de la medicina de urgencia. Método: se realizó una revisión bibliográfica de la literatura científica sobre el manejo de un paciente intoxicado por ATC. Se presenta la evidencia actual de las intervenciones terapéuticas más utilizadas. respecto al manejo inicial y enfrentamiento de la intoxicación por antidepresivos tricíclicos, en el contexto de la atención en un servicio de urgencia. Conclusión: la intoxicación por ATC puede presentarse con síntomas leves y signos precoces, así como con síntomas graves e incluso fatales, dados principalmente por complicaciones cardiovasculres y neurológicas. Su manejo se basa en el reconocimiento precoz, medidas de soporte y terapias específicas según la clínica que presente.

Managing poisoned patients continues to be a challenge for health personnel. Tricyclic antidepressant are a frequent diagnosis, and a pathology their can be very serious. Although the therapeutic indications for these drugs have changed over the years, their high availability means that their use for suicidal attempts continues to be present. Its clinical presentation is varied and given the mortality risk, it is crucial that this entity must be rapidly recognized by the physicians who care for them to initiate timely and effective treatment. Objective: Present the initial management and therapeutic strategies for tricyclic antidepressant intoxication, from emergency medicine perspective. Method: Bibliographic review of the scientific literature on this subject. Current evidence of the most widely used therapeutic interventions is described regarding the initial management and disposition of tricyclic antidepressant intoxication in the emergency department.

Effects of tricyclic antidepressants, selective serotonin reuptake inhibitors, and selective serotonin-norepinephrine reuptake inhibitors on the ocular surface / Efeitos dos antidepressivos tricíclicos, inibidores seletivos da recaptação da serotonina e inibidores da recaptação de serotonina e noradrenalina na superfície ocular

ABSTRACT Purpose: This study aimed to investigate the effects of tricyclic antidepressants, selective serotonin reuptake inhibitors, and selective serotonin noradrenaline reuptake inhibitors on the ocular surface. Methods: The study included 330 eyes of 165 patients using antidepressants and 202 eyes of 101 controls. Tear fluid breakup time, Schirmer I test, and Ocular Surface Disease Index (OSDI) questionnaire were administered. Beck Depression Inventory and Beck Anxiety Inventory were applied to record drug use, dosages, psychiatric disease duration, and remission time. Results: Mean tear fluid breakup time was 14.29 ± 4.81 (4-26) sec, and Schirmer I test value was 16.05 ± 5.89 (2-28) mm in study group. Tear fluid breakup time was 18.16 ± 2.12 (15-24) sec and Schirmer I test value was 16.64 ± 2.31 (15-24) mm in control group (p<0.001 and p=0.005, respectively). In study group, 38.18% (n=63) of patients had dry eye, and 17% (n=18) of patients in control group had dry eye (p<0.001). The mean OSDI score was 82.56 ± 16.21 (66-100) in the tricyclic antidepressants Group, 60.02 ± 29.18 (10-100) in the serotonin reuptake inhibitors Group, and 22.30 ± 20.87 (0-75) in the serotonin-noradrenaline reuptake inhibitors Group (p<0.001). Mean tear fluid breakup time was 14.36 ± 3.35 (10-20) sec in tricyclic antidepressants Group, 13.94 ± 5.81 (4-26) sec in the serotonin reuptake inhibitors Group, and 14.93 ± 4.20 (6-20) sec in serotonin-noradrenaline reuptake inhibitors Group (p=0.730). The mean Schirmer I test value was 9.90 ± 7.22 (2-30) mm in tricyclic antidepressants Group, 15.55 ± 5.15 (2-25) mm in serotonin reuptake inhibitors Group and 17.71 ± 4.21 (10-30) mm in serotonin-noradrenaline reuptake inhibitors Group (p<0.001). There was no statistically significant difference between OSDI score, tear fluid breakup time, and Schirmer I test values in serotonin reuptake inhibitors and serotonin-no­radrenaline reuptake inhibitors subgroups. Conclusions: Dry eye is common in antidepressant users, but considering the ocular surface, serotonin-noradrenaline reuptake inhibitors may be more reliable than other antidepressants. Patients using serotonin-noradrenaline reuptake inhibitors have lower OSDI scores. Serotonin-noradrenaline reuptake inhibitors, which are useful in chronic pain syndromes, may also have a corrective effect on dry eye symptoms.

RESUMO Objetivo: O objetivo deste estudo é investigar os efeitos dos antidepressivos tricíclicos, dos inibidores da recaptação da serotonina e dos inibidores da recaptação da serotonina e noradrenalina na superfície ocular. Métodos: Foram incluídos no estudo 330 olhos de 165 pacientes em uso de antidepressivos e 202 olhos de 101 controles. Foi medido o tempo de ruptura do fluido lacrimal e foram administrados o teste de Schirmer I e o questionário Ocular Surface Disease Index (OSDI). Os Inventários de Depressão e de Ansiedade de Beck foram aplicados ao uso dos medicamentos e foram registrados as dosagens, a duração da doença psiquiátrica e o tempo de remissão. Resultados: No grupo de estudo, o tempo médio de ruptura do fluido lacrimal foi de 14,29 ± 4,81 segundos (intervalo de 4-26 segundos) e o valor médio do teste de Schirmer I foi de 16,05 ± 5,89 mm (intervalo de 2-28 mm). No grupo controle. o tempo médio de rompimento do fluido lacrimal foi de 18,16 ± 2,12 segundos (intervalo de 15-24 segundos) e o valor do teste de Schirmer I foi de 16,64 ± 2,31 mm (intervalo de 15-24 mm), com p<0,001 e p=0,005, respectivamente. No grupo de estudo, 38,18% (n=63) dos pacientes tinham olho seco, enquanto no grupo controle 17% (n=18) tinham olho seco (p<0,001). O escore médio no OSDI foi de 82,56 ± 16,21 (intervalo 66-100) no grupo dos antidepressivos tricíclicos, 60,02 ± 29,18 (10-100) no grupo dos inibidores da recaptação da serotonina e 22,30 ± 20,87 (0-75) no grupo dos inibidores da recaptação da serotonina e noradrenalina (p<0,001). O tempo médio de rompimento do fluido lacrimal foi de 14,36 ± 3,35 segundos (intervalo de 10-20 segundos) no grupo dos antidepressivos tricíclicos, 13,94 ± 5,81 segundos (intervalo de 4-26 segundos) no grupo dos inibidores da recaptação de serotonina e 14,93 ± 4,20 segundos (intervalo de 6-20 segundos) no grupo dos inibidores da recaptação de serotonina e noradrenalina (p=0,730). O valor médio do teste de Schirmer I foi de 9,90 ± 7,22 mm (intervalo de 2-30 mm) no grupo dos antidepressivos tricíclicos, 15,55 ± 5,15 mm (intervalo de 2-25 mm) no grupo dos inibidores da recaptação da serotonina e 17,71 ± 4,21 mm (intervalo de 10-30 mm) no grupo dos inibidores da recaptação da serotonina e noradrenalina (p<0,001). Não houve diferença estatisticamente significativa no escore OSDI, no tempo de ruptura do fluido lacrimal e nos valores do teste de Schirmer I entre os subgrupos de pacientes em uso de inibidores da recaptação de serotonina e de inibidores da recaptação de serotonina e noradrenalina. Conclusões: Olho seco é uma queixa comum em usuários de antidepressivos, mas no que diz respeito à superfície ocular, inibidores da recaptação de serotonina e noradrenalina podem ser mais confiáveis que outros antidepressivos. Pacientes em uso de inibidores da recaptação de serotonina e noradrenalina têm escores menores no questionário OSDI. Os inibidores da recaptação da serotonina e noradrenalina, úteis nas síndromes de dor crônica, também podem ter um efeito corretivo nos sintomas de olho seco.

6-nitrodopamine is a major endogenous modulator of human vas deferens contractility.

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.

Clomipramine and alprazolam to treat noise phobia in a dog: case report / Uso de clomipramina e alprazolam no tratamento de cão com sensibilidade à ruídos: relato de caso

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)

Clomipramine and alprazolam to treat noise phobia in a dog: case report / Uso de clomipramina e alprazolam no tratamento de cão com sensibilidade à ruídos: relato de caso

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 patient’s 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.

Electric field-assisted multiphase extraction to increase selectivity and sensitivity in liquid chromatography-mass spectrometry and paper spray mass spectrometry.

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.

Post-neutering urethral sphincter mechanism incompetence in female dogs

Female dogs neutering is a routine surgery that aims to prevent diseases as well as to help populational control. Urinary incontinence is one of the most significant unwanted consequences following the procedure. Pharmacological treatment is recommended for such case, and alpha-adrenergic and estrogenic drugs have been the most frequent choices reported in literature. Besides, tricyclic antidepressants are also able to control clinical signs. The exact mechanism involved with this condition is not yet fully understood. Estrogen deficiency with a subsequent loss of urethral tonus is believed to trigger clinical signs. However, it is possible that other factors such as gonadotropins and gonadotropin-releasing hormone levels may play a part on this complex mechanism of the post-neutering urinary incontinence.(AU)

Post-neutering urethral sphincter mechanism incompetence in female dogs

Female dogs neutering is a routine surgery that aims to prevent diseases as well as to help populational control. Urinary incontinence is one of the most significant unwanted consequences following the procedure. Pharmacological treatment is recommended for such case, and alpha-adrenergic and estrogenic drugs have been the most frequent choices reported in literature. Besides, tricyclic antidepressants are also able to control clinical signs. The exact mechanism involved with this condition is not yet fully understood. Estrogen deficiency with a subsequent loss of urethral tonus is believed to trigger clinical signs. However, it is possible that other factors such as gonadotropins and gonadotropin-releasing hormone levels may play a part on this complex mechanism of the post-neutering urinary incontinence.

Supramolecular microextraction combined with paper spray ionization mass spectrometry for sensitive determination of tricyclic antidepressants in urine.

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.

Detection of potential risks in the prescription of tricyclic antidepressants through an online clinical alert system.

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.

Pharmacogenomics in chronic pain therapy: from disease to treatment and challenges for clinical practice.

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.

A New Methodology to Create Polymeric Nanocarriers Containing Hydrophilic Low Molecular-Weight Drugs: A Green Strategy Providing a Very High Drug Loading.

To date, a large number of active molecules are hydrophilic and aromatic low molecular-weight drugs (HALMD). Unfortunately, the low capacity of these molecules to interact with excipients and the fast release when a formulation containing them is exposed to biological media jeopardize the elaboration of drug delivery systems by using noncovalent interactions. In this work, a new, green, and highly efficient methodology to noncovalently attach HALMD to hydrophilic aromatic polymers to create nanocarriers is presented. The proposed method is simple and consists in mixing an aqueous solution containing HALMD (model drugs: imipramine, amitriptyline, or cyclobenzaprine) with another aqueous solution containing the aromatic polymer [model polymer: poly(sodium 4-styrenesulfonate) (PSS)]. NMR experiments demonstrate strong chemical shifting of HALMD aromatic rings when interacting with PSS, evidencing aromatic-aromatic interactions. Ion pair formation and aggregation produce the collapse of the system in the form of nanoparticles. The obtained nanocarriers are spheroidal, their size ranging between 120 and 170 nm, and possess low polydispersity (≤0.2) and negative zeta potential (from -60 to -80 mV); conversely, the absence of the aromatic group in the polymer does not allow the formation of nanostructures. Importantly, in addition to high drug association efficiencies (≥90%), the formed nanocarriers show drug loading values never evidenced for other systems comprising HALMD, reaching ≈50%. Diafiltration and stopped flow experiments evidenced kinetic drug entrapment governed by molecular rearrangements. Importantly, the nanocarriers are stable in suspension for at least 18 days and are also stable when exposed to different high ionic strength, pH, and temperature values. Finally, they are transformable to a reconstitutable dry powder without losing their original characteristics. Considering the large quantity of HALMD with importance in therapeutics and the simplicity of the presented strategy, we envisage these results as the basis to elaborate a number of drug delivery systems with applications in different pathologies.

A concise and versatile route to tetrahydro-1-benzazepines carrying [a]-fused heterocyclic units: synthetic sequence and spectroscopic characterization, and the molecular and supramolecular structures of one intermediate and two products.

A concise, efficient and versatile route from simple starting materials to tricyclic tetrahydro-1-benzazepines carrying [a]-fused heterocyclic units is reported. Thus, the easily accessible methyl 2-[(2-allyl-4-chlorophenyl)amino]acetate, (I), was converted, via (2RS,4SR)-7-chloro-2,3,4,5-tetrahydro-1,4-epoxy-1-benzo[b]azepine-2-carboxylate, (II), to the key intermediate methyl (2RS,4SR)-7-chloro-4-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-2-carboxylate, (III). Chloroacetylation of (III) provided the two regioisomers methyl (2RS,4SR)-7-chloro-1-(2-chloroacetyl)-4-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-2-carboxylate, (IVa), and methyl (2RS,4SR)-7-chloro-4-(2-chloroacetoxy)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-2-carboxylate, C14H15Cl2NO4, (IVb), as the major and minor products, respectively, and further reaction of (IVa) with aminoethanol gave the tricyclic target compound (4aRS,6SR)-9-chloro-6-hydroxy-3-(2-hydroxyethyl)-2,3,4a,5,6,7-hexahydrobenzo[f]pyrazino[1,2-a]azepine-1,4-dione, C15H17ClN2O4, (V). Reaction of ester (III) with hydrazine hydrate gave the corresponding carbohydrazide (VI), which, with trimethoxymethane, gave a second tricyclic target product, (4aRS,6SR)-9-chloro-6-hydroxy-4a,5,6,7-tetrahydrobenzo[f][1,2,4]triazino[4,5-a]azepin-4(3H)-one, C12H12ClN3O2, (VII). Full spectroscopic characterization (IR, 1H and 13C NMR, and mass spectrometry) is reported for each of compounds (I)-(III), (IVa), (IVb) and (V)-(VII), along with the molecular and supramolecular structures of (IVb), (V) and (VII). In each of (IVb), (V) and (VII), the azepine ring adopts a chair conformation and the six-membered heterocyclic rings in (V) and (VII) adopt approximate boat forms. The molecules in (IVb), (V) and (VII) are linked, in each case, into complex hydrogen-bonded sheets, but these sheets all contain a different range of hydrogen-bond types: N-H...O, C-H...O, C-H...N and C-H...π(arene) in (IVb), multiple C-H...O hydrogen bonds in (V), and N-H...N, O-H...O, C-H...N, C-H...O and C-H...π(arene) in (VII).

Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi.

Chagas disease is caused by infection with the parasite protozoan Trypanosoma cruzi and affects about 8 million people in 21 countries in Latin America. The main form of treatment of this disease is still based on the use of two drugs, benznidazole and nifurtimox, which both present low cure rates in the chronic phase and often have serious side-effects. Herein, we describe the synthesis of tricyclic coumarins that were obtained via NHC organocatalysis and evaluation of their trypanocidal activity. Molecular docking studies against trypanosomal enzyme triosephosphate isomerase (TIM) were carried out, as well as a theoretical study of the physicochemical parameters. The tricyclic coumarins were tested in vitro against the intracellular forms of Trypanosoma cruzi. Among the 18 compounds tested, 10 were more active than the reference drug benznidazole. The trypanocidal activity of the lead compound was rationalized by molecular docking study which suggested the strong interaction with the enzyme TIM by T. cruzi and therefore indicating a possible mode of action. Furthermore, the selectivity index of eight tricyclic coumarins with high anti-T. cruzi activity was above 50 and thus showing that these lead compounds are viable candidates for further in vivo assays.

Use of antidepressive agents as a possibility in the management of periodontal diseases: A systematic review of experimental studies.

Antidepressant agents have anti-inflammatory functions that could be interesting as adjuvants in periodontal therapy. The aim of the present study was to analyze the effect of antidepressive drugs in the management of periodontal disease. The MEDLINE, Scopus, Embase, LILACS, and SciELO databases were searched. To be included, the studies had to be experimental studies; randomized, controlled; double-blinded; or blinded studies. A total of 565 articles were initially searched, of which five were selected for the systematic review. All studies used rats, and three different drugs were evaluated: tianeptine, venlafaxine, and fluoxetine. Two of these studies evaluated the effect of antidepressive agents in rats submitted to both ligature-induced periodontitis and depression models, showing that depressive rats had greater alveolar bone loss (ABL). Only the venlafaxine study was not able to find any significant ABL reduction in the group that used this antidepressive drug. The other four studies showed statistically-significant differences, favoring the group with the antidepressant agent. Treatments that are able to modulate the brain-neuroendocrine-immune system could be used as an adjuvant to periodontal disease management. However, studies on humans and animals are scarce, limiting the conclusion of a positive effect in the present systematic review.

Manejo perioperatorio de pacientes usuarios de antidepresivos / Perioperative management of patients using antidepressants

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.

Consideraciones para el uso de anestesia en pacientes que se encuentren bajo tratamiento con antidepresivos tricíclicos / Considerations for the use of anesthesia in patients undergoing tricyclic antidepressant treatment

Los pacientes bajo tratamiento con antidepresivos tricíclicos a los que se les ha suministrado anestesia han padecido los efectos hipotensores de ambos fármacos. Tradicionalmente se recomendaba la suspensión de estos medicamentos hasta dos semanas antes de la cirugía, sin embargo, en la actualidad se plantea que los mismos no deberían suspenderse, ya que a pesar de los efectos secundarios y las posibles interacciones con los agentes anestésicos, se han descrito casos de suicidio tras su suspensión. Por tales razones se realizó esta revisión bibliográfica con el objetivo de actualizar sobre consideraciones para el uso de anestesia en pacientes que se encuentren bajo tratamiento con antidepresivos tricíclicos. Se pudo constatar que en los estudios realizados al respecto se plantea que la individualización de la técnica quirúrgica, el uso de medicación preanestésica, la disminución de la estimulación simpática y un adecuado control del dolor posoperatorio, resultará en una disminución de los efectos deletéreos de la asociación entre antidepresivos tricíclicos y agentes anestésicos.

Patients undergoing tricyclic antidepressant treatment given anesthesia have experienced the hypotensive effects of both drugs. Traditionally it was recommended to suspend these drugs until two weeks before surgery; however, it is currently proposed that they should not be discontinued, since despite the side effects and possible interactions with anesthetic agents, cases of suicide have been described after its suspension. For these reasons, this bibliographic review was carried out aimed at updating considerations for the use of anesthesia in patients undergoing treatment with tricyclic antidepressants. It was observed that in the developed studies it is suggested that surgical technique individualization, use of pre-anesthetic medication, reduction of sympathetic stimulation and an adequate control of postoperative pain, will result in a decrease in the deleterious effects produced by the association of tricyclic antidepressants and anesthetic agents.

Polycyclic ferrocenyl(dihydro)thiazepine derivatives: Diastereo-selective synthesis, characterization, electrochemical behavior, theoretical and biological investigation.

The reaction of E-2-ferrocenylmethylidenetetralones and E,E-2,6-bis-(ferrocenylmethylidene)-cyclohexanone with 2-aminothiophenol proceed with high diastereoselectivity, forming the ~4.5:1 mixture of trans- and cis-isomers of polycyclic ferrocenylthiazepines, respectively. The reactions of E,E-2,5-bis-(ferrocenylmethylidene)cyclopentanone and E,E-3,5-bis-(ferrocenylmethylidene)-1-methyl-4-piperidone with 2-aminothiophenol take place stereo specifically to form the diastereomeric tricyclic thiazepines of cis- and trans-configuration, respectively. The structures of the obtained compounds were established by IR, 1H and 13C NMR spectroscopy and mass-spectrometry. The structures of the trans-tetralino[1,2a]-, trans-5,7-dimethyltetralino[1,2a]-2-ferrocenyl [1,5]benzo-2,3-dihydrothiazepines and cis-5-ferrocenyl-methylidenecyclopentano[1,2a]-2-ferrocenyl- [1,5]benzo-2,3-dihydrothiazepine were confirmed by X-ray diffraction analysis. An electrochemical study reveals that the diferrocenyl derivatives belong to a Class I compounds of the Robin-Day classification. This behavior is explained by the analysis of frontier orbitals as calculated by density functional theory, showing that only one ferrocenyl unit participates in the generation of HOMO and LUMO orbitals. Compounds 4a and 4c showed similar capacity to inhibit the proliferation of HM1: IMSS trophozoite cultures than the first choice drug for human amoebiasis treatment, metronidazole. Morphological changes induced in the trophozoites after drug exposure suggest a redox in balance as the probable mechanism of the parasite death.