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1.
BMC Psychiatry ; 22(1): 74, 2022 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-35093063

RESUMO

BACKGROUND: Akathisia tends to develop as an early complication of antipsychotic treatment in a dose-dependent manner. Although withdrawal akathisia has been reported after the discontinuation or dose reduction of typical antipsychotic drugs, akathisia following atypical antipsychotic drug withdrawal remains a rare phenomenon. CASE PRESENTATION: A 24-year-old woman with an acute psychotic episode was admitted and initially treated with aripiprazole. The aripiprazole dose was titrated up to 30 mg/day over 9 days and maintained for the next 3 days; however, her psychotic symptoms persisted without change. She was switched to amisulpride, with the dose increased over 2 weeks to 1000 mg/day. Subsequently, although the patient's psychotic episode subsided, her serum prolactin levels increased markedly. After discharge, the amisulpride dose was increased to 1200 mg/day owing to auditory hallucinations and was maintained with quetiapine (100-200 mg/day) and benztropine (1 mg/day) for 13 weeks. Given the potential for hyperprolactinemia as a side effect, the amisulpride dose was reduced to 800 mg/day concurrently with the discontinuation of benztropine; however, these changes resulted in severe restlessness without other extrapyramidal symptoms. The withdrawal akathisia disappeared over 2 weeks after switching to aripiprazole (10 mg/day) with propranolol (40 mg/day) and the patient's prolactin levels had normalized after 6 months of aripiprazole monotherapy. CONCLUSIONS: The present case highlights the potential for the development of withdrawal akathisia when the dose of amisulpride is tapered abruptly. Thus, a slow tapering and careful monitoring are recommended when switching from amisulpride to other antipsychotic drugs. Furthermore, this case suggests that changing the regimen to aripiprazole with propranolol may be a potential option for amisulpride withdrawal akathisia superimposed on pre-existing hyperprolactinemia.


Assuntos
Antipsicóticos , Hiperprolactinemia , Transtornos Psicóticos , Adulto , Amissulprida/efeitos adversos , Antipsicóticos/efeitos adversos , Aripiprazol/efeitos adversos , Benzotropina/uso terapêutico , Feminino , Humanos , Hiperprolactinemia/induzido quimicamente , Prolactina , Propranolol/efeitos adversos , Agitação Psicomotora/tratamento farmacológico , Agitação Psicomotora/etiologia , Transtornos Psicóticos/complicações , Transtornos Psicóticos/tratamento farmacológico , Adulto Jovem
2.
BMC Musculoskelet Disord ; 22(1): 826, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34579675

RESUMO

BACKGROUND: Knee osteoarthritis is a major cause of pain and disability. Pain control is poor, with most patients remaining in moderate to severe pain. This may be because central causes of pain, a common contributor to knee pain, are not affected by current treatment strategies. Antidepressants, such as amitriptyline, have been used to treat chronic pain in other conditions. The aim of this randomised, double blind, controlled trial, is to determine whether low dose amitriptyline reduces pain in people with painful knee osteoarthritis over 3 months compared to benztropine, an active placebo. METHODS/DESIGN: One hundred and sixty people with painful radiographic knee osteoarthritis will be recruited via clinicians, local and social media advertising. Participants will be randomly allocated in a 1:1 ratio to receive either low dose amitriptyline (25 mg) or active placebo (benztropine mesylate, 1 mg) for 3 months. The primary outcome is change from baseline in knee pain (WOMAC pain subscale) at 12 weeks. Secondary outcomes include change in function (total WOMAC) and the proportion of individuals achieving a substantial response (≥ 50% reduction in pain intensity, measured by Visual Analog Scale, VAS, from no pain to worst pain imaginable, 0-100 mm) and moderate response (≥ 30% reduction in pain intensity, measured by VAS) at 12 weeks. Intention to treat analyses will be performed. Subgroup analyses will be done. DISCUSSION: This study will provide high level evidence regarding the effectiveness of low dose amitriptyline compared to benztropine in reducing pain and improving function in knee OA. This trial has the potential to provide an effective new therapeutic approach for pain management in knee osteoarthritis, with the potential of ready translation into clinical practice, as it is repurposing an old drug, which is familiar to clinicians and with a well described safety record. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry prior to recruitment commencing ( ACTRN12615000301561 , March 31, 2015, amended 14 December 2018, February 2021). Additional amendment requested 18 July 2021.


Assuntos
Dor Crônica , Osteoartrite do Joelho , Amitriptilina , Austrália , Benzotropina , Dor Crônica/diagnóstico , Dor Crônica/tratamento farmacológico , Método Duplo-Cego , Humanos , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
3.
Commun Biol ; 4(1): 926, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34326460

RESUMO

Patients with cardiovascular comorbidities are more susceptible to severe infection with SARS-CoV-2, known to directly cause pathological damage to cardiovascular tissue. We outline a screening platform using human embryonic stem cell-derived cardiomyocytes, confirmed to express the protein machinery critical for SARS-CoV-2 infection, and a SARS-CoV-2 spike-pseudotyped virus system. The method has allowed us to identify benztropine and DX600 as novel inhibitors of SARS-CoV-2 infection in a clinically relevant stem cell-derived cardiomyocyte line. Discovery of new medicines will be critical for protecting the heart in patients with SARS-CoV-2, and for individuals where vaccination is contraindicated.


Assuntos
Antivirais/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Células-Tronco Embrionárias Humanas/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/virologia , SARS-CoV-2/fisiologia , Benzotropina/farmacologia , Humanos , Miócitos Cardíacos/citologia , Peptídeos/farmacologia
4.
Psychopharmacology (Berl) ; 237(12): 3783-3794, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32964243

RESUMO

RATIONALE: Methylphenidate and d-amphetamine, medications used for treatment of attention deficit hyperactivity disorder (ADHD), are used recreationally and self-administered by laboratory animals. Benztropine (BZT) analogs, like those medications, increase synaptic dopamine levels but are less effective in maintaining self-administration, suggesting clinical utility with less abuse liability. OBJECTIVES: The current study was designed to evaluate potential therapeutic effects of BZT analogs related to ADHD. METHODS: Rats responded under a delay-discounting procedure in which responses on one lever produced immediate delivery of a single food pellet and alternative responses produced four food pellets either immediately or with various temporal delays, with those delays arranged in ascending or random orders in different groups of rats. Selection of the smaller more immediate reinforcer has been suggested as an aspect of "impulsivity," a trait with suggested involvement in ADHD. Other rats were studied under fixed-interval (FI) 300-s schedules to assess drug effects on behavior under temporal control. RESULTS: d-Amphetamine, methylphenidate, and the BZT analog AHN 1-055, but not AHN 2-005 or JHW 007, increased selection of the large, delayed reinforcer with either arrangement of delays. All drugs changed the temporal distribution of responses within the FI from one with responses concentrated at the end to a more uniform distribution. Changes in the temporal distribution of FI responding occurred with drugs that did not affect discounting suggesting that discounting does not arise directly from the same temporal control processes controlling FI responding. CONCLUSIONS: AHN 1-055 may be of clinical utility in the treatment of ADHD.


Assuntos
Benzotropina/análogos & derivados , Benzotropina/farmacologia , Condicionamento Operante/efeitos dos fármacos , Desvalorização pelo Atraso/efeitos dos fármacos , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Benzotropina/uso terapêutico , Condicionamento Operante/fisiologia , Desvalorização pelo Atraso/fisiologia , Inibidores da Captação de Dopamina/farmacologia , Inibidores da Captação de Dopamina/uso terapêutico , Relação Dose-Resposta a Droga , Comportamento Impulsivo/efeitos dos fármacos , Comportamento Impulsivo/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Autoadministração
6.
Am J Case Rep ; 21: e922393, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32506071

RESUMO

BACKGROUND Antipsychotic medications are associated with multiple adverse effects, including metabolic syndrome, prolonged QT interval, and extrapyramidal symptoms. Acute laryngeal dystonia (ALD) is a rare and lethal form of extrapyramidal reaction. CASE REPORT A 27-year-old woman with schizophrenia on risperidone presented to our Emergency Department with a sensation of choking and respiratory distress, mimicking a panic attack. She developed a generalized dystonic reaction in the hospital, leading to diagnosis risperidone-associated ALD as a cause of her initial problems. She was discharged with an emphasis on being compliant with anticholinergic medication. However, her persistent respiratory symptoms prompted us to revisit the management plan. Her risperidone dose was tapered down to discontinue and an alternate drug was chosen. CONCLUSIONS ALD must be considered as a differential diagnosis when patients on antipsychotic medications present with respiratory distress. Our case highlights the association of ALD with an atypical antipsychotic agent, risperidone. Prompt recognition of this entity is necessary to prevent complications and guide definitive management.


Assuntos
Antipsicóticos/efeitos adversos , Distonia/induzido quimicamente , Doenças da Laringe/induzido quimicamente , Risperidona/efeitos adversos , Adulto , Benzotropina/uso terapêutico , Distonia/diagnóstico , Distonia/tratamento farmacológico , Feminino , Humanos , Doenças da Laringe/diagnóstico , Doenças da Laringe/tratamento farmacológico , Esquizofrenia/tratamento farmacológico
7.
J Addict Med ; 13(5): 412-414, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30844875

RESUMO

: Reporting of intoxication and withdrawal from aberrant use of over-the-counter medication has been sparse and inconsistent in literature. Attributed to their anticholinergic properties, medications such as dimenhydrinate (Gravol) taken in supratherapeutic doses have been associated with euphoria, anxiolysis, and hallucinations. We present a case of a woman in her forties, with a psychiatric history of bipolar disorder, and complex concurrent medical history including familial Mediterranean fever (FMF), and fibromyalgia, admitted for withdrawal management of her intravenous dimenhydrinate use. As a result of her FMF, there were numerous hospital admissions and treatment which required intravenous access. Hence, a physician-inserted intravenous access port was placed on her chest. The port was maintained monthly with the help of a community agency. In this port, she was injecting 100 to 200 mg of dimenhydrinate hourly for its euphoric and calming effects, consuming upwards of 2400 mg/d. Comprehensive laboratory work-up and urine drug screening were unremarkable. Vital signs were stable. Her mental status at time of admission was lethargic, unfocused, but calm. Her withdrawal symptoms included severe nausea, vomiting, sedation, headaches, dizziness, anxiety, and muscle stiffness. Her detoxification was managed with benztropine and lorazepam, and was well tolerated. The patient was discharged to a community inpatient rehabilitation center. Urine drug testing before discharge was negative. This case draws attention to the addictive potential of dimenhydrinate and offers a regime for its medical withdrawal management. Additionally, this case highlights that screening and management of over-the-counter medications warrants further clinical consideration and investigation.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Dimenidrinato/envenenamento , Envenenamento/diagnóstico , Psicotrópicos/envenenamento , Benzotropina/administração & dosagem , Dimenidrinato/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Lorazepam/administração & dosagem , Pessoa de Meia-Idade , Envenenamento/tratamento farmacológico , Psicotrópicos/administração & dosagem
8.
Acta Neuropathol Commun ; 7(1): 9, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30657060

RESUMO

The endogenous cholinergic system plays a key role in neuronal cells, by suppressing neurite outgrowth and myelination and, in some cancer cells, favoring tumor growth. Platinum compounds are widely used as part of first line conventional cancer chemotherapy; their efficacy is however limited by peripheral neuropathy as a major side-effect. In a multiple sclerosis mouse model, benztropine, that also acts as an anti-histamine and a dopamine re-uptake inhibitor, induced the differentiation of oligodendrocytes through M1 and M3 muscarinic receptors and enhanced re-myelination. We have evaluated whether benztropine can increase anti-tumoral efficacy of oxaliplatin, while preventing its neurotoxicity.We showed that benztropine improves acute and chronic clinical symptoms of oxaliplatin-induced peripheral neuropathies in mice. Sensory alterations detected by electrophysiology in oxaliplatin-treated mice were consistent with a decreased nerve conduction velocity and membrane hyperexcitability due to alterations in the density and/or functioning of both sodium and potassium channels, confirmed by action potential analysis from ex-vivo cultures of mouse dorsal root ganglion sensory neurons using whole-cell patch-clamp. These alterations were all prevented by benztropine. In oxaliplatin-treated mice, MBP expression, confocal and electronic microscopy of the sciatic nerves revealed a demyelination and confirmed the alteration of the myelinated axons morphology when compared to animals injected with oxaliplatin plus benztropine. Benztropine also prevented the decrease in neuronal density in the paws of mice injected with oxaliplatin. The neuroprotection conferred by benztropine against chemotherapeutic drugs was associated with a lower expression of inflammatory cytokines and extended to diabetic-induced peripheral neuropathy in mice.Mice receiving benztropine alone presented a lower tumor growth when compared to untreated animals and synergized the anti-tumoral effect of oxaliplatin, a phenomenon explained at least in part by benztropine-induced ROS imbalance in tumor cells.This report shows that blocking muscarinic receptors with benztropine prevents peripheral neuropathies and increases the therapeutic index of oxaliplatin. These results can be rapidly transposable to patients as benztropine is currently indicated in Parkinson's disease in the United States.


Assuntos
Antineoplásicos/administração & dosagem , Benzotropina/administração & dosagem , Oxaliplatina/administração & dosagem , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Animais , Linhagem Celular Tumoral , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/prevenção & controle , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiopatologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Masculino , Camundongos Endogâmicos BALB C , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/fisiopatologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiopatologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/fisiologia
10.
Neurochem Int ; 123: 34-45, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30125594

RESUMO

The dopamine transporter (DAT) is a neuronal membrane protein that is responsible for reuptake of dopamine (DA) from the synapse and functions as a major determinant in control of DA neurotransmission. Cocaine and many psychostimulant drugs bind to DAT and block reuptake, inducing DA overflow that forms the neurochemical basis for euphoria and addiction. Paradoxically, however, some ligands such as benztropine (BZT) bind to DAT and inhibit reuptake but do not produce these effects, and it has been hypothesized that differential mechanisms of binding may stabilize specific transporter conformations that affect downstream neurochemical or behavioral outcomes. To investigate the binding mechanisms of BZT on DAT we used the photoaffinity BZT analog [125I]N-[n-butyl-4-(4‴-azido-3‴-iodophenyl)]-4',4″-difluoro-3α-(diphenylmethoxy)tropane ([125I]GA II 34) to identify the site of cross-linking and predict the binding pose relative to that of previously-examined cocaine photoaffinity analogs. Biochemical findings show that adduction of [125I]GA II 34 occurs at residues Asp79 or Leu80 in TM1, with molecular modeling supporting adduction to Leu80 and a pharmacophore pose in the central S1 site similar to that of cocaine and cocaine analogs. Substituted cysteine accessibility method protection analyses verified these findings, but identified some differences in structural stabilization relative to cocaine that may relate to BZT neurochemical outcomes.


Assuntos
Benzotropina/farmacologia , Sítios de Ligação/efeitos dos fármacos , Cocaína/farmacologia , Dopamina/metabolismo , Relação Estrutura-Atividade , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Humanos , Radioisótopos do Iodo/farmacologia
11.
Front Immunol ; 9: 2784, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555470

RESUMO

Though promoting remyelination in multiple sclerosis (MS) has emerged as a promising therapeutic strategy, it does not address inflammatory signals that continue to induce neuronal damage and inhibit effectiveness of repair mechanisms. Our lab has previously characterized the immunomodulatory tetrapeptide, tuftsin, which induces an anti-inflammatory shift in microglia and macrophages. This targeted anti-inflammatory agent improves physical deficits in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we sought to determine whether tuftsin is also effective in combination with benztropine, an FDA-approved drug that stimulates remyelination, in both EAE and in the cuprizone model of demyelination. We show that combining these two agents to promote anti-inflammatory and remyelinating mechanisms alleviates symptoms in EAE and lessens pathological hallmarks in both MS models. Importantly, tuftsin is required to transform the inflammatory CNS environment normally present in EAE/MS into one of an anti-inflammatory nature, and benztropine is required in the cuprizone model to improve remyelination. Our data further support tuftsin's beneficial immunomodulatory activity in the context of EAE, and show that when studying remyelination in the absence of an autoimmune insult, tuftsin still activated microglia toward an anti-inflammatory fate, but benztropine was necessary for significant repair of the damaged myelin. Overall, tuftsin effectively combined with benztropine to significantly improve MS-like pathologies in both models.


Assuntos
Benzotropina/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Bainha de Mielina/imunologia , Tuftsina/farmacologia , Animais , Cuprizona/efeitos adversos , Cuprizona/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Camundongos , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Bainha de Mielina/patologia
12.
Int J Mol Sci ; 19(11)2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30441827

RESUMO

Recent studies have established that dietary protein restriction improves metabolic health and glucose homeostasis. SLC6A19 (B°AT1) is the major neutral amino acid transporter in the intestine and carries out the bulk of amino acid absorption from the diet. Mice lacking SLC6A19 show signs of protein restriction, have improved glucose tolerance, and are protected from diet-induced obesity. Pharmacological blockage of this transporter could be used to induce protein restriction and to treat metabolic diseases such as type 2 diabetes. A few novel inhibitors of SLC6A19 have recently been identified using in vitro compound screening, but it remains unclear whether these compounds block the transporter in vivo. To evaluate the efficacy of SLC6A19 inhibitors biomarkers are required that can reliably detect successful inhibition of the transporter in mice. A gas chromatography mass spectrometry (GC-MS)-based untargeted metabolomics approach was used to discriminate global metabolite profiles in plasma, urine and faecal samples from SLC6A19ko and wt mice. Due to inefficient absorption in the intestine and lack of reabsorption in the kidney, significantly elevated amino acids levels were observed in urine and faecal samples. By contrast, a few neutral amino acids were reduced in the plasma of male SLC6A19ko mice as compared to other biological samples. Metabolites of bacterial protein fermentation such as p-cresol glucuronide and 3-indole-propionic acid were more abundant in SLC6A19ko mice, indicating protein malabsorption of dietary amino acids. Consistently, plasma appearance rates of [14C]-labelled neutral amino acids were delayed in SLC6A19ko mice as compared to wt after intra-gastric administration of a mixture of amino acids. Receiver operating characteristic (ROC) curve analysis was used to validate the potential use of these metabolites as biomarkers. These findings provide putative metabolite biomarkers that can be used to detect protein malabsorption and the inhibition of this transporter in intestine and kidney.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inibidores , Aminoácidos/sangue , Doenças Metabólicas/sangue , Aminoácidos/urina , Animais , Benzotropina/farmacologia , Biomarcadores/metabolismo , Biomarcadores/urina , Proteínas na Dieta/metabolismo , Feminino , Absorção Intestinal , Masculino , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/urina , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Reabsorção Renal
13.
ACS Chem Biol ; 13(8): 2288-2299, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-29893552

RESUMO

Genetic and epigenetic alterations in FK506-binding protein 5 ( FKBP5) have been associated with increased risk for psychiatric disorders, including post-traumatic stress disorder (PTSD). Some of these common variants can increase the expression of FKBP5, the gene that encodes FKBP51. Excess FKBP51 promotes hypothalamic-pituitary-adrenal (HPA) axis dysregulation through altered glucocorticoid receptor (GR) signaling. Thus, we hypothesized that GR activity could be restored by perturbing FKBP51. Here, we screened 1280 pharmacologically active compounds and identified three compounds that rescued FKBP51-mediated suppression of GR activity without directly activating GR. One of the three compounds, benztropine mesylate, disrupted the association of FKBP51 with the GR/Hsp90 complex in vitro. Moreover, we show that removal of FKBP51 from this complex by benztropine restored GR localization in ex vivo brain slices and primary neurons from mice. In conclusion, we have identified a novel disruptor of the FKBP51/GR/Hsp90 complex. Targeting this complex may be a viable approach to developing treatments for disorders related to aberrant FKBP51 expression.


Assuntos
Benzotropina/farmacologia , Depressão/tratamento farmacológico , Proteínas de Choque Térmico HSP90/metabolismo , Receptores de Glucocorticoides/metabolismo , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Benzotropina/química , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Depressão/metabolismo , Descoberta de Drogas , Humanos , Camundongos , Terapia de Alvo Molecular , Ligação Proteica/efeitos dos fármacos , Transtornos de Estresse Pós-Traumáticos/metabolismo , Proteínas de Ligação a Tacrolimo/antagonistas & inibidores
14.
J Pharmacol Exp Ther ; 366(3): 527-540, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29945932

RESUMO

Atypical dopamine transporter (DAT) inhibitors, despite high DAT affinity, do not produce the psychomotor stimulant and abuse profile of standard DAT inhibitors such as cocaine. Proposed contributing features for those differences include off-target actions, slow onsets of action, and ligand bias regarding DAT conformation. Several 3α-(4',4''-difluoro-diphenylmethoxy)tropanes were examined, including those with the following substitutions: N-(indole-3''-ethyl)- (GA1-69), N-(R)-2''-amino-3''-methyl-n-butyl- (GA2-50), N-2''aminoethyl- (GA2-99), and N-(cyclopropylmethyl)- (JHW013). These compounds were previously reported to have rapid onset of behavioral effects and were presently evaluated pharmacologically alone or in combination with cocaine. DAT conformational mode was assessed by substituted-cysteine accessibility and molecular dynamics (MD) simulations. As determined by substituted-cysteine alkylation, all BZT analogs except GA2-99 showed bias for a cytoplasmic-facing DAT conformation, whereas cocaine stabilized the extracellular-facing conformation. MD simulations suggested that several analog-DAT complexes formed stable R85-D476 "outer gate" bonds that close the DAT to extracellular space. GA2-99 diverged from this pattern, yet had effects similar to those of other atypical DAT inhibitors. Apparent DAT association rates of the BZT analogs in vivo were slower than that for cocaine. None of the compounds was self-administered or stimulated locomotion, and each blocked those effects of cocaine. The present findings provide more detail on ligand-induced DAT conformations and indicate that aspects of DAT conformation other than "open" versus "closed" may facilitate predictions of the actions of DAT inhibitors and may promote rational design of potential treatments for psychomotor-stimulant abuse.


Assuntos
Comportamento Animal/efeitos dos fármacos , Benzotropina/química , Benzotropina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Nitrogênio/química , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Masculino , Simulação de Dinâmica Molecular , Conformação Proteica , Ratos , Ratos Sprague-Dawley
15.
J Clin Neurosci ; 51: 12-17, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29475576

RESUMO

Sialorrhea is a common distress associated with certain neurological disorders. The aim of this study is to compare the pharmacological agents used for treating sialorrhea by network meta-analysis. Electronic databases were searched for randomized clinical trials comparing active drugs with either placebo or other active drugs. Total drooling scores was the primary outcome measure. Inverse variance heterogeneity model was used for both direct and mixed treatment comparison analysis. Twenty one studies were included in the systematic review and 15 in the meta-analysis. Compared to placebo, benztropine, botulinum toxins A and B are associated with a significant reduction in the frequency and severity of drooling both in the overall neurological disorders as well as for children with cerebral palsy. Only botulinum toxin A and B were associated with significant therapeutic effects in Parkinson's disease. Benztropine and botulinum toxins A and B were observed to be effective in reducing sialorrhea associated with neurological disorders.


Assuntos
Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/tratamento farmacológico , Sialorreia/tratamento farmacológico , Sialorreia/etiologia , Benzotropina/uso terapêutico , Toxinas Botulínicas Tipo A/uso terapêutico , Criança , Pré-Escolar , Feminino , Glicopirrolato/uso terapêutico , Humanos , Antagonistas Muscarínicos/uso terapêutico , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Escopolamina/uso terapêutico
16.
Neurosci Lett ; 671: 88-92, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29452175

RESUMO

There are currently no approved medications to effectively counteract the effects of methamphetamine (METH), reduce its abuse and prolong abstinence from it. Data accumulated in recent years have shown that a range of N-substituted benztropine (BZT) analogues possesses psychopharmacological features consistent with those of a potential replacement or "substitute" treatment for stimulant addiction. On the other hand, the evidence that antidepressant therapy may effectively prevent relapse to stimulant seeking is controversial. Here, we compared in rats the ability of the BZT analogue and high affinity dopamine (DA) reuptake inhibitor, JHW-007, and the antidepressant, trazodone, administered during extinction sessions after chronic METH self-administration, to alter METH-primed reinstatement of drug seeking. The data showed that trazodone produced paradoxical effects on lever pressing during extinction of METH self-administration, decreasing active, but increasing inactive, lever pressing. JHW-007 did not have any observable effects on extinction training. Importantly, JHW-007 significantly attenuated METH-primed reinstatement, whereas trazodone enhanced it. These findings lend support to the candidacy of selective DA uptake blockers, such as JHW-007, as potential treatments for METH addiction, but not to the use of antidepressant medication as a single therapeutic approach for relapse prevention.


Assuntos
Benzotropina/análogos & derivados , Estimulantes do Sistema Nervoso Central/administração & dosagem , Condicionamento Operante/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Metanfetamina/administração & dosagem , Animais , Autoantígenos , Comportamento Aditivo , Benzotropina/farmacologia , Masculino , Ratos , Ratos Long-Evans , Inibidores de Captação de Serotonina/farmacologia , Trazodona/farmacologia
17.
Psychopharmacology (Berl) ; 235(1): 47-58, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28932889

RESUMO

RATIONALE AND OBJECTIVES: Benztropine (BZT) analogs and other atypical dopamine uptake inhibitors selectively decrease cocaine self-administration at doses that do not affect responding maintained by other reinforcers. Those effects were further characterized in the current study using a behavioral economic assessment of how response requirement (price) affects reinforcers obtained (consumption) in rats. METHODS: Two groups of rats were trained to press levers with food (45-mg pellet) or cocaine (0.32 mg/kg/injection) reinforcement under fixed-ratio (FR) 5-response schedules. In selected sessions, the FR requirement was increased (5-80) during successive 20-min components to determine demand curves, which plot consumption against price. An exponential function was fitted to the data to derive the consumption at zero price (Q 0) and the rate of decrease in consumption (essential value, EV) with increased price. The BZT analogs, AHN1-055, AHN2-005, JHW007 (3.2-10 or 17.8 mg/kg, each), vehicle, or comparison drugs (methylphenidate, ketamine), were administered i.p. before selected demand-curve determinations. RESULTS: Consumption of cocaine or food decreased with increased FR requirement. Each drug shifted the demand curve rightward at the lowest doses and leftward/downward at higher doses. The effects on EV and Q 0 were greater for cocaine than for food-reinforced responding. Additionally, the effects of the BZT analogs on EV and Q 0 were greater than those obtained with a standard dopamine transport inhibitor, methylphenidate, and the NMDA antagonist, ketamine (1.0-10.0 mg/kg, each). With these latter drugs, the demand-curve parameters were affected similarly with cocaine and food-maintained responding. CONCLUSIONS: The current findings, obtained using a behavioral economic assessment, suggest that BZT analogs selectively decrease the reinforcing effectiveness of cocaine.


Assuntos
Comportamento Animal/efeitos dos fármacos , Benzotropina/análogos & derivados , Benzotropina/farmacologia , Transtornos Relacionados ao Uso de Cocaína/economia , Transtornos Relacionados ao Uso de Cocaína/psicologia , Inibidores da Captação de Dopamina/farmacologia , Economia Comportamental , Animais , Antagonistas de Aminoácidos Excitatórios/farmacologia , Alimentos , Injeções Intraperitoneais , Ketamina/farmacologia , Masculino , Metilfenidato/farmacologia , Ratos , Ratos Sprague-Dawley , Esquema de Reforço , Reforço Psicológico , Autoadministração
18.
J Med Chem ; 60(24): 10172-10187, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29227643

RESUMO

The development of medications to treat cocaine use disorders has thus far defied success, leaving this patient population without pharmacotherapeutic options. As the dopamine transporter (DAT) plays a prominent role in the reinforcing effects of cocaine that can lead to addiction, atypical DAT inhibitors have been developed that prevent cocaine from binding to DAT, but they themselves are not cocaine-like. Herein, a series of novel DAT inhibitors were synthesized, and based on its pharmacological profile, the lead compound 10a was evaluated in phase I metabolic stability studies in mouse liver microsomes and compared to cocaine in locomotor activity and drug discrimination paradigms in mice. A molecular dynamic simulation study supported the hypothesis that atypical DAT inhibitors have similar binding poses at DAT in a conformation that differs from that of cocaine. Such differences may ultimately contribute to their unique behavioral profiles and potential for development as cocaine use disorder therapeutics.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos/métodos , Relação Estrutura-Atividade , Animais , Benzotropina/química , Células COS , Chlorocebus aethiops , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Simulação de Dinâmica Molecular , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ratos Sprague-Dawley , Tropanos/química
19.
J Chromatogr Sci ; 55(9): 961-968, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29048492

RESUMO

Two accurate, precise and highly selective stability-indicating methods were adopted for simultaneous determination of benztropine mesylate (BNZ) in presence of its hepatotoxic and carcinogenic degradation product, benzophenone (BPH) either in pure form or in the pharmaceutical formulation without any preliminary separation steps. The first method is a thin layer chromatography (TLC)-densitometric method that depended on separation of BNZ from its degradate on TLC aluminum plates precoated with silica gel 60 F254 as the stationary phase using a developing system consisted of hexane:methylene chloride:triethylamine (5:5:0.6, by volume) and scanning the separated bands at 235 nm. Linear regression analysis data for the calibration plots of BNZ and BPH showed perfect linear relationships over the concentration range of 1.5-10 and 1-10 µg band-1, respectively. The second method is (UPLC) method, at which the mixture was separated on a reversed phase C8 analytical column (1.9 µm ps, 50 mm × 2.1 i.d.) using a mobile phase of acetonitrile: aqueous sodium dodecyl sulfate (50:50, v/v) Adjusted to pH = 3 with phosphoric acid, at a flow rate of 0.5 mL min-1. Quantification was achieved at 210 nm based on peak area and linear calibration curves over the concentration ranges of (20-200 µg mL-1) and (5-50 µg mL-1) for BNZ and BPH, respectively, were obtained. The investigated methods were successfully applied to available dosage form and method validation has been carried out. The results obtained by applying the proposed methods were statistically analyzed and compared with those obtained by reported one and no significant differences were obtained regarding both accuracy and precision.


Assuntos
Benzotropina/análise , Benzotropina/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia em Camada Delgada/métodos , Carcinógenos/análise , Carcinógenos/química , Densitometria/métodos , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes
20.
Rev. Hosp. Ital. B. Aires (2004) ; 37(3): 105-111, Sept. 2017. tab.
Artigo em Espanhol | LILACS | ID: biblio-1087981

RESUMO

La enfermedad con cuerpos de Lewy incluye 2 entidades que podrían ser consideradas variantes clínicas de una misma patología: la demencia con cuerpos de Lewy y la demencia en enfermedad de Parkinson. Con la finalidad de describir correctamente lo que sucede en la evolución de la enfermedad se divide el cuadro en etapa prodrómica y de demencia propiamente dicha. La primera está clínicamente representada por aquel período en el cual, si bien el paciente exhibe algunos signos y síntomas propios de la enfermedad, no reúne criterios de demencia. A pesar de ser difícil de definir y por carecerse todavía de contundentes datos clínicos y biomarcadores, se caracteriza principalmente por deterioro leve selectivo en función atencional ­ visuoespacial, trastorno del sueño REM y disautonomía‒. La segunda etapa está claramente caracterizada en los criterios de consenso del año 2005. Recientemente hemos publicado la validación de un instrumento llamado ALBA Screening Instrument, que permite diagnosticar con alta sensibilidad y especificidad la enfermedad aun en etapas tempranas y diferenciarla de otras patologías semejantes. La tomografía por emisión de positrones (PET) para transportador de dopamina es el procedimiento de referencia (gold standard) del diagnóstico. El tratamiento sintomático con anticolinesterásicos y neurolépticos atípicos favorece una buena evolución de la enfermedad y es fundamental tener en cuenta evitar medicamentos que pueden dañar gravemente a los pacientes como los anticolinérgicos y antipsicóticos típicos. Los avances en el diagnóstico y la difusión del impacto de esta enfermedad en la población contribuirán a generar mayores esfuerzos de investigación para hallar un tratamiento eficaz, preventivo o curativo o de ambas características. (AU)


Lewy body disease includes 2 entities that could be considered clinical variants of the same pathology: Dementia with Lewy bodies and Parkinson's disease Dementia. Two stages of the disease are described in this review, a prodromal stage and one of explicit dementia. The first one is clinically represented by that period in which, the patient exhibits some typical features of the disease, but not dementia criteria. Despite being difficult to define the prodromal stage and that strong clinical data and biomarkers are still lacking, there is evidence to characterize it mainly by mild selective impairment in attention and visuo-spatial function, REM sleep disorder and dysautonomia. The second stage is clearly characterized in the known consensus criteria of 2005. We have recently published the validation of an instrument called ALBA Screening Instrument which showed a high sensitivity and specificity for diagnosis of the disease even in the early stages. It´s useful to differentiate the disease from other similar pathologies. Positron Emission Tomography for dopamine transporter is the gold standard of diagnosis in life. Symptomatic treatment with anticholinesterases and atypical neuroleptics help patients in their evolution of the disease. Anticholinergics and typical antipsychotics are agents to avoid in the treatmen of the disease because can severely damage patients. Future advances in the diagnosis and dissemination of the knowledge of the disease will contribute to generate greater research efforts to find an effective preventive and / or curative treatment. (AU)


Assuntos
Humanos , Doença por Corpos de Lewy/tratamento farmacológico , Doença por Corpos de Lewy/diagnóstico por imagem , Doença de Parkinson/patologia , Atenção , Sinais e Sintomas , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Benzotropina/efeitos adversos , Biperideno/efeitos adversos , Carbidopa/administração & dosagem , Carbidopa/uso terapêutico , Levodopa/administração & dosagem , Levodopa/uso terapêutico , Triexifenidil/efeitos adversos , Inibidores da Colinesterase/uso terapêutico , Clozapina/administração & dosagem , Clozapina/uso terapêutico , Antagonistas Muscarínicos/efeitos adversos , Antagonistas de Dopamina/efeitos adversos , Agonistas de Dopamina/efeitos adversos , Antagonistas Colinérgicos/efeitos adversos , Risperidona/efeitos adversos , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/etiologia , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/patologia , Transtorno do Comportamento do Sono REM/complicações , Demência , Disautonomias Primárias/complicações , Sintomas Prodrômicos , Rivastigmina/administração & dosagem , Rivastigmina/uso terapêutico , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/uso terapêutico , Olanzapina/efeitos adversos , Donepezila/administração & dosagem , Donepezila/uso terapêutico , Haloperidol/efeitos adversos , Antagonistas dos Receptores Histamínicos/efeitos adversos , Hipnóticos e Sedativos/efeitos adversos , Antidepressivos Tricíclicos/efeitos adversos
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