RESUMO
Baloxavir marboxil (BXM) treatment-emergent polymerase acid (PA) I38X amino acid substitution (AAS) in the resistant variants of influenza viruses raise concerns regarding their emergence and spread. This study investigated the impact of 1 or 5 mg/kg BXM and 25 mg/kg oseltamivir phosphate (OS) (single or combination therapy) on the occurrence of resistance-related substitutions during the sequential lung-to-lung passages of AH1N1)pdm09 virus in mice. Deep sequencing analysis revealed that 67% (n = 4/6) of the population treated with BXM single therapy (1 or 5 mg/kg) possessed the treatment-emergent PA-I38X AAS variants (I38T, I38S, and I38V). Notably, BXM-OS combination therapy impeded PA-I38X AAS emergence. Although the doses utilized in the mouse model may not be directly translated into the clinically equivalent doses of each drugs, these findings offer insights toward alternative therapies to mitigate the emergence of influenza antiviral resistance.
Assuntos
Dibenzotiepinas/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/genética , Morfolinas/farmacologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Oseltamivir/farmacologia , Piridonas/farmacologia , Triazinas/farmacologia , Substituição de Aminoácidos , Animais , Antivirais/farmacologia , Modelos Animais de Doenças , Farmacorresistência Viral/efeitos dos fármacos , Camundongos , Infecções por Orthomyxoviridae/virologia , Carga Viral/efeitos dos fármacosAssuntos
Antivirais/uso terapêutico , Dibenzotiepinas/uso terapêutico , Farmacorresistência Viral , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/tratamento farmacológico , Morfolinas/uso terapêutico , Piridonas/uso terapêutico , Triazinas/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Influenza Humana/virologia , Japão , Masculino , Testes de Sensibilidade Microbiana , Mutação , RNA Polimerase Dependente de RNA/genética , Proteínas Virais/genéticaAssuntos
Ácidos Carbocíclicos/uso terapêutico , Antivirais/uso terapêutico , Farmacorresistência Viral , Guanidinas/uso terapêutico , Vírus da Influenza B/genética , Influenza Humana/diagnóstico , Adulto , Dibenzotiepinas/uso terapêutico , Humanos , Indonésia , Vírus da Influenza B/isolamento & purificação , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Japão , Masculino , Testes de Sensibilidade Microbiana , Morfolinas/uso terapêutico , Mutação , Neuraminidase/metabolismo , Piranos/uso terapêutico , Piridonas/uso terapêutico , Ácidos Siálicos/uso terapêutico , Triazinas/uso terapêutico , Zanamivir/uso terapêuticoAssuntos
Antivirais/uso terapêutico , Betacoronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Adenina/análogos & derivados , Adenina/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Amidas/uso terapêutico , Antimaláricos/uso terapêutico , COVID-19 , China , Cloroquina/uso terapêutico , Ensaios Clínicos como Assunto , Cobicistat/uso terapêutico , Proteases 3C de Coronavírus , Cisteína Endopeptidases/metabolismo , Dibenzotiepinas , Combinação de Medicamentos , Descoberta de Drogas , Quimioterapia Combinada , Emtricitabina/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Indóis/uso terapêutico , Lopinavir/uso terapêutico , Medicina Tradicional Chinesa , Morfolinas , Oseltamivir/uso terapêutico , Oxazinas/uso terapêutico , Pandemias , Pirazinas/uso terapêutico , Piridinas/uso terapêutico , Piridonas , RNA Polimerase Dependente de RNA/metabolismo , Ritonavir/uso terapêutico , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismo , Tenofovir/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Proteínas não Estruturais Virais/metabolismo , Tratamento Farmacológico da COVID-19RESUMO
Susceptibility of influenza A viruses to baloxavir can be affected by changes at amino acid residue 38 in the polymerase acidic (PA) protein. Information on replicative fitness of PA-I38-substituted viruses remains sparse. We demonstrated that substitutions I38L/M/S/T not only had a differential effect on baloxavir susceptibility (9- to 116-fold) but also on in vitro replicative fitness. Although I38L conferred undiminished growth, other substitutions led to mild attenuation. In a ferret model, control viruses outcompeted those carrying I38M or I38T substitutions, although their advantage was limited. These findings offer insights into the attributes of baloxavir-resistant viruses needed for informed risk assessment.
Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H3N2/genética , Infecções por Orthomyxoviridae/tratamento farmacológico , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Replicação Viral/genética , Substituição de Aminoácidos , Animais , Dibenzotiepinas , Modelos Animais de Doenças , Cães , Furões , Sequenciamento de Nucleotídeos em Larga Escala , Células Madin Darby de Rim Canino , Masculino , Testes de Sensibilidade Microbiana , Morfolinas , Infecções por Orthomyxoviridae/virologia , Piridonas , RNA Polimerase Dependente de RNA/genética , Estações do Ano , Resultado do Tratamento , Proteínas Virais/genéticaRESUMO
Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), an essential enzyme in the initiation of mRNA synthesis of influenza viruses. In the present study, we evaluated the efficacy of BXM against influenza virus infection in mouse models. Single-day oral administration of BXM completely prevented mortality due to infection with influenza A and B virus in mice. Moreover, 5-day repeated administration of BXM was more effective for reducing mortality and body weight loss in mice infected with influenza A virus than oseltamivir phosphate (OSP), even when the treatment was delayed up to 96 hours post infection (p.i.). Notably, administration of BXM, starting at 72 hours p.i. led to significant decrease in virus titers of >2-log10 reduction compared to the vehicle control within 24 hours after administration. Virus reduction in the lung was significantly greater than that observed with OSP. In addition, profound and sustained reduction of virus titer was observed in the immunocompromised mouse model without emergence of variants possessing treatment-emergent amino acid substitutions in the target protein. In our immunocompetent and immunocompromised mouse models, delayed treatment with BXM resulted in rapid and potent reduction in infectious virus titer and prevention of signs of influenza infection, suggesting that BXM could extend the therapeutic window for patients with influenza virus infection regardless of the host immune status.
Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Oxazinas/farmacologia , Piridinas/farmacologia , Tiepinas/farmacologia , Triazinas/farmacologia , Administração Oral , Animais , Antivirais/administração & dosagem , Dibenzotiepinas , Modelos Animais de Doenças , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Feminino , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunocompetência , Hospedeiro Imunocomprometido , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/fisiologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/fisiologia , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Influenza Humana/virologia , Camundongos , Camundongos Endogâmicos BALB C , Morfolinas , Orthomyxoviridae/fisiologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Oseltamivir/farmacologia , Oxazinas/administração & dosagem , Piridinas/administração & dosagem , Piridonas , Tiepinas/administração & dosagem , Triazinas/administração & dosagem , Replicação Viral/efeitos dos fármacosRESUMO
The novel cap-dependent endonuclease inhibitor baloxavir marboxil was approved for the treatment of influenza virus infection in Japan in February 2018. Two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA) were detected in baloxavir-treated children in December 2018. This mutation is known to confer reduced susceptibility to baloxavir, and the two mutant viruses exhibited 76- and 120-fold reduced susceptibility to baloxavir.
Assuntos
Antivirais/uso terapêutico , Endonucleases/antagonistas & inibidores , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/tratamento farmacológico , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Substituição de Aminoácidos/genética , Antivirais/administração & dosagem , Dibenzotiepinas , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Endonucleases/genética , Humanos , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Influenza Humana/diagnóstico , Japão , Testes de Sensibilidade Microbiana , Morfolinas , Piridonas , Resultado do TratamentoRESUMO
In a Mycobacterium smegmatis mutant library screen, transposon mutants with insertions in fhaA, dprE2, rpsT, and parA displayed hypersusceptibility to antibiotics, including the ß-lactams meropenem, ampicillin, amoxicillin, and cefotaxime. Sub-MIC levels of octoclothepin, a psychotic drug inhibiting ParA, phenocopied the parA insertion and enhanced the bactericidal activity of meropenem against Mycobacterium tuberculosis in combination with clavulanate. Our study identifies novel factors associated with antibiotic resistance, with implications in repurposing ß-lactams for tuberculosis treatment.
Assuntos
Antibacterianos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , Tuberculose/tratamento farmacológico , beta-Lactamas/metabolismo , Ácido Clavulânico/farmacologia , Dibenzotiepinas/farmacologia , Resistência Microbiana a Medicamentos/genética , Meropeném , Testes de Sensibilidade Microbiana , Tienamicinas/farmacologia , Tuberculose/microbiologia , beta-Lactamases/genéticaAssuntos
Antimaníacos/efeitos adversos , Antipsicóticos/efeitos adversos , Delírio/induzido quimicamente , Dibenzotiepinas/efeitos adversos , Esquizofrenia/tratamento farmacológico , Ácido Valproico/efeitos adversos , Adulto , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , MasculinoRESUMO
OBJECTIVE: To identify inhibitors of the essential chromosome partitioning protein ParA that are active against Mycobacterium tuberculosis. METHODS: Antisense expression of the parA orthologue MSMEG_6939 was induced on the Mycobacterium smegmatis background. Screening of synthetic chemical libraries was performed to identify compounds with higher anti-mycobacterial activity in the presence of parA antisense. Differentially active compounds were validated for specific inhibition of purified ParA protein from M. tuberculosis (Rv3918c). ParA inhibitors were then characterized for their activity towards M. tuberculosis in vitro. RESULTS: Under a number of culture conditions, parA antisense expression in M. smegmatis resulted in reduced growth. This effect on growth provided a basis for the detection of compounds that increased susceptibility to expression of parA antisense. Two compounds identified from library screening, phenoxybenzamine and octoclothepin, also inhibited the in vitro ATPase activity of ParA from M. tuberculosis. Structural in silico analyses predict that phenoxybenzamine and octoclothepin undergo interactions compatible with the active site of ParA. Octoclothepin exhibited significant bacteriostatic activity towards M. tuberculosis. CONCLUSIONS: Our data support the use of whole-cell differential antisense screens for the discovery of inhibitors of specific anti-tubercular drug targets. Using this approach, we have identified an inhibitor of purified ParA and whole cells of M. tuberculosis.
Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Segregação de Cromossomos/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Adenosina Trifosfatases/antagonistas & inibidores , Adenosina Trifosfatases/metabolismo , Proteínas de Bactérias/metabolismo , Dibenzotiepinas/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Mycobacterium smegmatis/crescimento & desenvolvimento , Mycobacterium tuberculosis/crescimento & desenvolvimento , Fenoxibenzamina/farmacologia , RNA Antissenso/biossíntese , RNA Antissenso/genéticaRESUMO
Dizocilpine (MK-801; 0.3 mg/kg i.p.)-induced disruption in prepulse inhibition of the acoustic startle response (PPI) can be preferentially restored by "atypical" antipsychotics. In contrast, some findings indicate that not all of the "atypical" antipsychotics, such as clozapine and risperidone, are effective in restoring the NMDA antagonist-induced deficits in PPI. In our study, we evaluated the effect of four different "atypical" antipsychotic drugs on deficits in PPI induced by MK-801. Zotepine and risperidone have high affinities to D2-like and 5-HT2A receptors, while clozapine and olanzapine have multipharmacological profiles with the highest affinities to serotonin 5-HT1A,2A/2C receptors and muscarinic receptors. Results have shown that MK-801 disrupted PPI and increased the ASR in rats. Our results showed no effect of zotepine (1 and 2 mg/kg) and risperidone (0.1 and 1 mg/kg) on disrupted PPI by MK-801. Administration of clozapine (5 and 10 mg/kg) and olanzapine (2.5 and 5 mg/kg) restored the deficits in PPI induced by MK-801. Additionally, we found a decrease of approximately 46% in PPI after administration of clozapine (5 mg/kg) and olanzapine (2.5 and 5 mg/kg) without MK-801 treatment. In summary, the four "atypical" antipsychotics had different efficacies to restore the disrupted PPI by MK-801. Only clozapine and olanzapin restored the MK-801-induced deficits in PPI.
Assuntos
Antipsicóticos/farmacologia , Benzodiazepinas/farmacologia , Clozapina/farmacologia , Dibenzotiepinas/farmacologia , Maleato de Dizocilpina/antagonistas & inibidores , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Reflexo de Sobressalto/efeitos dos fármacos , Risperidona/farmacologia , Estimulação Acústica , Animais , Relação Dose-Resposta a Droga , Masculino , Olanzapina , Ratos , Ratos Wistar , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptores de Dopamina D2/agonistas , Receptores Muscarínicos/efeitos dos fármacosRESUMO
The antipsychotic, zotepine, as well as possessing affinity for dopamine D1- and D2-1ike receptors, has high affinity for the noradrenaline (NA) transporter and inhibits [3H]NA uptake by rat frontal cortex synaptosomes, in vitro. The present studies investigated the effects of zotepine on extracellular NA in the frontal cortex of freely moving rats using in vivo microdialysis. Removal of calcium from the perfusate reduced extracellular NA by 70.5% and prevented the 50 mM KCl-stimulated increase in NA levels. Zotepine (0.5-1.5 mg kg(-1) i.p.), evoked biphasic, dose-dependent rises in extracellular NA with maximal increases observed at 60 min (+ 171.0%) and 240 min (+ 211.5%) post-treatment. The increases in NA levels were sustained for up to 100 min post-dosing. Clozapine (10.0 mg kg(-1) i.p.), resulted in a smaller, transient increase in NA levels (+ 72.0%) which lasted for 20 min post-treatment. Neither ziprasidone (3.0 mg kg(-1) i.p.) nor olanzapine (1.0 mg kg(-1) i.p.) influenced extracellular NA. Systemic treatment with the antidepressant desipramine (0.3 mg kg(-1) i.p.) resulted in a prolonged elevation of NA levels over 240 min (maximal increase of + 354.3%), whilst local infusion of nisoxetine (1-100 microM) through the dialysis probe increased NA levels in a concentration-dependent manner (up to 587.8% of control values). These data suggest that the inhibition of NA uptake by zotepine and its subsequent prolonged elevation of extracellular cortical NA may underlie the reported antidepressant properties of zotepine in schizophrenic patients.
Assuntos
Antipsicóticos/farmacologia , Dibenzotiepinas/farmacologia , Lobo Frontal/fisiologia , Norepinefrina/metabolismo , Análise de Variância , Animais , Cálcio/metabolismo , Desipramina/farmacologia , Espaço Extracelular/fisiologia , Fluoxetina/análogos & derivados , Fluoxetina/farmacologia , Lobo Frontal/efeitos dos fármacos , Cinética , Masculino , Microdiálise , Norepinefrina/antagonistas & inibidores , Potássio/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The effects of monatepil, a new calcium antagonist with alpha 1-blocking activity, and nitrendipine on lipoprotein and carbohydrate metabolism in 86 patients with mild-to-moderate hypertension were examined in a randomized, open-label, multicenter (32 hospitals) study. Thirty-nine patients treated with monatepil and 33 patients treated with nitrendipine completed the 12-week study. Monatepil and nitrendipine each significantly decreased both systolic and diastolic blood pressure. Changes in heart rate were not seen in either group. Monatepil administration significantly decreased total cholesterol, low density lipoprotein (LDL) cholesterol, the LDL cholesterol to high density lipoprotein (HDL) cholesterol ratio, apolipoprotein (Apo) B levels, and HbA1c levels, whereas no changes in these measurements were observed in nitrendipine-treated patients. Monatepil also significantly decreased lipoprotein(a) levels, but there were no significant changes in HDL cholesterol, Apo-AI, or Apo-E levels. After nitrendipine treatment, the C peptide concentration decreased significantly, although no significant changes were observed in fasting blood glucose or immunoreactive insulin levels. On the basis of these results, it can be concluded that monatepil belongs to a new class of antihypertensive calcium antagonist with favorable carbohydrate metabolism and lipid-lowering activity, although the clinical importance of these findings has not been established.
Assuntos
Antagonistas Adrenérgicos alfa/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Dibenzotiepinas/uso terapêutico , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Nitrendipino/uso terapêutico , Adulto , Idoso , Carboidratos/sangue , Humanos , Lipoproteínas/sangue , Lipoproteínas/efeitos dos fármacos , Pessoa de Meia-Idade , Piperazinas/uso terapêuticoRESUMO
Effects of monatepil ([(+/-)-N-(6,11-dihydrodibenzo[b, e]thiepin-11-yl)-4-(p-fluorophenyl)-1-piperazinebutyramide]m aleate, AJ-2615, CAS 103377-41-9), a novel calcium antagonist, on the cardiac conduction system were compared by electrocardiography with those of the existing calcium antagonists (diltiazem, verapamil and nifedipine) in isolated rabbit heart preparations in vitro and in anesthetized and conscious dogs in vivo. Monatepil (10(-7) mol/l) prolonged the atrio-His bundle conduction time (AH interval) in the Langendorff perfused rabbit heart, like diltiazem, verapamil and nifedipine. This prolongation was decreased to 1/10 in the presence of 3.6% bovine serum albumin. In anesthetized dogs, monatepil (0.1-1.0 mg/kg i.v.), unlike diltiazem and verapamil, did not prolong AH interval. In conscious dogs, monatepil even at 100 mg/kg p.o. did not affect electrocardiograms. At the high dose of 300 mg/kg p.o., only a slight prolongation of the QT interval was found, but the QTc interval was not affected. Diltiazem at 10 mg/kg p.o. caused a prolongation of the PR interval and a disappearance of QRS waves. In conscious renal hypertensive dogs, repeated administration of monatepil (10 mg/kg/d p.o. for 29 days) had little effect on the conduction system of the heart examined by electrocardiograms, albeit a persistent fall in blood pressure continued throughout the administration period. The above results suggest that monatepil is a highly safe drug in the treatment of hypertension.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Dibenzotiepinas/farmacologia , Eletrocardiografia/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Anestesia , Animais , Pressão Sanguínea/efeitos dos fármacos , Fascículo Atrioventricular/efeitos dos fármacos , Diltiazem/farmacologia , Cães , Feminino , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Técnicas In Vitro , Masculino , Nifedipino/farmacologia , Piperazinas/farmacologia , Coelhos , Verapamil/farmacologiaRESUMO
210 psychiatric outpatients with generalised anxiety disorder (71), or panic disorder (74), or dysthymic disorder (65) diagnosed by an interview schedule for DSM-III were allocated by constrained randomisation to one of five treatments: diazepam (28), dothiepin (28), placebo (28), cognitive and behaviour therapy (84), and a self-help treatment programme (42). All treatments were given for 6 weeks and then withdrawn by 10 weeks. Ratings of psychopathology were made by psychiatric assessors blind to both treatment and diagnosis before treatment and at 2, 4, 6, and 10 weeks after randomisation. 18 patients had insufficient data for analysis because of early drop-out. There were no important differences in treatment response between the diagnostic groups, but diazepam was less effective than dothiepin, cognitive and behaviour therapy, or self-help, these three treatments being of similar efficacy. Significantly more patients in the placebo group took additional psychotropic drugs in the 10 week period, and those allocated to dothiepin and cognitive and behaviour therapy took the least.
Assuntos
Transtornos de Ansiedade/terapia , Terapia Comportamental , Aconselhamento , Transtorno Depressivo/terapia , Diazepam/uso terapêutico , Dibenzotiepinas/uso terapêutico , Dotiepina/uso terapêutico , Terapia de Relaxamento , Adulto , Idoso , Análise de Variância , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/psicologia , Ensaios Clínicos como Assunto , Cognição , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/psicologia , Diazepam/administração & dosagem , Dotiepina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pânico/efeitos dos fármacos , Psicoterapia/métodos , Distribuição Aleatória , Fatores de TempoRESUMO
Three agents that significantly prolong cardiac allograft survival were tested in Lewis rats that were recipients of hearts from Lewis X Brown-Norway F1 hybrid donors. In the presence of azathioprine, the effects of daily administration of either the thromboxane antagonist (L 640,035), the platelet-activating factor (PAF) antagonist (BN 52021) or prednisolone were evaluated on the infiltration of cardiac allografts by syngeneic lymphocytes and platelets labeled with 111indium. As anticipated, platelet deposition was reduced by the thromboxane antagonist and unaffected by the PAF antagonist; the latter is likely due to the known absence of PAF receptors in rat platelets. In addition prednisolone had no effect. The increased accumulation of lymphocytes on days 4-5 was also unaffected by all three drugs. These experiments indicate that, in this model, graft survival is not necessarily related to lymphocyte and platelet infiltration of the graft. The data also provide evidence for the efficacy of the thromboxane receptor antagonist L 640,035 in preventing platelet deposition in vivo.
Assuntos
Plaquetas/citologia , Diterpenos , Transplante de Coração , Lactonas , Linfócitos/citologia , Glicoproteínas da Membrana de Plaquetas , Prednisolona/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Receptores Acoplados a Proteínas G , Tromboxanos/farmacologia , Animais , Azatioprina/farmacologia , Movimento Celular/efeitos dos fármacos , Dibenzotiepinas/farmacologia , Ginkgolídeos , Masculino , Extratos Vegetais/farmacologia , Ratos , Ratos EndogâmicosRESUMO
An animal model of tardive dyskinesia was used for the evaluation of potential antidyskinetic properties of the neuropeptide L-Prolyl-L-Leucyl-glycinamide (PLG) and related drugs: cyclo[glycine-(1-amino-1-cyclopentane) carbonyl]--c(CPC-Gly) and cyclo[alanine-(1-amino-1-cyclopentane) carbonyl]--c(CPC-Ala). Dopaminergic supersensitivity was induced by repeated administration of the neuroleptic drug isofloxythepin. Isofloxythepin (5 mg/kg/day po) after the withdrawal increased Bmax of 3H-spiperone striatal binding sites, significantly decreased HVA level in the striatum and induced tolerance to the cataleptic effects challenged by perphenazine. PLG, c(CPC-Gly) and c(CPC-Ala) counteracted supersensitive responses of isofloxythepin. The use of c(CPC-Gly) and c(CPC-Ala) in the prevention of tardive dyskinesia is proposed.
Assuntos
Discinesia Induzida por Medicamentos/tratamento farmacológico , Neuropeptídeos , Peptídeos Cíclicos/farmacologia , Receptores Dopaminérgicos/efeitos dos fármacos , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dibenzotiepinas , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Tolerância a Medicamentos , Lisurida/análogos & derivados , Lisurida/farmacologia , Hormônio Inibidor da Liberação de MSH/farmacologia , Masculino , Ratos , Ratos Endogâmicos , Receptores Dopaminérgicos/metabolismoRESUMO
The development of dopaminergic supersensitivity was evaluated, after single oral administration of the long-acting neuroleptic drug isofloxythepin, in nigrostriatal and tuberoinfundibular system in the rat. Isofloxythepin (5 mg/kg orally) increased concentration homovanillic acid (HVA) in the striatum for up to 24 h after administration, whereas a significant decrease below control values was found after 4-5 days. A similar biphasic effect appeared in behavior, since there was an enhancement of apomorphine stereotypy 4-5 days after administration of isofloxythepin (5 and 10 mg/kg orally). Both findings agree with the hypothesis of development of nigrostriatal dopaminergic supersensitivity at long intervals after isofloxythepin. On the other hand, the increase in prolactin (PRL) secretion induced by isofloxythepin indicated only the blocking action of this drug on dopamine receptors in the tuberoinfundibular system, and provided no evidence for tuberoinfundibular dopaminergic supersensitivity after neuroleptic treatment. It is concluded that a single dose of isofloxythepin is capable of inducing dopaminergic supersensitivity in the nigrostriatal system, but not in the tuberoinfundibular system.
Assuntos
Antipsicóticos/farmacologia , Dibenzotiepinas/farmacologia , Receptores Dopaminérgicos/efeitos dos fármacos , Animais , Apomorfina/farmacologia , Corpo Estriado/efeitos dos fármacos , Ácido Homovanílico/metabolismo , Humanos , Hipotálamo/efeitos dos fármacos , Masculino , Eminência Mediana/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Prolactina/sangue , Ratos , Ratos Endogâmicos , Comportamento Estereotipado/efeitos dos fármacos , Substância Negra/efeitos dos fármacosRESUMO
In a dominant-lethal assay in mice the following tricyclic neuroleptics were tested: prothiaden, imipramine, oxyprothepin decanoate and docloxythepin. No dominant-lethal effect was induced by these neuroleptics, even when administered at doses many times as great as clinical doses. The reduced percentages of pregnancies, in females who had copulated with males receiving docloxythepin, observed during and immediately after its administration, were directly connected with marked sedation induced in the males by this neuroleptic.