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1.
Int J Pharm Compd ; 24(2): 104-108, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32196472

RESUMO

Although pilocarpine hydrochloride tablets are currently indicated for the treatment of xerostomia, their adverse effects are frequently reported. The development of a new, low-dose pilocarpine solution for topical oral-cavity use is needed. This article discusses a few clinical trials to formulate a topical low-dose solution of pilocarpine hydrochloride for the treatment of xerostomia and presents two low dose, stable formulations of pilocarpine topical spray that can improve the patient's quality of life with minimal adverse effects.


Assuntos
Neoplasias de Cabeça e Pescoço , Agonistas Muscarínicos/uso terapêutico , Xerostomia , Humanos , Agonistas Muscarínicos/administração & dosagem , Pilocarpina/administração & dosagem , Pilocarpina/uso terapêutico , Qualidade de Vida , Xerostomia/tratamento farmacológico
2.
Drug Deliv ; 26(1): 952-964, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31544551

RESUMO

The objective of this work was to investigate phytantriol-based liquid crystal (LC) gels including cubic (Q2) and hexagonal (H2) phase for ocular delivery of pilocarpine nitrate (PN) to treat glaucoma. The gels were produced by a vortex method and confirmed by crossed polarized light microscopy, small-angle X-ray scattering, and rheological measurements. Moreover, the release behaviors and permeation results of PN from the gels were estimated using in vitro studies. Finally, the anti-glaucoma effect of LC gels was evaluated by in vivo animal experiments. The inner structure of the gels was Pn3m-type Q2 and H2 phase, and both of them showed pseudoplastic fluid properties based on characterization techniques. In vitro release profiles suggested that PN could be sustainably released from LC gels within 48 h. Compared with eye drops, Q2 and H2 gel produces a 5.25-fold and 6.23-fold increase in the Papp value (p < .05), respectively, leading to a significant enhancement of corneal penetration. Furthermore, a good biocompatibility and longer residence time on precorneal for LC gels confirmed by in vivo animal experiment. Pharmacokinetic studies showed that LC gels could maintain PN concentration in aqueous humor for at least 12 h after administration and remarkably improve the bioavailability of drug. Additionally, in vivo pharmacodynamics studies indicated that LC gels had a more significant intraocular pressure-lowering and miotic effect compared to eye drops. These research findings hinted that LC gels would be a promising pharmaceutical strategy for ocular application to enhance the efficacy of anti-glaucoma.


Assuntos
Córnea/efeitos dos fármacos , Géis/administração & dosagem , Géis/química , Glaucoma/tratamento farmacológico , Cristais Líquidos/química , Pilocarpina/administração & dosagem , Pilocarpina/química , Administração Oftálmica , Animais , Humor Aquoso/efeitos dos fármacos , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos/métodos , Pressão Intraocular/efeitos dos fármacos , Masculino , Nanopartículas/química , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/química , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Coelhos
3.
Oral Dis ; 25(8): 1937-1944, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520497

RESUMO

OBJECTIVES: Pilocarpine (PILO) and cevimeline (CEV) are muscarinic acetylcholine receptor agonists that stimulate salivary gland function. The aim of this investigation was to retrospectively run a head-to-head comparison for their effectiveness and frequency of adverse effects in patients with hyposalivation. METHODS: A retrospective chart review was conducted for patients seen at the Oral Medicine Clinic at Tufts University School of Dental Medicine (TUSDM) and was prescribed PILO or CEV. Patients' demographics, medical history/medication, stimulated salivary (SS), and unstimulated salivary (US) flow recorded at the initial visit and at 3- and 6-month follow-ups were collected. Changes in dosage/frequency, side effects, and drug discontinuation were also reported. RESULTS: A total of 110 patients' charts were reviewed. The majority of subjects (91%) were females with an average age of 61. At 3-month follow-up, the use of CEV showed significant improvement in SS compared to PILO (p = .033) but not in US (p = .10). At 6-month follow-up, there was no significant difference in SS or US between the two groups (SS: p = .09; US: p = .71). The use of PILO was associated with a higher proportion of adverse effects compared to CEV (p = .04). The overall adherence rate was significantly higher in the CEV group (p = .0056). CONCLUSIONS: The effectiveness of CEV and PILO is comparable. However, PILO seems to be associated with more reporting of side effects.


Assuntos
Agonistas Muscarínicos/uso terapêutico , Pilocarpina/uso terapêutico , Quinuclidinas/uso terapêutico , Tiofenos/uso terapêutico , Xerostomia/tratamento farmacológico , Adulto , Idoso , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Pilocarpina/administração & dosagem , Quinuclidinas/administração & dosagem , Estudos Retrospectivos , Tiofenos/administração & dosagem , Fatores de Tempo
4.
Cell Mol Biol (Noisy-le-grand) ; 65(5): 59-63, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31304908

RESUMO

Epilepsy is a common chronic disease of the central nervous system that can last for years or even decades, causing serious adverse effects on the body, mind, and psychology of patients. Traditional antiepileptic drugs can effectively control seizures, but because of large individual differences, serious adverse reactions, narrow therapeutic window and other shortcomings, more effective, new treatment drugs are looked for. Streptocaulon griffithii is a plant of Asclepiadaceae. 16-O-acetyldigitoxigenin (ACE) is a strong cardiac glycoside isolated from methanol extract of Streptocaulon griffithii. The aim of this study was to investigate the antiepileptic effect of ACE on Pilocarpine (Pilo) induced epilepsy in mice, and to explore the effect of mTOR signaling pathway on its antiepileptic effect. The results showed that ACE had antiepileptic and neuroprotective effects on Pilo induced epilepsy mice. ACE attenuates Pilo induced seizures by inhibiting the activation of p-mTOR/p-70S6K pathway, and inhibits Pilocarpine induced brain damage by inhibiting mTOR signaling pathway. These results suggest that ACE has a promising future in the treatment of epilepsy and other nervous system diseases.


Assuntos
Anticonvulsivantes/farmacologia , Digitoxigenina/análogos & derivados , Digitoxigenina/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Anticonvulsivantes/uso terapêutico , Apocynaceae/química , Caspase 3/metabolismo , Digitoxigenina/uso terapêutico , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pilocarpina/administração & dosagem , Pilocarpina/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo
5.
eNeuro ; 6(4)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31331937

RESUMO

Many experimental approaches require housing rodents in individual cages, including in epilepsy research. However, rats and mice are social animals; and individual housing constitutes a stressful situation. The goal of the present study was to determine the effects of individual housing as compared to conditions maintaining social contact on stress markers and epilepsy. Control male mice socially housed during pretest and then transferred to individual cages for six weeks displayed anhedonia, increased anxiety and biological markers of stress as compared to pretest values or mice kept socially housed during six weeks. Pilocarpine (pilo)-treated mice housed together showed increased levels of anhedonia, anxiety and stress markers as well as decreased cognitive performance as compared to the control group. The differences were more significant in pilo-treated mice housed individually. Anxiety correlated linearly with cognitive performance and stress markers independently of the experimental conditions. In the male rat pilo model, seizures were sixteen times more frequent in singly housed animals as compared to animals kept in pairs. Daily interactions with an experimenter in otherwise singly housed animals was sufficient to produce results identical to those found in animals kept in pairs. We propose that social isolation produces a severe phenotype in terms of stress and seizure frequency as compared to animals maintaining social contact (at least in these two models), a factor that needs to be taken into account for data interpretation, in particular for preclinical studies.


Assuntos
Epilepsia/fisiopatologia , Abrigo para Animais , Convulsões/fisiopatologia , Isolamento Social , Estresse Psicológico/fisiopatologia , Anedonia/fisiologia , Animais , Ansiedade/complicações , Ansiedade/fisiopatologia , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/complicações , Masculino , Pilocarpina/administração & dosagem , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/complicações , Estresse Psicológico/complicações
7.
Int J Biol Macromol ; 135: 1043-1051, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31158424

RESUMO

BACKGROUND: Xerostomia is caused by different factors such as side effects of medication, radiotherapy by head and neck cancer as well as Sjögren syndrome. AIM: The goal was to synthesize novel preactivated chitosan conjugates and to design adhesive dosage forms comprising sialagogue pilocarpine. METHODS: Unmodified chitosan (CH) was covalently linked to sulfhydryl possessing mercaptonicotinic acid (MNA) via amide bond formation. In a second step, preactivation occurred via disulfide bond establishment between sulfhydryl linked chitosan and preactivation ligand MNA. Mucoadhesive and mucoprotective properties were scrutinized on buccal mucosa. Safety assessment was performed on head and neck squamous cells. Histology assay was conducted on buccal tissue. Pilocarpine was scrutinized in terms of controlled release behavior. RESULTS: Novel preactivated CH was successfully synthesized and considered as not harmful to the cells at all. Furthermore, mucoadhesion was 1.3-fold improved in the presence of preactivated chitosan as compared to respective unmodified one. Pilocarpine exhibited a 3.1-fold controlled release in presence of novel synthesized chitosan as in comparison to unmodified CH. CONCLUSION: The novelty of this promising polymeric carrier lies in the synthesis procedure leading to a pronounced mucoadhesive, mucoprotecting and controlled release encouraging dosage form in the management of xerostomia.


Assuntos
Adesivos/química , Quitosana/química , Portadores de Fármacos/química , Pilocarpina/administração & dosagem , Adesivos/síntese química , Linhagem Celular , Quitosana/síntese química , Cromatografia Líquida de Alta Pressão , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Estrutura Molecular , Mucosa Bucal , Pilocarpina/química , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Reologia , Xerostomia/tratamento farmacológico
8.
Pharmacol Biochem Behav ; 182: 7-11, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31082418

RESUMO

BACKGROUND: Drug resistance is a major problem in the treatment of epilepsy. There is a critical need for new epilepsy models to evaluate antiepileptic compounds. Pentylenetetrazole- (PTZ) and pilocarpine-induced seizures are well-established models of human epilepsy. Generally, PTZ or pilocarpine has been used to produce seizures in experimental models. In this study, we explored the possibility of creating new epilepsy and seizure models by co-administration of PTZ and pilocarpine. METHODS: The protocol was divided into three parts: A) Kindling experiments: the animals received PTZ or co-administration doses of PTZ and pilocarpine every other day for a period of 26 days. B) Seizure experiments, for induction of seizure, the animals received one dose of PTZ, pilocarpine or co-administration doses of PTZ and pilocarpine. C) Evaluation of antiepileptic drugs: the animals received phenytoin or sodium valproate 20 min before injection of PTZ, pilocarpine or co-administration doses of PTZ and pilocarpine. RESULTS: The co-administration of pilocarpine and PTZ could induce seizure, which has behavioral similarity between electrical and chemical kindling. Pilocarpine (50 mg/kg) + PTZ (37.5 mg/kg) was the appropriate dose for kindling induction. Animals with this dose reached the stage five seizures significantly faster than those with PTZ alone. Unlike the seizure induced by PTZ, or pilocarpine, induction of seizure by PTZ + pilocarpine was resistant to phenytoin and sodium valproate treatment. As compared to the PTZ model of kindling, this model visualized the seizure behavior better and had resistance to two most popular antiepileptic drugs. CONCLUSION: Our results indicated that co-administration of pilocarpine and PTZ could provide a new modified model of seizure and kindling resisting to phenytoin and sodium valproate.


Assuntos
Convulsivantes/farmacologia , Modelos Animais de Doenças , Excitação Neurológica/efeitos dos fármacos , Mióticos/farmacologia , Pentilenotetrazol/farmacologia , Pilocarpina/farmacologia , Convulsões/induzido quimicamente , Animais , Anticonvulsivantes/efeitos adversos , Convulsivantes/administração & dosagem , Resistência a Medicamentos , Epilepsia/tratamento farmacológico , Masculino , Mióticos/administração & dosagem , Pentilenotetrazol/administração & dosagem , Fenitoína/farmacologia , Pilocarpina/administração & dosagem , Ratos , Ratos Wistar , Ácido Valproico/farmacologia
9.
J Urol ; 202(3): 564-573, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31009289

RESUMO

PURPOSE: We evaluated the efficacy and safety of a combination of 2 mg tolterodine and 9 mg pilocarpine, vs tolterodine monotherapy in patients with overactive bladder. MATERIALS AND METHODS: We enrolled patients with overactive bladder symptoms in a multicenter, randomized, double-blind, parallel, active control study. Patients were randomized to the combination or 2 mg tolterodine twice daily for 12 weeks. After the double-blind period finished all patients were started on the combination for 12 weeks. Study co-primary end points were the change from baseline in the mean number of daily micturitions and cumulative incidence of dry mouth at the end of 12 weeks. Secondary end points were other overactive bladder symptoms, the total xerostomia inventory score and results of a visual analogue scale for dry mouth at the end of 12 and 24 weeks. RESULTS: The mean change in the number of daily micturitions from baseline to 12 weeks was -1.49 and -1.74 in the combination and tolterodine monotherapy groups, respectively. The mean difference was -0.26 (95% CI -0.79-0.27), confirming noninferiority. At 12 weeks the incidence of dry mouth was lower in the combination group than in the tolterodine monotherapy group (30.0% vs 42.9%, p = 0.009). All secondary and other efficacy outcomes related to overactive bladder symptoms improved in each group with no significant differences between the groups at 12 weeks. Changes from baseline in the total xerostomia inventory score and the visual analogue scale for dry mouth were significantly lower in the combination group than in the tolterodine monotherapy group. CONCLUSIONS: Tolterodine and pilocarpine alleviated dry mouth in patients with overactive bladder while maintaining anticholinergic efficacy similar to that of tolterodine.


Assuntos
Antagonistas Colinérgicos/administração & dosagem , Agonistas Muscarínicos/administração & dosagem , Pilocarpina/administração & dosagem , Tartarato de Tolterodina/administração & dosagem , Bexiga Urinária Hiperativa/tratamento farmacológico , Xerostomia/epidemiologia , Idoso , Antagonistas Colinérgicos/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Agonistas Muscarínicos/efeitos adversos , Pilocarpina/efeitos adversos , Tartarato de Tolterodina/efeitos adversos , Resultado do Tratamento , Micção/efeitos dos fármacos , Xerostomia/induzido quimicamente , Xerostomia/prevenção & controle
10.
Neurochem Res ; 44(5): 1262-1268, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30877518

RESUMO

Botulinum neurotoxins (BoNTs) block the release of a series of neurotransmitters, which are pivotal for neuron action. Intrahippocampal administration of BoNTs inhibits glutamate release, protects neurons against cell death, and attenuates epileptic seizures. Compared with intrahippocampal administration, intranasal delivery is less invasive and more practical for chronic drug administration. To assess whether intranasal administration is feasible, we examined the role of botulinum neurotoxin A (BoNT/A) in hippocampal neuronal injury after status epilepticus (SE) induced by pilocarpine. Our data showed BoNT/A could bypass the blood-brain barrier (BBB) and entered the olfactory bulb and hippocampal neurons. In addition, SE could result in up-regulation of pro-apoptotic proteins (Caspase-3, Bax), down-regulation of anti-apoptotic protein Bcl-2 and neuronal death in hippocampus. BoNT/A could suppress the expression of Caspase-3 and Bax, attenuate the decrease of Bcl-2, and inhibit hippocampal neuron death induced by SE. Meanwhile, there was no significant difference in cognitive behavior between the BoNT/A-pretreated rats and normal rats. Thus, we provided a more convenient and less invasive route for taking advantage of BoNT/A in the field of anti-epilepsy.


Assuntos
Toxinas Botulínicas Tipo A/farmacologia , Morte Celular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Pilocarpina/farmacologia , Administração Intranasal/métodos , Animais , Toxinas Botulínicas Tipo A/administração & dosagem , Hipocampo/metabolismo , Lítio/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Pilocarpina/administração & dosagem , Ratos Sprague-Dawley , Convulsões/induzido quimicamente
11.
Int J Pharm ; 562: 31-41, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30878587

RESUMO

The aim of this paper was to develop hexagonal liquid crystalline (HII) gels that can be used as a novel ocular delivery system for pilocarpine nitrate (PN). HII gels were prepared by a vortex method using phytantriol/triglyceride/water (71.15: 3.85: 26, w/w) ternary system. The gels were characterized by crossed polarized light microscopy, small-angle X-ray scattering, differential scanning calorimetry and rheology. And, in vitro drug release behavior and ex vivo corneal permeation were investigated. Finally, preocular residence time evaluation, eye irritation test, histological examination and miotic tests were studied in vivo and compared with carbopol gel. Based on various characterization techniques, the inner structure of the gels were HII mesophase and exhibited a pseudoplastic fluid behaviour. In vitro release results revealed that PN could be released continuously from HII gel over a period of 24 h. The ex vivo apparent permeability coefficient of HII gel was 3.15-fold (P < 0.01) higher than that of the Carbopol gel. Compared with Carbopol gel, HII gel displayed longer residence time on the eyeballs surface using fluorescent labeling technology. Furthermore, the HII gel caused no ocular irritation was estimated by corneal hydration levels, Draize test and histological inspection. Additionally, in vivo miotic study showed that HII gel had a remarkably long-lasting decrease in the pupil diameter of rabbits. In conclusion, HII gels would be a promising sustained-release formulation for ocular drug delivery.


Assuntos
Cristais Líquidos , Mióticos/administração & dosagem , Pilocarpina/administração & dosagem , Administração Oftálmica , Animais , Córnea/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos , Géis , Masculino , Mióticos/química , Pilocarpina/química , Coelhos
13.
J Neurosci ; 39(11): 2144-2156, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30665947

RESUMO

Neurotrophic factors are candidates for treating epilepsy, but their development has been hampered by difficulties in achieving stable and targeted delivery of efficacious concentrations within the desired brain region. We have developed an encapsulated cell technology that overcomes these obstacles by providing a targeted, continuous, de novo synthesized source of high levels of neurotrophic molecules from human clonal ARPE-19 cells encapsulated into hollow fiber membranes. Here we illustrate the potential of this approach for delivering glial cell line-derived neurotrophic factor (GDNF) directly to the hippocampus of epileptic rats. In vivo studies demonstrated that bilateral intrahippocampal implants continued to secrete GDNF that produced high hippocampal GDNF tissue levels in a long-term manner. Identical implants robustly reduced seizure frequency in the pilocarpine model. Seizures were reduced rapidly, and this effect increased in magnitude over 3 months, ultimately leading to a reduction of seizures by 93%. This effect persisted even after device removal, suggesting potential disease-modifying benefits. Importantly, seizure reduction was associated with normalized changes in anxiety and improved cognitive performance. Immunohistochemical analyses revealed that the neurological benefits of GDNF were associated with the normalization of anatomical alterations accompanying chronic epilepsy, including hippocampal atrophy, cell degeneration, loss of parvalbumin-positive interneurons, and abnormal neurogenesis. These effects were associated with the activation of GDNF receptors. All in all, these results support the concept that the implantation of encapsulated GDNF-secreting cells can deliver GDNF in a sustained, targeted, and efficacious manner, paving the way for continuing preclinical evaluation and eventual clinical translation of this approach for epilepsy.SIGNIFICANCE STATEMENT Epilepsy is one of the most common neurological conditions, affecting millions of individuals of all ages. These patients experience debilitating seizures that frequently increase over time and can associate with significant cognitive decline and psychiatric disorders that are generally poorly controlled by pharmacotherapy. We have developed a clinically validated, implantable cell encapsulation system that delivers high and consistent levels of GDNF directly to the brain. In epileptic animals, this system produced a progressive and permanent reduction (>90%) in seizure frequency. These benefits were accompanied by improvements in cognitive and anxiolytic behavior and the normalization of changes in CNS anatomy that underlie chronic epilepsy. Together, these data suggest a novel means of tackling the frequently intractable neurological consequences of this devastating disorder.


Assuntos
Epilepsia/tratamento farmacológico , Fator Neurotrófico Derivado de Linhagem de Célula Glial/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Convulsões/tratamento farmacológico , Animais , Encapsulamento de Células , Linhagem Celular , Sistemas de Liberação de Medicamentos/métodos , Epilepsia/induzido quimicamente , Humanos , Masculino , Pilocarpina/administração & dosagem , Ratos Sprague-Dawley , Convulsões/induzido quimicamente
14.
AAPS PharmSciTech ; 20(1): 32, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30603986

RESUMO

The purpose of this paper was to investigate the potential of liquid crystalline (LC) gels for ophthalmic delivery, so as to enhance the bioavailability of pilocarpine nitrate (PN). The gels were prepared by a vortex method using phytantriol and water (in the ratio of 73:27 w/w). Their inner structures were confirmed by crossed polarized light microscopy, small-angle X-ray scattering, attenuated total reflectance-Fourier transform infrared spectrum, and rheology. The in vitro release studies revealed that PN could keep sustained release from the gels over a period of 12 h. The ex vivo apparent permeability coefficient of the gels demonstrated a 3.83-folds (P < 0.05) increase compared with that of eye drops. The corneal hydration levels of the gel maintained in the normal range of 79.46 ± 2.82%, hinting that the gel could be considered non-damaging and safe to the eyes. Furthermore, in vivo residence time evaluation suggested that a better retention performance of LC gel was observed in rabbit's eyes compared to eye drops. In vivo ocular irritation study indicated that LC gel was nonirritant and might be suitable for various eye applications. In conclusion, LC gels might represent a potential ophthalmic delivery strategy to overcome the limitations of eye drops.


Assuntos
Córnea/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Álcoois Graxos/administração & dosagem , Cristais Líquidos , Mióticos/administração & dosagem , Pilocarpina/administração & dosagem , Administração Oftálmica , Animais , Córnea/metabolismo , Álcoois Graxos/metabolismo , Géis , Masculino , Mióticos/metabolismo , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/metabolismo , Permeabilidade/efeitos dos fármacos , Pilocarpina/metabolismo , Coelhos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Água/química
15.
Int J Mol Sci ; 20(3)2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30696017

RESUMO

Dry mouth or xerostomia is a frequent medical condition among the polymedicated elderly population. Systemic pilocarpine is included in the first line of pharmacological therapies for xerostomia. However, the efficacy of existing pilocarpine formulations is limited due to its adverse side effects and multiple daily dosages. To overcome these drawbacks, a localized formulation of pilocarpine targeting the salivary glands (SG) was developed in the current study. The proposed formulation consisted of pilocarpine-loaded Poly(lactic-co-glycolic acid) (PLGA)/poly(ethylene glycol) (PEG) nanofiber mats via an electrospinning technique. The nanofiber mats were fully characterized for their size, mesh porosity, drug encapsulation efficiency, and in vitro drug release. Mat biocompatibility and efficacy was evaluated in the SG organ ex vivo, and the expression of proliferation and pro-apoptotic markers at the cellular level was determined. In vivo short-term studies were performed to evaluate the saliva secretion after acute SG treatment with pilocarpine-loaded nanofiber mats, and after systemic pilocarpine for comparison purposes. The outcomes demonstrated that the pilocarpine-loaded mats were uniformly distributed (diameter: 384 ± 124 nm) in a highly porous mesh, and possessed a high encapsulation efficiency (~81%). Drug release studies showed an initial pilocarpine release of 26% (4.5 h), followed by a gradual increase (~46%) over 15 d. Pilocarpine-loaded nanofiber mats supported SG growth with negligible cytotoxicity and normal cellular proliferation and homeostasis. Salivary secretion was significantly increased 4.5 h after intradermal SG treatment with drug-loaded nanofibers in vivo. Overall, this study highlights the strengths of PLGA/PEG nanofiber mats for the localized daily delivery of pilocarpine and reveals its potential for future clinical translation in patients with xerostomia.


Assuntos
Sistemas de Liberação de Medicamentos , Nanofibras/química , Pilocarpina/administração & dosagem , Pilocarpina/farmacologia , Glândulas Salivares/fisiopatologia , Animais , Materiais Biocompatíveis/farmacologia , Compartimento Celular , Morte Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Feminino , Injeções Intradérmicas , Antígeno Ki-67/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Nanofibras/ultraestrutura , Saliva/metabolismo , Glândulas Salivares/efeitos dos fármacos , Resultado do Tratamento
16.
Neurobiol Dis ; 121: 177-186, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30304705

RESUMO

Epilepsy produces chronic chemical changes induced by altered cellular structures, and acute ones produced by conditions leading into individual seizures. Here, we aim to quantify 24 molecules simultaneously at baseline and during periods of lowered seizure threshold in rats. Using serial hippocampal microdialysis collections starting two weeks after the pilocarpine-induced status epilepticus, we evaluated how this chronic epilepsy model affects molecule levels and their interactions. Then, we quantified the changes occurring when the brain moves into a pro-seizure state using a novel model of physiological ictogenesis. Compared with controls, pilocarpine animals had significantly decreased baseline levels of adenosine, homovanillic acid, and serotonin, but significantly increased levels of choline, glutamate, phenylalanine, and tyrosine. Step-wise linear regression identified that choline, homovanillic acid, adenosine, and serotonin are the most important features to characterize the difference in the extracellular milieu between pilocarpine and control animals. When increasing the hippocampal seizure risk, the concentrations of normetanephrine, serine, aspartate, and 5-hydroxyindoleacetic acid were the most prominent; however, there were no specific, consistent changes prior to individual seizures.


Assuntos
Encéfalo/metabolismo , Estado Epiléptico/metabolismo , Animais , Biomarcadores/metabolismo , Convulsivantes/administração & dosagem , Modelos Animais de Doenças , Espaço Extracelular/metabolismo , Masculino , Pilocarpina/administração & dosagem , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/diagnóstico
17.
IUBMB Life ; 71(2): 213-222, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30360015

RESUMO

This study aimed to identify the genes related to epilepsy and their effects on epilepsy, as well as the underlying mechanism. Using microarray analysis, differentially expressed genes (DEGs) were screened out and then used to build weighted gene coexpression networks using WGCNA. Module membership and evaluation of gene significance (GS) were adopted to detect hub genes. The DAVID online tool was used to understand the function of modules and target genes. The Licl-pilocarpine chronic rat epilepsy model was used to simulate mesial temporal lobe epilepsy with an initial precipitating injury. Hippocampal expression of the proteins solute carrier family 1 member 2 (SLC1A2), glial fibrillary acidic protein, interleukin-1ß (IL-1ß), tumor necrosis factor α (TNF-α), and N-methyl-d-aspartic acid receptor (NMDAR) was determined by ELISA and Western blot. Nissl staining was used to measure neuronal loss. Immunohistochemistry was performed to assess the percentage of positive cells to reflect the distribution of NMDAR1. Here, 3232 potential genes highly correlated with epilepsy were selected from the screened DEGs, among which SLC1A2 was related to brain development and its expression was significantly decreased in epilepsy patients. According to Gene Ontology and KEGG analysis, SLC1A2 mediates epilepsy through the glutamatergic synapse pathway. Tissue experiments suggested that Slc1a2 could genuinely ameliorate epilepsy through the glutamatergic synapse pathway, mitigate neuronal loss, and suppress astrocytosis and inflammatory responses. Our study suggested that low hippocampal content of SLC1A2 is a potential biomarker of epilepsy and may affect the function of neurons through the glutamatergic synapse pathway. © 2018 IUBMB Life, 71(1):213-222, 2019.


Assuntos
Epilepsia do Lobo Temporal/genética , Transportador 2 de Aminoácido Excitatório/genética , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Sinapses/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Biomarcadores/metabolismo , Morte Celular , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/fisiopatologia , Transportador 2 de Aminoácido Excitatório/metabolismo , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Cloreto de Lítio/administração & dosagem , Masculino , Neurônios/patologia , Pilocarpina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/patologia , Transmissão Sináptica , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
18.
Neurosci Lett ; 692: 64-68, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30391321

RESUMO

The blood-brain barrier (BBB) is a unique structure that controls substances exchange between the systemic circulation and the brain. Disruption of its integrity contributes to the development and progression of a variety of brain disorders including stroke, epilepsy and neurodegenerative diseases. It was shown that intracerebral thrombin level substantially increases following status epilepticus (SE). Inhibition of protease-activated receptor 1 (PAR1), the major thrombin receptor in the brain, produces an anti-epileptogenic and neuroprotective effects in an experimental model of temporal lobe epilepsy (TLE). Since serine proteases and PAR1 are implicated in the synaptic plasticity and memory formation, the aim of the present study was to elucidate the involvement of PAR1 in synaptic plasticity and behavior deficits following SE. Using lithium-pilocarpine model of TLE, we demonstrate that inhibition of PAR1 rescues SE-induced synaptic plasticity deficits in CA1 region of hippocampus. Although treatment with PAR1 antagonist does not ameliorate spatial learning deficits, it attenuates anxiolytic-like behavior in experimental rats after SE. Taken together; our data suggest an important role of PAR1 in SE-induced synaptic and behavioral alterations and provide a new insight into cellular mechanisms underlying behavioral impairments associated with epilepsy.


Assuntos
Região CA1 Hipocampal/fisiopatologia , Epilepsia do Lobo Temporal/fisiopatologia , Potenciação de Longa Duração , Receptor PAR-1/antagonistas & inibidores , Estado Epiléptico/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Lítio/administração & dosagem , Masculino , Pilocarpina/administração & dosagem , Pirróis/administração & dosagem , Quinazolinas/administração & dosagem , Ratos Wistar , Estado Epiléptico/induzido quimicamente
19.
J Ocul Pharmacol Ther ; 34(8): 590-595, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30192156

RESUMO

PURPOSE: The purpose of the study was to determine the 24-h effects of pilocarpine 2% ophthalmic solution on intraocular pressure (IOP) and ocular perfusion pressure (OPP) when used in addition to prostaglandin analog (PGA) therapy. METHODS: Twenty-seven patients with ocular hypertension (OHTN) or open angle glaucoma who were receiving stable monotherapy with a PGA were admitted to an inpatient sleep laboratory for 24-h monitoring of IOP, blood pressure (BP), and heart rate over 2 separate visits. The first baseline visit was performed under PGA monotherapy only. During the second 24-h visit, pilocarpine 2% was administered four times daily in addition to their normal PGA dosing. For each study visit, measurements of all study metrics were performed every 2 h in the habitual position. OPP was calculated as 2/3[diastolic BP +1/3(systolic BP - diastolic BP)] - IOP. RESULTS: During the diurnal period, pilocarpine significantly reduced IOP from a baseline of 18.2 ± 0.5 mmHg on PGA monotherapy to 17.1 ± 0.4 mmHg, P < 0.01. Similarly, pilocarpine significantly lowered IOP during the nocturnal period from 21.1 ± 0.7 to 20.0 ± 0.6 mmHg, P < 0.01. Mean OPP was unchanged from baseline levels after the addition of pilocarpine in both the diurnal and nocturnal periods. Mean systolic BP was significantly reduced during the nocturnal period only (-3.16 ± 1.5 mmHg, P = 0.03). CONCLUSIONS: In patients taking PGA monotherapy, the addition of pilocarpine can significantly lower IOP throughout the diurnal and nocturnal periods, but has no effect on OPP.


Assuntos
Glaucoma/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/tratamento farmacológico , Soluções Oftálmicas/farmacologia , Pilocarpina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Glaucoma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/diagnóstico , Soluções Oftálmicas/administração & dosagem , Pilocarpina/administração & dosagem , Estudos Prospectivos , Tonometria Ocular
20.
Biochem Pharmacol ; 156: 431-443, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30195730

RESUMO

Epilepsy is one of the serious neurological sequelae of bacterial meningitis. Rifampicin, the well-known broad spectrum antibiotic, is clinically used for chemoprophylaxis of meningitis. Besides its antibiotic effects, rifampicin has been proven to be an effective neuroprotective candidate in various experimental models of neurological diseases. In addition, rifampicin was found to have promising antioxidant, anti-inflammatory and anti-apoptotic effects. Herein, we investigated the anticonvulsant effect of rifampicin at experimental meningitis dose (20 mg/kg, i.p.) using lithium-pilocarpine model of status epilepticus (SE) in rats. Additionally, we studied the effect of rifampicin on seizure induced histopathological, neurochemical and behavioral abnormalities. Our study showed that rifampicin pretreatment attenuated seizure activity and the resulting hippocampal insults marked by hematoxylin and eosin. Markers of oxidative stress, neuroinflammation and apoptosis were evaluated, in the hippocampus, 24 h after SE induction. We found that rifampicin pretreatment suppressed oxidative stress as indicated by normalized malondialdehyde and glutathione levels. Rifampicin pretreatment attenuated SE-induced neuroinflammation and decreased the hippocampal expression of interleukin-1ß, tumor necrosis factor-α, nuclear factor kappa-B, and cyclooxygenase-2. Moreover, rifampicin mitigated SE-induced neuronal apoptosis as indicated by fewer positive cytochrome c immunostained cells and lower caspase-3 activity in the hippocampus. Furthermore, Morris water maze testing at 7 days after SE induction showed that rifampicin pretreatment can improve cognitive dysfunction. Therefore, rifampicin, currently used in the management of meningitis, has a potential additional advantage of ameliorating its epileptic sequelae.


Assuntos
Hipocampo/patologia , Cloreto de Lítio/toxicidade , Transtornos da Memória/induzido quimicamente , Pilocarpina/toxicidade , Rifampina/farmacologia , Convulsões/induzido quimicamente , Animais , Apoptose/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Cloreto de Lítio/administração & dosagem , Masculino , Transtornos da Memória/prevenção & controle , Estresse Oxidativo , Pilocarpina/administração & dosagem , Ratos , Ratos Wistar , Convulsões/tratamento farmacológico
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