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1.
BMJ Case Rep ; 14(2)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526531

RESUMO

This report describes two patients with acute-onset ptosis, oculomotor dysfunction, ataxia and drowsiness, referable to the midbrain tegmentum. Both patients had previously suffered severe closed head injuries requiring craniotomy for cerebral decompression. Serial brain scans in both cases revealed a newly developing cleft in the midbrain, with features suggestive of abnormal cerebrospinal fluid (CSF) flow across the aqueduct. A trial of acetazolamide was initiated to reduce CSF production, followed by a third ventriculostomy for CSF diversion in one patient, which resulted in arrested disease progression and partial recovery. There are only two previous reports in the literature of midbrain clefts that developed as remote sequelae of head trauma. We postulate that altered CSF flow dynamics in the aqueduct, possibly related to changes in brain compliance, may be contributory. Early recognition and treatment may prevent irreversible structural injury and possible death.


Assuntos
Encefalopatias/diagnóstico por imagem , Lesões Encefálicas Difusas/diagnóstico por imagem , Aqueduto do Mesencéfalo/diagnóstico por imagem , Craniectomia Descompressiva , Traumatismos Cranianos Fechados/cirurgia , Mesencéfalo/diagnóstico por imagem , Acetazolamida/uso terapêutico , Ataxia/fisiopatologia , Blefaroptose , Encefalopatias/fisiopatologia , Encefalopatias/terapia , Lesões Encefálicas Difusas/fisiopatologia , Inibidores da Anidrase Carbônica/uso terapêutico , Líquido Cefalorraquidiano , Progressão da Doença , Disartria/fisiopatologia , Humanos , Hidrodinâmica , Imagem por Ressonância Magnética , Masculino , Transtornos da Motilidade Ocular/fisiopatologia , Ventriculostomia , Adulto Jovem
2.
J Med Chem ; 64(3): 1713-1724, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33523653

RESUMO

Carbonic anhydrase IX (CAIX) is considered a target for therapeutic intervention in solid tumors. In this study, the efficacy of the inhibitor, 4-(3-(2,4-difluorophenyl)-oxoimidazolidin-1-yl)benzenesulfonamide (SLC-149), is evaluated on CAIX and a CAIX-mimic. We show that SLC-149 is a better inhibitor than acetazolamide against CAIX. Binding of SLC-149 thermally stabilizes CAIX-mimic at lower concentrations compared to that of CAII. Structural examinations of SLC-149 bound to CAIX-mimic and CAII explain binding preferences. In cell culture, SLC-149 is a more effective inhibitor of CAIX activity in a triple-negative breast cancer cell line than previously studied sulfonamide inhibitors. SLC-149 is also a better inhibitor of activity in cells expressing CAIX versus CAXII. However, SLC-149 has little effect on cytotoxicity, and high concentrations are required to inhibit cell growth, migration, and invasion. These data support the hypothesis that CAIX activity, shown to be important in regulating extracellular pH, does not underlie its ability to control cell growth.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/uso terapêutico , Anidrase Carbônica II/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Modelos Moleculares , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
3.
BMJ Case Rep ; 14(2)2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33541940

RESUMO

A 25-year-old man presented with decreased vision in both eyes, approximately 4 years following bilateral bright ocular cosmetic iris implantation. On examination, he was found to have bilateral elevated intraocular pressures, anterior chamber cells and flare, chronic peripheral anterior synechiae and significantly reduced endothelial cell counts. Ultrasound biomicroscopy demonstrated compression of the peripheral iris, resulting in synechial angle closure in both eyes. Surgical removal of the implants was performed without additional complication. On removal, bilateral iris atrophy was evident with non-reacting pupils and permanent mydriasis. Optical coherence tomography angiography showed a reduction in iris vasculature density that is more pronounced in the area of the iris atrophic defects. This case suggests that cosmetic iris implants may compress iris vasculature, resulting in decreased iris perfusion resulting in atrophic mydriasis and iris defects. This is a potential novel mechanism for complications in eyes with cosmetic iris implants.


Assuntos
Pressão Intraocular , Doenças da Íris/complicações , Iris/cirurgia , Midríase/diagnóstico , Próteses e Implantes/efeitos adversos , Acetaminofen/uso terapêutico , Acetazolamida/uso terapêutico , Administração Intravenosa , Adulto , Analgésicos não Entorpecentes/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Humanos , Latanoprosta/uso terapêutico , Masculino , Soluções Oftálmicas/uso terapêutico , Tomografia de Coerência Óptica
4.
J Stroke Cerebrovasc Dis ; 29(10): 105184, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912560

RESUMO

AIM: We aimed to describe otogenic lateral sinovenous thrombosis (OLST), a rare, potentially life-threatening complication of otomastoiditis. METHODS: Children diagnosed with OLST in a tertiary-care Hospital from 2014 to 2019 was retrospectively selected. Clinical and radiological features, timing of diagnosis, treatment and outcome are reported. RESULTS: Seven children (5 males) were studied. Fever and neurological symptoms (headache, lethargy, diplopia, dizziness and papilledema) were always present. Otalgia and/or otorrhea were found in 6 children; none had signs of mastoiditis. Diagnosis was reached after 7 days (median) from clinical onset. Brain CT-scan was performed in 5 children being diagnostic for 3. Venography-MRI detected OLST and mastoiditis in all cases without parenchymal lesions. Treatment was based on intravenous rehydration, antibiotic and low-molecular weight heparin; acetazolamide was added in 3 children. Mastoidectomy and ventriculoperitoneal-shunting were selectively performed. Patients were discharged after 26 days (median). Follow-up neuroimaging showed sinus recanalization after a median time of 6 months. CONCLUSION: A multidisciplinary approach is needed to optimize diagnostic-therapeutic protocols of pediatric OLST.


Assuntos
Otorreia de Líquido Cefalorraquidiano/complicações , Dor de Orelha/complicações , Trombose do Seio Lateral/etiologia , Mastoidite/complicações , Adolescente , Fatores Etários , Antibacterianos/uso terapêutico , Anticoagulantes/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Otorreia de Líquido Cefalorraquidiano/diagnóstico , Otorreia de Líquido Cefalorraquidiano/terapia , Criança , Pré-Escolar , Dor de Orelha/diagnóstico , Dor de Orelha/terapia , Feminino , Hidratação , Humanos , Trombose do Seio Lateral/diagnóstico por imagem , Trombose do Seio Lateral/terapia , Masculino , Mastoidectomia , Mastoidite/diagnóstico , Mastoidite/terapia , Estudos Retrospectivos , Resultado do Tratamento , Derivação Ventriculoperitoneal
5.
Klin Monbl Augenheilkd ; 237(10): 1241-1258, 2020 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-32777830

RESUMO

Glaucoma is the leading cause of irreversible blindness in Germany and in the world. Due to the multifactorial genesis of the disease, there are multiple therapeutic approaches for preventing its progression. The goal of the commonly used topical glaucoma medication is to reduce the intraocular pressure and therefore prevent further damage to the optic nerve. There are different medications of various pharmacological classes that are intended to reduce intraocular pressure, namely, ß-adrenergic antagonists, adrenergic agonists, parasympathomimetic agents, prostaglandin analogues, carbonic anhydrase inhibitors, hyperosmotic agents, and the 2017 U. S. FDA approved Rho kinase inhibitor, Netarsudil.After determining a patient centered target pressure, which depends upon various factors, an individual treatment regimen should be chosen with one or more agents. Although reducing the intraocular pressure remains the main therapeutic focus, there is increasing evidence indicating that oxidative stress also plays a key role in the pathogenesis of the primary open angle glaucoma. Therefore, direct and indirect neuroprotective agents like Magnesium, Coenzym Q10, Ginkgo biloba and others are getting more and more attention. While there is still a need for further clinical trials, these substances are getting more popular as an adjunct in glaucoma therapy.


Assuntos
Glaucoma de Ângulo Aberto , Glaucoma , Antagonistas Adrenérgicos beta/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Alemanha , Glaucoma/tratamento farmacológico , Humanos , Pressão Intraocular
6.
Eur J Pharmacol ; 888: 173487, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-32805256

RESUMO

Acute kidney injury (AKI) is an important complication of COVID-19 encompassing a wide range of presentations. SARS-CoV-2 is proposed to cause AKI in the patients through various mechanisms. We are, nevertheless, far from a comprehensive understanding of the underlying pathophysiological mechanisms of the kidney injury in this infection. AKI has been shown to be a marker of disease severity and also a negative prognostic factor for survival. Unfortunately, no effective preventive strategy to decrease the risk of kidney damage in these patients has yet been identified. In this hypothesis, we highlight the potential protective effects of acetazolamide, a carbonic anhydrase inhibitor, in preventing the proximal tubular damage caused by the virus through disrupting the virus-endosome fusion and also interfering with the lysosomal proteases. Our proposed mechanisms could pave the way for further in vitro studies and subsequent clinical trials.


Assuntos
Acetazolamida/uso terapêutico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/prevenção & controle , Inibidores da Anidrase Carbônica/uso terapêutico , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Humanos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/virologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Resultado do Tratamento
7.
PLoS One ; 15(6): e0234690, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555666

RESUMO

The alternative mechanical theory of glaucoma, in which an increased pressure difference across the lamina cribrosa (difference between intraocular and intracranial pressure; IOP and ICP), rather than solely an elevated IOP, leads to structural and functional vision loss, is still controversial. If the theory is true, a drug that simultaneously lowers both the IOP and ICP may be ineffective. The aim of this study was to determine how acetazolamide (AAZ; a drug prescribed in glaucoma that aims to lower the IOP) affects both IOP and ICP in glaucoma patients and to compare the magnitude and time course of the induced pressure changes with those of healthy subjects not taking AAZ. IOP and noninvasive ICP (measured through emissions from the ear) were measured in 20 glaucoma patients taking 125 mg of AAZ twice daily. Measurements were taken for 30 minutes before taking the drug and for 2 hours post-ingestion. Comparisons were made with 13 age-similar controls. After 12 hours with no anti-glaucoma medication, AAZ did not further reduce IOP in glaucoma patients compared to controls (P = 0.58) but did reduce ICP compared to controls (P = 0.035), by approximately 4 mmHg. Our findings suggest that there are periods during the day when the pressure difference across the lamina cribrosa is larger in case of AAZ use. Future studies should focus on improving the noninvasive ICP testing, different doses and dosing schedules of AAZ, and the time course of IOP in glaucoma patients not taking AAZ.


Assuntos
Acetazolamida/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Glaucoma/tratamento farmacológico , Pressão Intracraniana/efeitos dos fármacos , Pressão Intraocular/efeitos dos fármacos , Acetazolamida/uso terapêutico , Idoso , Inibidores da Anidrase Carbônica/uso terapêutico , Feminino , Glaucoma/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade
8.
J Med Chem ; 63(10): 5185-5200, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32364386

RESUMO

Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures, and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. Here, a drug design strategy based on the observation of (dis)similarities between the target CA active sites was planned with benzenesulfonamide derivatives and, for the first time, a phosphorus-based linker. Potent and selective CA II/VII inhibitors were identified among the synthesized phenyl(thio)phosphon(amid)ates 3-22. X-ray crystallography depicted the binding mode of phosphonic acid 3 to both CAs II and VII. The most promising derivatives, after evaluation of their stability in acidic media, were tested in a mouse model of oxaliplatin-induced neuropathy. The most potent compound racemic mixture was subjected to HPLC enantioseparation, and the identification of the eutomer, the (S)-enantiomer, allowed to halve the dose totally relieving allodynia in mice.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/uso terapêutico , Anidrases Carbônicas/metabolismo , Hiperalgesia/tratamento farmacológico , Oxaliplatina/toxicidade , Animais , Antineoplásicos/toxicidade , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Temperatura Baixa/efeitos adversos , Cristalografia por Raios X/métodos , Modelos Animais de Doenças , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/enzimologia , Masculino , Camundongos , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/enzimologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
9.
Muscle Nerve ; 62(4): 430-444, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32270509

RESUMO

The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.


Assuntos
Fadiga/fisiopatologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/fisiopatologia , Mialgia/fisiopatologia , Transtornos Miotônicos/fisiopatologia , Acetazolamida/uso terapêutico , Idade de Início , Inibidores da Anidrase Carbônica/uso terapêutico , Canais de Cloreto/genética , Eletrodiagnóstico , Eletromiografia , Testes Genéticos , Humanos , Lamotrigina/uso terapêutico , Mexiletina/uso terapêutico , Miotonia Congênita/tratamento farmacológico , Miotonia Congênita/genética , Miotonia Congênita/fisiopatologia , Transtornos Miotônicos/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Guias de Prática Clínica como Assunto , Ranolazina/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico
10.
J Clin Neurosci ; 73: 252-258, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32037062

RESUMO

Cerebral collaterals is crucially important in the pathophysiology of acute ischemic stroke and associated with outcome after reperfusion therapy. We explored the effectiveness of collateral augmentation treatment with a combination of acetazolamide (ACZ) and head-down tilt (HDT) in the transient middle cerebral artery occlusion (MCAO) rat model. Transient MCAO was induced in all animals for 1.5 h, followed by reperfusion for 22.5 h. Seventy-two male Wistar rats were divided into four treatment groups: control, ACZ, HDT, and combination. Twenty sham rats, which underwent surgery, were randomly allocated to these groups. Twenty-four hours after MCAO or sham surgery, we measured the infarction volume, brain edema (aquaporin-4 [AQP4], and brain water content), and neurological deficits (Garcia and Longa tests). Collateral augmentation treatments were associated with reduced infarction volume, less brain edema, and better neurological outcomes compared with untreated animals. More specifically, ACZ and HDT treatments resulted in small infarction volumes, and HDT was associated with a low AQP4 expression and improved neurological score, while the combination of ACZ and HDT improved neurological scores and reduced brain water content. This study shows that collateral augmentation treatments are associated with a better stroke prognosis compared with untreated animals after transient MCAO. The combination of ACZ and HDT seems to have some synergistic effect, but was not proven to be superior to HDT treatment alone.


Assuntos
Acetazolamida/uso terapêutico , Anticonvulsivantes/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Decúbito Inclinado com Rebaixamento da Cabeça , Infarto da Artéria Cerebral Média/terapia , Acetazolamida/administração & dosagem , Animais , Anticonvulsivantes/administração & dosagem , Inibidores da Anidrase Carbônica/administração & dosagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Ratos , Ratos Wistar
11.
J Med Chem ; 63(6): 3317-3326, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32031797

RESUMO

The design of three dual-tailed sulfonamide series 11a-11g, 14a-14h, and 16a-16e as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors are presented. All compounds were evaluated for inhibitory action against pharmacologically relevant human CA isoforms I, II, IV, and VII. Compounds 11a-11g emerged as potent CA inhibitors against the four tested isoforms with a significant selectivity to CA II, which is implicated in glaucoma (Ki in the range 0.36-6.9 nM). X-ray crystallographic analysis of three compounds (11a, 11d, and 11g) bound to CA II showed the validity of the adopted drug design strategy as specific moieties within the ligand structure interacted directly with the hydrophobic and hydrophilic halves of the CA II active site. Compounds 11b-11d and 11g were evaluated for their intraocular pressure-lowering effects in a rabbit model of glaucoma. 11b and 11d showed significant efficacy when compared to the clinically used drug dorzolamide.


Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Anidrases Carbônicas/metabolismo , Glaucoma/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Animais , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/metabolismo , Anidrases Carbônicas/química , Domínio Catalítico , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Masculino , Estrutura Molecular , Ligação Proteica , Coelhos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo
12.
PLoS One ; 15(1): e0227595, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929565

RESUMO

OBJECTIVE: To evaluate the prescribing trends of glaucoma drugs in six major cities of China from 2013 to 2017. METHODS: A descriptive analysis using pharmacy prescription data was conducted. Outpatient prescription data was extracted from the Hospital Prescription Analysis Cooperative Project. Prescribing patterns, trends of visits, and corresponding expenditures for glaucoma medications were analyzed. RESULTS: A total of 84297 ambulatory prescriptions were included in the current study. Visits by glaucoma patients increased from 13808 in 2013 to 20060 in 2017. Over the same period, the yearly expenditure for glaucoma drugs increased from 2.33 million to 3.95 million Chinese Yuan (CNY). Among all the six classes of glaucoma drugs (prostaglandin analogues, carbonic anhydrase inhibitors, α-receptor agonists, ß-receptor antagonists, cholinergic agonists and fixed combinations), ß-receptor antagonists were the most commonly prescribed in 2013, accounting for 34.3% of patients, but gradually decreased to 27.1% in 2017. Prostaglandin analogues became the most frequently prescribed drugs in 2017, accounting for 30.2% of the visits. Prostaglandin analogues are the most expensive and yielded a total expenditure of 2.34 million CNY in 2017, followed by carbonic anhydrase inhibitors, α-receptor agonists, ß-receptor antagonists, fixed combinations, and cholinergic agonists. Combination therapy became increasingly prescribed in 2017. CONCLUSION: Glaucoma prescribing practices exhibited substantial changes over the study period. The number of glaucoma prescriptions continuously increased from 2013 to 2017, leading to increased prescription costs. These findings implied a similar trend observed in previous studies, as well as recommendations in the appropriate guidelines.


Assuntos
Glaucoma/tratamento farmacológico , Padrões de Prática Médica/tendências , Adolescente , Agonistas alfa-Adrenérgicos/economia , Agonistas alfa-Adrenérgicos/uso terapêutico , Antagonistas Adrenérgicos beta/economia , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Inibidores da Anidrase Carbônica/economia , Inibidores da Anidrase Carbônica/uso terapêutico , China , Agonistas Colinérgicos/economia , Agonistas Colinérgicos/uso terapêutico , Cidades , Quimioterapia Combinada/economia , Quimioterapia Combinada/tendências , Feminino , Glaucoma/economia , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica/economia , Prostaglandinas Sintéticas/economia , Prostaglandinas Sintéticas/uso terapêutico , Estudos Retrospectivos , Adulto Jovem
13.
Eur J Paediatr Neurol ; 25: 181-186, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31810576

RESUMO

BACKGROUND: Paroxysmal tonic upgaze (PTU), defined as an involuntary upward movement of the eyes, has been considered as a benign phenomenon but may also be associated with ataxia and developmental delay. METHODS: We report eight children with PTU; six of them also exhibiting symptoms of ataxia and/or developmental delay. Treatment with carbonic anhydrase inhibition was offered to children with persisting and/or severe forms. RESULTS: Whole-exome sequencing and genome-wide array analysis (n = 7) did not reveal mutations in the three known genes associated with PTU (CACNA1A, GRID2, SEPSECS), whereas by MLPA a heterozygous deletion of exon 31 of the CACNA1A gene could be detected in one patient, her mother and two further family members. Further exome and array analysis showed no recurrent variants in potentially novel PTU-related genes in more than one patient. A de novo variant at a highly conserved position in the SIM1 gene was detected in one patient, for which a pathogenic effect could be speculated. Carbonic anhydrase inhibition was started in five children and proved at least partially effective in all of them. CONCLUSION: Irrespective of the clinical background and the molecular basic mechanism of PTU, therapeutic carbonic anhydrase inhibition was effective in all five children (acetazolamide, n = 3; sultiame, n = 2) who received this treatment.


Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Fixação Ocular , Transtornos da Motilidade Ocular/tratamento farmacológico , Acetazolamida/uso terapêutico , Pré-Escolar , Feminino , Fixação Ocular/efeitos dos fármacos , Humanos , Lactente , Masculino , Mutação , Transtornos da Motilidade Ocular/genética , Tiazinas/uso terapêutico
14.
Eur J Ophthalmol ; 30(2): 293-298, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30526051

RESUMO

AIM: To evaluate the effectiveness of brinzolamide-brimonidine fixed combination to control the intraocular pressure elevation throughout the first 24 h following uncomplicated phacoemulsification cataract surgery. PATIENTS AND METHODS: A total of 62 patients who underwent phacoemulsification cataract surgery were included in this prospective randomized comparative case series. The brinzolamide-brimonidine fixed combination group (34 eyes) was administered a single dose of brinzolamide-brimonidine fixed combination immediately after phacoemulsification. No treatment was administered in the control group (28 eyes). Intraocular pressure was measured 1 day before surgery (baseline) and at 6, 12 and 24 h postoperatively. RESULTS: The brinzolamide-brimonidine fixed combination group had significantly lower intraocular pressure at 6, 12 and 24 h after phacoemulsification compared to baseline (p < 0.0001 for all comparisons), while in control group, intraocular pressure was significantly higher at 6 and 12 h after surgery compared to baseline (p < 0.001 and p < 0.0001, respectively). In control group, an intraocular pressure elevation ⩾ 5 mm Hg was noted in 32.4% of the eyes at 6 and 12 h and in 5.9% of eyes at 24 h after surgery, while in brinzolamide-brimonidine fixed combination group, only 8.8% of the eyes at 6 h postoperatively had such an intraocular pressure elevation. CONCLUSION: The administration of a single drop of brinzolamide-brimonidine fixed combination effectively prevented intraocular pressure elevations and intraocular pressure spikes during the first 24 h after uneventful phacoemulsification.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Tartarato de Brimonidina/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/prevenção & controle , Facoemulsificação , Sulfonamidas/uso terapêutico , Tiazinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/etiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Tonometria Ocular
15.
Am J Ophthalmol ; 209: 141-150, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31377283

RESUMO

PURPOSE: To identify factors associated with the successful treatment of malignant glaucoma (MG). DESIGN: Retrospective case series. METHODS: Setting: single institution; study population: 64 eyes (55 subjects) with MG; observation procedure(s): chart review; main outcome measures: anatomy, intraocular pressure (IOP), best visual acuity (BVA). RESULTS: 87.5% (n=56/64) of eyes with MG required surgical intervention. Vitrectomy was more likely to be successful in eyes with a history of <3 incisional surgeries, <3 glaucoma drops, or IOP ≤30 mm Hg (P < .05). If vitrectomy was performed within 30 days, recovery of anatomy, BVA, and IOP occurred sooner (P < .05). IOP reduction was greater in subjects treated with oral carbonic anhydrase inhibitors (P = .016) or Nd:YAG laser hyaloidotomy (P = .007), and without a history of MG (P = .007). Time to maximal improvement was significantly longer for IOP and BVA than anatomy (P < .001). Treatment of MG with an oral carbonic anhydrase inhibitor hastened anatomic recovery (P = .01). Time to improvement in BVA was significantly faster in men and African Americans (P < .05). Time to maximal reduction in IOP occurred sooner in eyes that underwent anterior chamber reformation in clinic (P < .002). Trabeculectomy surgery prior to MG was associated with prolonged recovery of anatomy, BVA, and IOP (P < .05). CONCLUSIONS: Earlier vitrectomy may shorten recovery times for MG. Nd:YAG laser hyaloidotomy and oral carbonic anhydrase inhibitors may lead to greater IOP reduction. The time to maximal improvement in IOP and BVA may be longer than the time to anatomic resolution. Although trabeculectomy may impede time to recovery from MG, oral carbonic anhydrase inhibitors may shorten the time to anatomic recovery and anterior chamber reformation may hasten IOP recovery.


Assuntos
Anti-Hipertensivos/administração & dosagem , Glaucoma de Ângulo Fechado/terapia , Pressão Intraocular/fisiologia , Iridectomia/métodos , Iris/cirurgia , Acuidade Visual/fisiologia , Idoso , Idoso de 80 Anos ou mais , Inibidores da Anidrase Carbônica/uso terapêutico , Feminino , Glaucoma de Ângulo Fechado/tratamento farmacológico , Glaucoma de Ângulo Fechado/fisiopatologia , Glaucoma de Ângulo Fechado/cirurgia , Humanos , Lasers de Estado Sólido/uso terapêutico , Masculino , Microscopia Acústica , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Tempo , Tomografia de Coerência Óptica , Resultado do Tratamento , Vitrectomia
16.
Chest ; 157(2): 394-402, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31047953

RESUMO

Sleep-disordered breathing (SDB), including OSA and central sleep apnea, is highly prevalent in patients with heart failure (HF). Multiple studies have reported this high prevalence in asymptomatic as well as symptomatic patients with reduced left ventricular ejection fraction (HFrEF), as well as in those with HF with preserved ejection fraction. The acute pathobiologic consequences of OSA, including exaggerated sympathetic activity, oxidative stress, and inflammation, eventually could lead to progressive left ventricular dysfunction, repeated hospitalization, and excessive mortality. Large numbers of observational studies and a few small randomized controlled trials have shown improvement in various cardiovascular consequences of SDB with treatment. There are no long-term randomized controlled trials to show improved survival of patients with HF and treatment of OSA. One trial of positive airway pressure treatment of OSA included patients with HF and showed no improvement in clinical outcomes. However, any conclusions derived from this trial must take into account several important pitfalls that have been extensively discussed in the literature. With the role of positive airway pressure as the sole therapy for SDB in HF increasingly questioned, a critical examination of long-accepted concepts in this field is needed. The objective of this review was to incorporate recent advances in the field into a phenotype-based approach to the management of OSA in HF.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas/métodos , Terapia por Estimulação Elétrica , Insuficiência Cardíaca/fisiopatologia , Apneia Obstrutiva do Sono/terapia , Acetazolamida/uso terapêutico , Dióxido de Carbono , Inibidores da Anidrase Carbônica/uso terapêutico , Exercício Físico , Insuficiência Cardíaca/complicações , Humanos , Nervo Hipoglosso , Hipotonia Muscular , Oxigenoterapia , Músculos Faríngeos , Fenótipo , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/fisiopatologia
17.
J Med Chem ; 63(5): 2325-2342, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31689108

RESUMO

Multitarget nonsteroidal anti-inflammatory drug (NSAID)-carbonic anhydrase inhibitor (CAI) agents for the management of rheumatoid arthritis are reported. The evidence of the plasma stability of the amide-linked hybrids previously reported prompted us to investigate their pain-relieving mechanism of action. A bioisosteric amide to ester substitution yielded a series of derivatives showing potent target CAs inhibition and to undergo cleavage in rat or human plasma depending on the NSAID portion. A selection of derivatives were assayed in vitro to indirectly evaluate their effect on COX-1 and COX-2. MD simulations demonstrated that the entire hybrids are also able to efficiently bind the COX active site. In a rat model of RA, the most promising derivative (5c) showed major antihyperalgesic action compared with the equimolar coadministration of the single agents. The gathered data provided new insights on the action mechanism of these multitarget compounds, which induce markedly improved pain relief compared with the parent NSAIDs.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Inibidores da Anidrase Carbônica/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Desenho de Fármacos , Desenvolvimento de Medicamentos , Humanos , Masculino , Simulação de Dinâmica Molecular , Dor/tratamento farmacológico , Ratos , Ratos Sprague-Dawley
18.
Korean J Ophthalmol ; 33(6): 493-499, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31833245

RESUMO

PURPOSE: We sought to elucidate the influence of acetazolamide on choroidal structure changes during the treatment of central serous chorioretinopathy (CSC). METHODS: This was a retrospective study of 45 eyes from 45 patients with acute CSC who were divided into an acetazolamide group (group 1, n = 20) and an observation group (group 2, n = 25). The main outcome measures were the changes in best-corrected visual acuity, subretinal fluid (SRF) height, subfoveal choroidal thickness (SFCT), and choroidal vascularity index (CVI) at one week, one month, two months, and three months, respectively. RESULTS: Although statistical significance was not reached, best-corrected visual acuity improved in both groups at month 3 (from 0.06 ± 0.07 to 0.01 ± 0.03 in group 1 and 0.17 ± 0.24 to 0.09 ± 0.18 in group 2; p = 0.083 and 0.183, respectively). Separately, SRF height and CVI showed a significant decrease at three months in both groups (all p < 0.05), while a significant SRF height decrease was also noted in group 1 at one month (p = 0.038). In group 1, a significant decrease in the SFCT and CVI started at one week and one month (p = 0.021 and 0.008), respectively. However, in group 2, a significant decrease in the SFCT and CVI started at one month and two months (p = 0.005 and 0.015), respectively. CONCLUSIONS: Acetazolamide has no effect on final functional or anatomical status at three months in eyes with CSC but does shorten the time for SRF absorption and accompanying choroidal structural changes.


Assuntos
Acetazolamida/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Coriorretinopatia Serosa Central/tratamento farmacológico , Corioide/efeitos dos fármacos , Adulto , Estudos de Casos e Controles , Coriorretinopatia Serosa Central/diagnóstico por imagem , Coriorretinopatia Serosa Central/fisiopatologia , Corioide/irrigação sanguínea , Corantes/administração & dosagem , Feminino , Angiofluoresceinografia , Humanos , Verde de Indocianina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Líquido Sub-Retiniano , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia
19.
Int J Mol Sci ; 20(23)2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31810330

RESUMO

Carbonic anhydrases (CAs) are a family of enzymes involved in the pH regulation of metabolically active cells/tissues. Upregulation of the CAIX/XII isoforms is associated with hypoxic tumours and clinically linked with malignant progression, treatment resistance and poor prognosis. The elucidation of the crystal structure of the catalytic domains of CAIX/XII provided the basis for the generation of CAIX/XII selective inhibitors based on the sulfonamide, sulfamate and coumarins chemical structures. Ureido-substituted benzenesulfonamide CAIX/XII inhibitors have shown significant potential, with U-104 (SLC-0111) currently present in clinical Phase I/II. Ureido-substituted sulfamate CAIX/XII inhibitors have received less attention despite encouraging preclinical test results. In triple-negative breast cancer (TNBC), ureidosulfamates revealed a significant antitumour (FC9-398A) and antimetastatic potential (S4). In small cell lung cancer (SCLC), a cancer cell type very sensitive to a dysregulation in CAIX signaling, S4 treatment was particularly effective when combined with cisplatin with no evidence of acquired cisplatin-resistance. These successful anticancer strategies should provide a solid basis for future studies on ureido-substituted sulfamates.


Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Relação Estrutura-Atividade , Sulfonamidas/uso terapêutico , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/genética , Anidrases Carbônicas/efeitos dos fármacos , Anidrases Carbônicas/genética , Humanos , Compostos de Fenilureia/uso terapêutico , Ácidos Sulfônicos/química , Ácidos Sulfônicos/uso terapêutico
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