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1.
BMC Gastroenterol ; 21(1): 361, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34600483

RESUMO

BACKGROUND: Ixekizumab is monoclonal antibody targeted against interleukin-17 (IL-17) and has been approved for use in chronic plaque psoriasis. Despite its efficacy in treating psoriasis, concerns have been raised regarding Ixekizumab's potential to induce and exacerbate inflammatory bowel disease (IBD). CASE PRESENTATION: Here we report the new onset of severe drug-associated colitis with surgical complications in a 45-year-old male patient who was receiving Ixekizumab therapy for chronic plaque psoriasis. Review of the patient's colonic pathology demonstrated acute inflammatory changes with features of Crohn's disease. The patient remained disease-free 9-months following his hospitalization and cessation of Ixekizumab. CONCLUSIONS: This case raises suspicion for an association between Ixekizumab and IBD and calls on clinicians to have heightened awareness of potential risks before prescribing anti-IL-17 agents.


Assuntos
Colite , Doença de Crohn , Fármacos Dermatológicos , Preparações Farmacêuticas , Psoríase , Anticorpos Monoclonais Humanizados , Colite/induzido quimicamente , Colite/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do Tratamento
2.
Environ Monit Assess ; 193(10): 685, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34599667

RESUMO

A standard method to test the aquatic toxicity of biologically active household chemicals (BAHC), including those with very low water solubility, is proposed. The method uses the common marine models Paracentrotus lividus embryos and Acartia clausi larvae, in order to advance towards derivation of water quality criteria for these emerging pollutants that currently lack environmental standards. Depending on the water solubility and octanol-water partition coefficient (Kow) of the substance, the protocol consists of testing the toxicity of the substances by serial dilutions of water stocks, dimethyl-sulfoxide stocks, or 100 mg/L lixiviates in seawater. When this method is applied to eleven model BAHC, the pharmaceutical fluoxetine, the antioxidant butylated hydroxytoluene, and the UV filters broadly present in cosmetics octocrylene and 4-methylbenzylidene camphor, are classified as very toxic to aquatic life, since their EC50 values are < 1 mg/L. In general, both biological models, P. lividus and A. clausi, yield the same classification of the substances tested, but variations in the classification of aquatic toxicity depending on methodological aspects are discussed. The use of A. clausi nauplii provides more protecting value to the toxicity parameters obtained by using this protocol.


Assuntos
Cosméticos , Preparações Farmacêuticas , Poluentes Químicos da Água , Animais , Cosméticos/toxicidade , Monitoramento Ambiental , Técnicas de Diluição do Indicador , Plásticos , Poluentes Químicos da Água/toxicidade
3.
Anal Chim Acta ; 1182: 338959, 2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34602190

RESUMO

Volatile solvents are excellent extraction media for liquid-liquid extractions. However, their use in supported liquid membranes (SLMs) is limited by their evaporation from SLM and thus poor SLM stability and they have never been considered truly useful for electromembrane extraction (EME). In this contribution, volatile solvents were systematically investigated as liquid membranes for EME and their extraction characteristics were comprehensively examined for the first time. A short plug of a water immiscible volatile solvent (a free liquid membrane (FLM)) was sandwiched between two aqueous plugs (donor and acceptor solutions) in a narrow-bore polymeric tubing. Evaporation of the volatile FLM was thus completely avoided and excellent stability of the phase interface was ensured. Suitability of volatile FLMs for EMEs was justified by µ-EMEs of nortriptyline, haloperidol, loperamide and papaverine as model non-polar basic drugs. Extraction performance of µ-EME through ethyl acetate was comparable or better to that through standard non-volatile EME solvents and a high extraction selectivity was achieved for nortriptyline and haloperidol extracted through chloroform. µ-EMEs through the volatile FLMs were characterized by high extraction recoveries (62%-99% for standards and 40-89% for body fluids), low electric currents (10-1380 nA), no susceptibility to matrix ions and suitability for pretreatment of raw body fluids (human urine and serum). Resulting extracts were analysed by capillary electrophoresis with ultraviolet detection (CE/UV). Repeatability of the µ-EME-CE/UV method was excellent with intra-day and inter-day RSD values 0.8-3.2% and 1.8-4.6%, respectively. Further experiments demonstrated additional advantages of volatile FLMs by nearly exhaustive µ-EMEs of atenolol as the polar basic drug with no need for FLM modification by ionic carriers. The presented comprehensive examination of volatile solvents has broadened the range of liquid membranes suitable for EME and it is believed that this proof-of-concept study will stimulate further interest in a deeper investigation of volatile phase interfaces in EME.


Assuntos
Membranas Artificiais , Preparações Farmacêuticas , Eletricidade , Eletroforese Capilar , Humanos , Solventes
4.
Br J Nurs ; 30(17): S4-S8, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34605266

RESUMO

Freelance medical writer Christine Clark (chris@salt.u-net.com) reports on an online meeting held in April 2021 on protecting nursing staff working in oncology from exposure to hazardous drugs.


Assuntos
Neoplasias , Enfermeiras e Enfermeiros , Exposição Ocupacional , Preparações Farmacêuticas , Substâncias Perigosas , Humanos , Neoplasias/tratamento farmacológico , Exposição Ocupacional/prevenção & controle
5.
BMC Bioinformatics ; 22(1): 477, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34607569

RESUMO

BACKGROUND: Deep learning methods are a proven commodity in many fields and endeavors. One of these endeavors is predicting the presence of adverse drug-drug interactions (DDIs). The models generated can predict, with reasonable accuracy, the phenotypes arising from the drug interactions using their molecular structures. Nevertheless, this task requires improvement to be truly useful. Given the complexity of the predictive task, an extensive benchmarking on structure-based models for DDIs prediction was performed to evaluate their drawbacks and advantages. RESULTS: We rigorously tested various structure-based models that predict drug interactions using different splitting strategies to simulate different real-world scenarios. In addition to the effects of different training and testing setups on the robustness and generalizability of the models, we then explore the contribution of traditional approaches such as multitask learning and data augmentation. CONCLUSION: Structure-based models tend to generalize poorly to unseen drugs despite their ability to identify new DDIs among drugs seen during training accurately. Indeed, they efficiently propagate information between known drugs and could be valuable for discovering new DDIs in a database. However, these models will most probably fail when exposed to unknown drugs. While multitask learning does not help in our case to solve the problem, the use of data augmentation does at least mitigate it. Therefore, researchers must be cautious of the bias of the random evaluation scheme, especially if their goal is to discover new DDIs.


Assuntos
Preparações Farmacêuticas , Bases de Dados Factuais , Interações Medicamentosas
6.
Int J Chron Obstruct Pulmon Dis ; 16: 2687-2695, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34611397

RESUMO

COVID-19 has affected millions of patients, caregivers, and clinicians around the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads via droplets and close contact from person to person, and there has been an increased concern regarding aerosol drug delivery due to the potential aerosolizing of viral particles. To date, little focus has been given to aerosol drug delivery to patients with COVID-19 treated at home to minimize their hospital utilization. Since most hospitals were stressed with multiple admissions and experienced restricted healthcare resources in the era of COVID-19 pandemic, treating patients with COPD at home became essential to minimize their hospital utilization. However, guidance on how to deliver aerosolized medications safely and effectively to this patient population treated at home is still lacking. In this paper, we provide some strategies and rationales for device and interface selection, delivery technique, and infection control for patients with COPD who are being treated at home in the era of COVID-19 and beyond.


Assuntos
COVID-19 , Preparações Farmacêuticas , Doença Pulmonar Obstrutiva Crônica , Humanos , Pandemias , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , SARS-CoV-2
7.
J Environ Manage ; 299: 113532, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34614559

RESUMO

Diclofenac (DCF), ibuprofen (IBU), propranolol (PRO), triclosan (TCS) and linear alkylbenzene sulfonate (LAS) can be recalcitrant in Wastewater Treatment Plants (WWTP). The removal of these compounds was investigated in scale-up (69 L) Expanded Granular Sludge Bed (EGSB) reactor, fed with sanitary sewage from the São Carlos-SP (Brazil) WWTP and 200 mg L-1 of ethanol. The EGSB was operated in three phases: (I) hydraulic retention time (HRT) of 36±4 h; (II) HRT of 20±2 h and (III) HRT of 20±2 h with ethanol. Phases I and II showed no significant difference in the removal of LAS (63 ± 11-65 ± 12 %), DCF (37 ± 18-35 ± 11 %), IBU (43 ± 18-44 ± 16 %) and PRO (46 ± 25-51 ± 23 %) for 13±2-15 ± 2 mg L-1, 106 ± 32-462 ± 294 µg L-1, 166 ± 55-462 ± 213 µg L-1 and 201 ± 113-250 ± 141 µg L-1 influent, respectively. Higher TCS removal was obtained in phase I (72 ± 17 % for 127 ± 120 µg L-1 influent) when compared to phase II (51 ± 13 % for 135 ± 119 µg L-1 influent). This was due to its greater adsorption (40 %) in the initial phase. Phase III had higher removal of DCF (42 ± 10 % for 107 ± 26 µg L-1 influent), IBU (50 ± 15 % for 164 ± 47 µg L-1 influent) and TCS (85 ± 15 % for 185 ± 148 µg L-1 influent) and lower removal of LAS (35 ± 14 % for 12 ± 3 mg L-1 influent) and PRO (-142 ± 177 % for 188 ± 88 µg L-1 influent). Bacteria similar to Syntrophobacter, Smithella, Macellibacteroides, Syntrophus, Blvii28_wastewater-sludge_group and Bacteroides were identified in phase I with relative abundance of 3.1 %-4.7 %. Syntrophobacter was more abundant (15.4 %) in phase II, while in phase III, it was Smithella (12.7 %) and Caldisericum (15.1 %). Regarding the Archaea Domain, Methanosaeta was more abundant in phases I (84 %) and II (67 %), while in phase III it was Methanobacterium (86 %).


Assuntos
Preparações Farmacêuticas , Esgotos , Anaerobiose , Brasil , Higiene
8.
No Shinkei Geka ; 49(5): 1024-1030, 2021 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-34615762

RESUMO

More than half of the patients with severe head injuries are elderly people in Japan due to the impact of entering a super-aging society. Elderly people take antithrombotic drugs at a high rate. According to the Japan Neurotrauma Data Bank, many patients with head injuries taking antithrombotic drugs sustain falls, indicating an increased risk of deterioration due to low-energy trauma. It has also been pointed out that many hemorrhagic lesions occur due to the effects of antithrombotic drugs, and there is a risk that hematoma will increase later. As an appropriate response in such patients, if bleeding findings are noted on head CT, discontinuation/reversal of antithrombotic drugs should be considered even if the severity is mild. Reversal therapy should be performed in an appropriate manner as quickly and reliably as possible. Some effects of reversal therapy have been reported in small-scale observational studies. Discontinued antithrombotic drugs should be resumed in the neurotrauma subacute phase. Resuming antithrombotic drugs reduces the risk of ischemic complications, but increases the risk of bleeding complications. To summarize, the benefits of resuming antithrombotic drugs have been reported, and it is recommended that antithrombotic drugs be resumed 3-10 days after injury.


Assuntos
Lesões Encefálicas Traumáticas , Preparações Farmacêuticas , Idoso , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Fibrinolíticos/efeitos adversos , Humanos , Japão
9.
BMJ Case Rep ; 14(10)2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34607814

RESUMO

Lymphatic malformation (LM) that causes inguinoscrotal swelling is extremely rare. Surgery, sclerotherapy and pharmacotherapy have been reported as possible treatment options for LM. Recently, Eppikajutsuto (TJ-28), a traditional Japanese herbal medicine has emerged as therapeutic option for LM. We report the case of a 2-year-old boy who presented with a left inguinoscrotal swelling, which was diagnosed as retroperitoneal LM extending into the left scrotum. The surgical approach was less favourable, given the risk of damaging the testicular vasculature or the spermatic cord. Therefore, the patient received medical treatment with TJ-28. As a result, a volume reduction of 83% was obtained, as well as the unexpected consequence of the left testicle retracting into the inguinal area. Laparoscopic exploration was performed and a small bulge on the internal inguinal ring was detected. The patient's acquired cryptorchidism was subsequently treated by orchidopexy.


Assuntos
Criptorquidismo , Anormalidades Linfáticas , Pré-Escolar , Criptorquidismo/complicações , Criptorquidismo/cirurgia , Humanos , Masculino , Orquidopexia , Preparações Farmacêuticas , Extratos Vegetais
10.
Int J Pharm Compd ; 25(5): 372-377, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34623962

RESUMO

Dermal healing occurs via a linear sequence of events in which growth factors cause cell proliferation and a subsequent integration of changes that involve soluble mediators, parenchymal and blood cells, and the production of extracellular matrix. Myriad factors influence the process and progress of healing damaged skin, and numerous agents have been used alone or in combination with other active substances to enable both responses to skin injury or disease. In this third article in a series on compounding for dermal healing, the role of nitric oxide in dermal repair is examined, as is the effectiveness of both sildenafil and naltrexone in promoting recovery. Also provided are compounded skin-healing formulations that proved effective when treatment with commercially manufactured medications failed.


Assuntos
Óxido Nítrico , Preparações Farmacêuticas , Naltrexona , Citrato de Sildenafila , Cicatrização
11.
Int J Pharm Compd ; 25(5): 378-384, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34623963

RESUMO

The development of compounding science in the Republic of Uzbekistan began in ancient times. The emergence of medical science on the territory of modern Uzbekistan was associated with the activities of the famous physician Ibn Sina (Avicenna). His Canon of Medicine is still considered the main source of medical knowledge in the world. He paid great attention to herbal medicines, its collection, storage, and application. The main development of compounding in Uzbekistan fell within the 20th century, after the Main Directorate of Pharmacies was established and new pharmacies were opened in all cities. In the beginning of 1975, there were about 2000 pharmacies in Uzbekistan and all pharmacies were engaged in the preparation of medicines. Today, there are more than 14 thousand pharmacies in Uzbekistan, which belong to large pharmacy chains, in the structure of which there are compounding pharmacies that compound injections and infusions, nasal and eardrops, ointments and suppositories, tinctures, decoctions, etc. Among the pharmaceutical networks in Uzbekistan, JSC Dori-Darmon is one of the largest. JSC Dori-Darmon, having about 120 branches, provides the population of Uzbekistan with medicines. Another one, Osiyo Farm, specializes in the compounding of external solutions and semi-solid dosage forms, while JSC Dori- Darmon mainly dispenses injections, mixtures, and solutions for external use. In Uzbekistan, pharmaceutical compounding is regulated by the Law of the Republic of Uzbekistan No. 415-I. The development of the pharmaceutical market in Uzbekistan is very active since the number of pharmaceutical enterprises is increasing and new drugs of synthetic and herbal origin are being developed. The main educational institutions that train pharmacists are the Tashkent Pharmaceutical Institute and the Tashkent Medical College.


Assuntos
Serviços Comunitários de Farmácia , Preparações Farmacêuticas , Farmácia , Composição de Medicamentos , Humanos , Masculino , Uzbequistão
12.
Artigo em Chinês | MEDLINE | ID: mdl-34628806

RESUMO

Objective:To explore the distribution of pathogenic bacteria and drug sensitivity among patients with chronic suppurative otitis media. Methods:Patients with chronic suppurative otitis media who were hospitalized in the Department of Otolaryngology, People's Hospital, Peking University for surgery from January 1, 2019 to May 1, 2021 were enrolled as the subjects, then take the deep secretions of the external auditory canal for bacterial culture. Finally, the distribution and drug sensitivity of the pathogenic bacteria are analyzed. Results:A total of 126 patients were enrolled, of which 53 were culture-positive, and 57 strains of bacteria were isolated, including 47 strains of Gram-positive cocci, 10 strains of Gram-negative bacilli. Among Gram-positive cocci, 24 methicillin-sensitive staphylococcus aureus(MSSA) strains, 7 methicillin-resistant staphylococcus aureus(MRSA) strains, 14 coagulase-negative staphylococcus strains, 1 strain enterococcus faecium, and 1 strain otitis Zurich. 4 strains(4/10) of pseudomonas aeruginosa among Gram-negative bacilli. Among them, MSSA has a high resistance rate to levofloxacin, moxifloxacin, clindamycin, and gentamicin, and high sensitivity to oxacillin, vancomycin, linezolid, and rifampin. MRSA is highly resistant to common antibiotics except vancomycin, rifampicin, and linezolid. The Gram-negative bacilli have higher resistance rates to levofloxacin, aztreonam, ciprofloxacin, ceftazidime, and piperacillin/tazobactam, and to meropenem, imipenem, amika star, cefepoxime, cefoperazone/sulbactam, and tobramycin are more sensitive. The results of univariable and multivariable analysis showed that age and bacterial infection were independent factors related to dry ears, and the duration of the disease history was a non-independent factor. Conclusion:The main pathogenic bacteria infections in patients with chronic suppurative otitis media are MSSA, MRSA, and pseudomonas aeruginosa. Whether it is combined with bacterial infection and age are independent factors related to whether patients with chronic suppurative otitis media could have dry ears. Therefore, patients with chronic suppurative otitis media should be treated with specific antibiotics or surgical interventions as soon as possible in combination with drug sensitivity results to avoid prolonging disease course or causing serious infectious complications.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Otite Média Supurativa , Preparações Farmacêuticas , Infecções Estafilocócicas , Humanos , Testes de Sensibilidade Microbiana
13.
World J Gastroenterol ; 27(35): 5796-5802, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34629803

RESUMO

Drug-induced pancreatitis is a gastrointestinal adverse effect concerning about 2% of drugs. The majority of cases are mild to moderate but severe episodes can also occur, leading to hospitalization or even death. Unfortunately, the mechanisms of this adverse reaction are still not clear, hindering its prevention, and the majority of data available of this potentially life-threatening adverse effect are limited to case reports leading to a probable underestimation of this event. In particular, in this editorial, special attention is given to thiopurine-induced pancreatitis (TIP), an idiosyncratic adverse reaction affecting around 5% of inflammatory bowel disease (IBD) patients taking thiopurines as immunosuppressants, with a higher incidence in the pediatric population. Validated biomarkers are not available to assist clinicians in the prevention of TIP, also because of the inaccessibility of the pancreatic tissue, which limits the possibility to perform dedicated cellular and molecular studies. In this regard, induced pluripotent stem cells (iPSCs) and the exocrine pancreatic differentiated counterpart could be a great tool to investigate the cellular and molecular mechanisms underlying the development of this undesirable event. This particular type of stem cells is obtained by reprogramming adult cells, including fibroblasts and leukocytes, with a set of transcription factors known as the Yamanaka's factors. Maintaining unaltered the donors' genetic heritage, iPSCs represent an innovative model to study the mechanisms of adverse drug reactions in individual patients' tissues not easily obtainable from human probands. Indeed, iPSCs can differentiate under adequate stimuli into almost any somatic lineage, opening a new world of opportunities for researchers. Several works are already available in the literature studying liver, central nervous system and cardiac cells derived from iPSCs and adverse drug effects. However, to our knowledge no studies have been performed on exocrine pancreas differentiated from iPSCs and drug-induced pancreatitis, so far. Hence, in this editorial we focus specifically on the description of the study of the mechanisms of TIP by using IBD patient-specific iPSCs and exocrine pancreatic differentiated cells as innovative in vitro models.


Assuntos
Células-Tronco Pluripotentes Induzidas , Pancreatite , Preparações Farmacêuticas , Diferenciação Celular , Criança , Humanos , Pâncreas , Pancreatite/induzido quimicamente
14.
Zhonghua Wai Ke Za Zhi ; 59(10): 854-860, 2021 Oct 01.
Artigo em Chinês | MEDLINE | ID: mdl-34619912

RESUMO

Objectives: To establish a grading model on prognosis of drug-coated balloon (DCB) treatment on femoropopliteal de novo lesions, and assess whether patients at high risk could benefit from combination of directional atherectomy(DA). Methods: The clinical data of 114 patients with femoropopliteal de novo lesions admitted to Department of Vascular Surgery, Peking University People's Hospital from October 2015 to January 2019 were collected retrospectively. There were 95 patients(108 limbs) underwent DCB treatment, including 66 males and 29 females, aged 71.9 years old(range:48 to 91 years), and 19 patients (21 limbs) underwent DA combined with DCB treatment, including 13 males and 6 females, aged 69.5 years old(range: 62 to 80 years). The demographic data, intraoperative and postoperative conditions of the patients were collected. Cox regression model was performed for modeling and then goodness of fit was tested. Kaplan-Meier estimate was carried out between the two groups for patients at high risk and low risk, respectively. Results: All patients were followed up for more than 24 months. Restenosis occurred on 34 limbs in DCB group and 3 limbs in DA+DCB group. Severe calcification(HR=3.804, 95%CI:2.460 to 5.883), popliteal artery involvement (HR=2.104, 95%CI:1.368 to 3.236), long lesion (HR=1.824, 95%CI:1.196 to 2.780), poor runoff(HR=1.736, 95%CI:1.025 to 2.940), chronic kidney disease(HR=1.601, 95%CI:1.040 to 2.463) were independent risk factors of restenosis after DCB treatment, and were defined 3, 2, 1, 1 and 1 points, respectively. Total points≥3 was regarded as high risk group. Kaplan-Meier analysis showed that patients in low risk group did not benefit from DA+DCB comparing with DCB with regard to primary patency at 24 months (77.78% vs. 90.31%, P=0.271) while patients benefited from DA+DCB comparing with DCB in high risk group(88.26% vs. 20.80%, P<0.01). Conclusions: The grading model shows satisfying clinical value. The clinical effect of DA+DCB is better than DCB along in high risk group. Patients at high risk are supposed to receive aggressive vessel preparation like DA.


Assuntos
Angioplastia com Balão , Doença Arterial Periférica , Preparações Farmacêuticas , Idoso , Materiais Revestidos Biocompatíveis , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução Vascular
15.
Zhonghua Yan Ke Za Zhi ; 57(10): 734-742, 2021 Oct 11.
Artigo em Chinês | MEDLINE | ID: mdl-34619943

RESUMO

Ocular local or systemic medication may cause drug-related dry eye, which has become one of the important types of dry eye. A missed diagnosis or misdiagnosis of this type of dry eye is easy to occur clinically. To arouse the attention of ophthalmologists, experts from the Chinese Branch of the Asian Dry Eye Society and other related academic organizations have combined the new research progress and clinical practice associated with this specific disease, in terms of its definition, classification, risk factors, related drug types, pathogenesis, diagnosis, differential diagnosis, treatment principles and preventive measures, to form expert consensus opinions, hoping to promote the standardized diagnosis and treatment of drug-related dry eye in China. (Chin J Ophthalmol, 2021, 57: 734-742).


Assuntos
Síndromes do Olho Seco , Preparações Farmacêuticas , China , Consenso , Síndromes do Olho Seco/induzido quimicamente , Síndromes do Olho Seco/diagnóstico , Síndromes do Olho Seco/tratamento farmacológico , Olho , Humanos
16.
Molecules ; 26(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34500595

RESUMO

Amine-containing drugs often show poor pharmacological properties, but these disadvantages can be overcome by using a prodrug approach involving self-immolative linkers. Accordingly, we designed l-lactate linkers as ideal candidates for amine delivery. Furthermore, we designed linkers bearing two different cargos (aniline and phenol) for preferential amine cargo release within 15 min. Since the linkers carrying secondary amine cargo showed high stability at physiological pH, we used our strategy to prepare phosphate-based prodrugs of the antibiotic Ciprofloxacin. Therefore, our study will facilitate the rational design of new and more effective drug delivery systems for amine-containing drugs.


Assuntos
Aminas/química , Preparações Farmacêuticas/química , Fosfatos/química , Pró-Fármacos/química , Antibacterianos/química , Ciprofloxacina/química , Sistemas de Liberação de Medicamentos/métodos , Concentração de Íons de Hidrogênio , Ácido Láctico/química
17.
Lancet Neurol ; 20(10): 832-841, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34536405

RESUMO

BACKGROUND: Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US. METHODS: STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7-8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed). FINDINGS: From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0-5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26-100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91-100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8-44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 [67%] of 33), upper respiratory infection (11 [33%]), and increased alanine aminotransferase (nine [27%]). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study. INTERPRETATION: STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit-risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline. FUNDING: Novartis Gene Therapies.


Assuntos
Atrofia Muscular Espinal , Preparações Farmacêuticas , Atrofias Musculares Espinais da Infância , Criança , Terapia Genética , Humanos , Lactente , Infusões Intravenosas , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Atrofias Musculares Espinais da Infância/terapia
18.
Behav Neurol ; 2021: 6158275, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34552671

RESUMO

Insomnia, one of the most common sleep disorders, is thought to have an adverse effect on cognitive function. At the same time, people with cognitive dysfunction are more prone to insomnia. At present, pharmacotherapy is the main treatment for insomnia, but there are some shortcomings such as poor long-term efficacy and potential dependence. There is some evidence that acupuncture has some advantages in alleviating insomnia and improving cognitive function. This study is aimed at investigating the effects of acupuncture and drugs on cognitive function in patients with insomnia and evaluating the efficacy and safety of these two interventions, providing strong evidence for clinical decision-making. The study will retrieve eight major databases: China National Knowledge Infrastructure, Wanfang Database, VIP Database for Chinese Technical Periodicals, SinoMed, PubMed, Web of Science, Embase, and Cochrane Library. Dissertations, conference papers, and ongoing experiments will also be retrieved for supplement. Literature screening and data extraction will be completed by two authors independently (JJ and X-QW). If there were any disagreements, they would be discussed or referred to a third person for adjudication (W-ZW). Authors will use Cochrane risk of bias tool to assess the included studies. The Review Manager Statistical (RevMan) software is used to conduct the statistical process of meta-analysis, and funnel plot is used to evaluate reporting biases. The Grading of Recommendations Assessment Development and Evaluation (GRADE) Profiler can be used to be aware of the quality of evidence.


Assuntos
Terapia por Acupuntura , Preparações Farmacêuticas , Distúrbios do Início e da Manutenção do Sono , China , Cognição , Humanos , Metanálise como Assunto , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Revisões Sistemáticas como Assunto , Resultado do Tratamento
19.
Anal Chim Acta ; 1181: 338920, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34556207

RESUMO

Drug resistance poses an enormous challenge for successful chemotherapy. Glutathione S-transferase (GST) has been confirmed to be involved in the progression of drug resistance to some anticancer drugs, thus revealing that the role of GST in anticancer drug resistance is necessary. Herein, by taking advantage of frequency upconversion luminescence (FUCL) technology, we reported an FUCL probe (NRh-NDs) that can detect GST based on a rhodamine derivative structure decorated with a 2,4-dinitrobenzenesulfonyl group (NDs). The NRh-NDs showed excellent sensitivity and high selectivity for GST and released the emissive dye NRh-NH2, which showed emission and excitation wavelengths in vitro of 820 nm and 850 nm, respectively. The NRh-NDs probe successfully tested endogenic GST in U87, MCF-7 and A549 cells. The cell data showed that the increased levels of GST were positively related to cisplatin resistance but not to 5-fluorouracil resistance. These results suggested that the probe could be used as a visual tool to reveal the cause of drug resistance for cisplatin resistance in cancer treatment. Furthermore, it may serve as an effective tool to confirm the mechanism of antitumor drug resistance.


Assuntos
Antineoplásicos , Preparações Farmacêuticas , Células A549 , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistência a Medicamentos , Glutationa , Glutationa Transferase , Humanos , Células MCF-7
20.
Medicina (Kaunas) ; 57(9)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34577783

RESUMO

Background and objectives: The chromosome locus 20q11.21 is a commonly amplified locus in colorectal cancer, with a prevalence of 8% to 9%. Several candidate cancer-associated genes are transcribed from the locus. The therapeutic implications of the amplification in colorectal cancer remain unclear. Materials and Methods: Preclinical cell line models of colorectal cancer included in the Cancer Cell Line Encyclopedia (CCLE) collection were examined for the presence of amplifications in 20q11.21 genes. Correlations of the presence of 20q11.21 amplifications with gene essentialities and drug sensitivities were surveyed on salient databases for determination of therapeutic leads. Results: A significant subset of colorectal cancer cell lines in the CCLE (12 of 63 cell lines, 19%) bear amplifications of genes located at 20q11.21. Cancer-associated genes of the locus include ASXL1, DNMT3B, BCL2L1, TPX2, KIF3B and POFUT1. These genes are all amplified in the 12 cell lines, but they are variably over-expressed at the mRNA level, compared to non-amplified lines. 20q11.21 amplified cell lines are sensitive to various tyrosine kinase inhibitors and are resistant to chemotherapy drugs targeting the mitotic apparatus and microtubules. CRISPR and RNAi dependencies screening revealed, besides the ß-catenin and KRAS genes, a few recurrent gene dependencies in more than one cell line, including YAP1 and JUP. Conclusions: Cell line models of colorectal cancer with 20q11.21 gene amplifications display dependencies on the presence of specific genes and resistance or sensitivity to specific drugs and drug categories. Observations from in vitro models may form the basis for clinical drug development in this subtype of colorectal cancer. Genetic lesions conferring synthetic lethality to certain drugs or categories of drugs could be discovered with this approach.


Assuntos
Neoplasias Colorretais , Preparações Farmacêuticas , Linhagem Celular Tumoral , Cromossomos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Amplificação de Genes , Humanos , Cinesina , Fatores de Transcrição
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