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1.
Lupus ; 31(4): 472-481, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35258358

RESUMO

BACKGROUND: Antimalarials are first-line systemic therapy for cutaneous lupus erythematosus (CLE). While some patients unresponsive to hydroxychloroquine (HCQ) alone benefit from the addition of quinacrine (QC), a subset of patients is refractory to both antimalarials. METHODS: We classified CLE patients as HCQ-responders, HCQ+QC-responders, or HCQ+QC-nonresponders to compare immune profiles. Immunohistochemistry, immunofluorescence, and qRT-PCR were used to characterize inflammatory cells and cytokines in lesional skin. RESULTS: Immunohistochemistry showed that CD69+ T cells were higher in HCQ+QC-nonresponders compared to HCQ- and HCQ+QC-responders (p < 0.05). Immunofluorescence further identified these cells as CD69+CCR7+ circulating activated T cells. Myeloid dendritic cells were significantly higher in HCQ+QC-responders compared to both HCQ-responders and HCQ+QC-nonresponders. Plasmacytoid dendritic cells were significantly increased in HCQ-responders compared to HCQ- and HCQ+QC-nonresponders. No differences were found in the number of autoreactive T cells, MAC387+ cells, and neutrophils among the groups. CLASI scores of the HCQ+QC-nonresponder group positively correlated with CD69+CCR7+ circulating activated T cells (r = 0.6335, p < 0.05) and MAC387+ cells (r = 0.5726, p < 0.05). IL-17 protein expression was higher in HCQ+QC-responders compared to HCQ-responders or HCQ+QC-nonresponders, while IL-22 protein expression did not differ. mRNA expression demonstrated increased STAT3 expression in a subset of HCQ+QC-nonresponders. CONCLUSION: An increased number of CD69+CCR7+ circulating activated T cells and a strong correlation with CLASI scores in the HCQ+QC-nonresponders suggest these cells are involved in antimalarial-refractory skin disease. STAT3 is also increased in HCQ+QC-nonresponders and may also be a potential target for antimalarial-refractory skin disease.


Assuntos
Lúpus Eritematoso Cutâneo/tratamento farmacológico , Receptores CCR7 , Fator de Transcrição STAT3 , Antígenos CD , Antígenos de Diferenciação de Linfócitos T , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Feminino , Imunofluorescência , Humanos , Hidroxicloroquina/uso terapêutico , Imuno-Histoquímica , Lectinas Tipo C , Lúpus Eritematoso Cutâneo/imunologia , Masculino , Pessoa de Meia-Idade , Quinacrina/uso terapêutico , Receptores CCR7/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Linfócitos T , Resultado do Tratamento
2.
Int J Mol Sci ; 23(2)2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35055120

RESUMO

In this paper, we describe the synthesis of multilayer nanoparticles as a platform for the diagnosis and treatment of ischemic injuries. The platform is based on magnetite (MNP) and silica (SNP) nanoparticles, while quinacrine is used as an anti-ischemic agent. The synthesis includes the surface modification of nanoparticles with (3-glycidyloxypropyl)trimethoxysilane (GPMS), the immobilization of quinacrine, and the formation of a chitosan coating, which is used to fix the fluorophore indocyanine green (ICG) and colloidal quantum dots AgInS2/ZnS (CQDs), which serve as secondary radiation sources. The potential theranostic platform was studied in laboratory animals.


Assuntos
Isquemia/diagnóstico , Pontos Quânticos/química , Quinacrina/síntese química , Dióxido de Silício/química , Quitosana/química , Diagnóstico Precoce , Corantes Fluorescentes/química , Humanos , Isquemia/terapia , Nanopartículas de Magnetita/química , Estrutura Molecular , Nanopartículas , Medicina de Precisão , Quinacrina/química , Nanomedicina Teranóstica
3.
Toxicol Appl Pharmacol ; 436: 115860, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34998856

RESUMO

PARP inhibitors emerged as clinically effective anti-tumor agents in combination with DNA damaging agents but the toxicity of DNA damaging agents and their off-target effects caused serious problems in cancer therapy. They confer cytotoxicity in cancer cells both by catalytic inhibition and trapping of PARP-1 at the DNA damage site. There is a lack of direct evidence to quantitatively determine the trapped PARP-1 in cellular DNA. Here, we have precisely evaluated the mechanism of PARP trapping mediated anti-cancer action of Quinacrine (QC), BMN-673, and their combination (QC + BMN-673) in breast cancer cells. We introduced a strategy to measure the cellular PARP trapping potentiality of BMN-673 in QC pretreated cells using a fluorescence-based assay system. It was found that QC+ BMN-673 induced apoptosis by triggering DNA damage in breast cancer cells. Treatment with QC + BMN-673 stimulated the expression of PARP-1 in the chromatin compared to that of PARP-2 and PARP-3. QC + BMN-673 treatment also caused a dose-dependent and time-dependent accumulation of PARP-1 and inhibition of PARylation in the chromatin. Upregulation of BER components (pol-ß and FEN-1), an unchanged HR and NHEJ pathway proteins, and reduction of luciferase activity of the cells transfected with R-p21-P (LP-BER) were noted in combined drug-treated cells. Interestingly, silencing of pol-ß resulted in unchanged PARP-1 trapping and PAR activity in the chromatin with increasing time after QC + BMN-673 treatment without altering APC and FEN-1 expression. Thus, our data suggested that the QC + BMN-673 augmented breast cancer cell death by pol-ß mediated repair inhibition primarily through trapping of PARP-1 besides PARP-1 catalytic inhibition.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Cromatina/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Ftalazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Dano ao DNA/efeitos dos fármacos , Feminino , Endonucleases Flap/metabolismo , Humanos , Células MCF-7 , Quinacrina/farmacologia
4.
Nanomedicine ; 40: 102502, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34843984

RESUMO

Cancer stem cells (CSCs) are the tumor cell subpopulations that can self-renew, differentiate, initiate and maintain tumor growth. CSCs are frequently drug-resistant, resulting in tumor recurrence, metastasis, and angiogenesis. Herein, using in vitro oral squamous cell carcinoma (OSCC) CSCs and in vivo xenograft mice model, we have systematically studied the apoptotic potentiality of quinacrine-gold hybrid nanoparticle (QAuNP) and its underlying mechanism after NIR irradiation. QAuNP + NIR caused DNA damage and induced apoptosis in SCC-9-CSCs by deregulating mitochondrial membrane potential (ΔΨm) and activation of ROS. Upregulation of CASPASE-3 and DR-5/DR-4 and reduction of heat shock protein (HSP-70) up to 5-fold were also noticed upon the treatment. The increased expression of DR-5 and CASPASE-3 and decreased expression of HSP-70, CD-44 and Ki-67 were also noted in the xenograft mice treated with QAuNP + NIR + TRAIL. Thus, data suggest that the combined treatment enhances apoptosis in OSCC-CSCs by modulating HSP-70 in the DISC.


Assuntos
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias Bucais , Nanopartículas , Animais , Antineoplásicos/farmacologia , Apoptose , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Ouro/uso terapêutico , Humanos , Camundongos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/radioterapia , Células-Tronco Neoplásicas/patologia , Quinacrina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Travel Med ; 29(1)2022 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-34350966

RESUMO

RATIONALE FOR REVIEW: Giardiasis is one of the most common human protozoal infections worldwide. First-line therapy of giardiasis includes nitroimidazole antibiotics. However, treatment failure with nitroimidazoles is increasingly reported, with up to 45% of patients not responding to initial treatment. There is no clear consensus on the approach to the management of nitroimidazole-refractory giardiasis. This systematic review aims to summarize the literature on pharmacotherapy for nitroimidazole-refractory giardiasis. METHODS: We conducted a systematic review of the literature to determine the optimal management strategies for nitroimidazole-refractory giardiasis. We searched Pubmed/MEDLINE, Embase and Cochrane library using the following search terms 'Giardia' AND 'treatment failure' OR 'refractory giardia' OR 'resistant giardia' with date limits of 1 January 1970 to 30 June 2021. We included all reports on humans, which described clinical outcomes of individuals with treatment refractory giardiasis, including case series and case reports. A descriptive synthesis of the data was conducted with pooling of data for interventions. KEY FINDINGS: Included in this review were five prospective studies, three retrospective studies, seven case series and nine case reports. Across these reports, a wide heterogeneity of treatment regimens was employed, including retreatment with an alternative nitroimidazole, combination therapy with a nitroimidazole and another agent and monotherapy with non-nitroimidazole regimens, including quinacrine, paromomycin and nitazoxanide. Retreatment with a nitroimidazole was not an effective therapy for refractory giardiasis. However, treatment with a nitroimidazole in combination with albendazole had a cure rate of 66.9%. In the included studies, quinacrine monotherapy was administered to a total of 179 patients, with a clinical cure rate of 88.8%. Overall, quinacrine was fairly well tolerated. CONCLUSIONS: Reports on the treatment of nitroimidazole-refractory giardiasis demonstrate a heterogeneous approach to treatment. Of these, quinacrine appeared to be highly effective, though more data on its safety are needed.


Assuntos
Antiprotozoários , Giardia lamblia , Giardíase , Nitroimidazóis , Antiprotozoários/uso terapêutico , Giardíase/tratamento farmacológico , Humanos , Metronidazol/uso terapêutico , Nitroimidazóis/uso terapêutico , Estudos Prospectivos , Quinacrina/efeitos adversos , Quinacrina/uso terapêutico , Estudos Retrospectivos
6.
Nat Commun ; 12(1): 6936, 2021 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-34836965

RESUMO

Chemoresistance posts a major hurdle for treatment of acute leukemia. There is increasing evidence that prolonged and intensive chemotherapy often fails to eradicate leukemic stem cells, which are protected by the bone marrow niche and can induce relapse. Thus, new therapeutic approaches to overcome chemoresistance are urgently needed. By conducting an ex vivo small molecule screen, here we have identified Quinacrine (QC) as a sensitizer for Cytarabine (AraC) in treating acute lymphoblastic leukemia (ALL). We show that QC enhances AraC-mediated killing of ALL cells, and subsequently abrogates AraC resistance both in vitro and in an ALL-xenograft model. However, while combo AraC+QC treatment prolongs the survival of primary transplanted recipients, the combination exhibits limited efficacy in secondary transplanted recipients, consistent with the survival of niche-protected leukemia stem cells. Introduction of Cdc42 Activity Specific Inhibitor, CASIN, enhances the eradication of ALL leukemia stem cells by AraC+QC and prolongs the survival of both primary and secondary transplanted recipients without affecting normal long-term human hematopoiesis. Together, our findings identify a small-molecule regimen that sensitizes AraC-mediated leukemia eradication and provide a potential therapeutic approach for better ALL treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carbazóis/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Quinacrina/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carbazóis/uso terapêutico , Linhagem Celular Tumoral , Citarabina/farmacologia , Citarabina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Cultura Primária de Células , Quinacrina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Purinergic Signal ; 17(4): 725-735, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34713379

RESUMO

Quinacrine, a fluorescent amphipathic amine, has been used as a vital fluorescent probe to visualize vesicular storage of ATP in the field of purinergic signaling. However, the mechanism(s) by which quinacrine represents vesicular ATP storage remains to be clarified. The present study investigated the validity of the use of quinacrine as a vial fluorescent probe for ATP-storing organelles. Vesicular nucleotide transporter (VNUT), an essential component for vesicular storage and ATP release, is present in very low density lipoprotein (VLDL)-containing secretory vesicles in hepatocytes. VNUT gene knockout (Vnut-/-) or clodronate treatment, a VNUT inhibitor, disappeared vesicular ATP release (Tatsushima et al., Biochim Biophys Acta Molecular Basis of Disease 2021, e166013). Upon incubation of mice's primary hepatocytes, quinacrine accumulates in a granular pattern into the cytoplasm, sensitive to 0.1-µM bafilomycin A1, a vacuolar ATPase (V-ATPase) inhibitor. Neither Vnut-/- nor treatment of clodronate affected quinacrine granular accumulation. In vitro, quinacrine is accumulated into liposomes upon imposing inside acidic transmembranous pH gradient (∆pH) irrespective of the presence or absence of ATP. Neither ATP binding on VNUT nor VNUT-mediated uptake of ATP was affected by quinacrine. Consistently, VNUT-mediated uptake of quinacrine was negligible or under the detection limit. From these results, it is concluded that vesicular quinacrine accumulation is not due to a consequence of its interaction with ATP but due to ∆pH-driven concentration across the membranes as an amphipathic amine. Thus, quinacrine is not a vital fluorescent probe for vesicular ATP storage.


Assuntos
Trifosfato de Adenosina/metabolismo , Hepatócitos/efeitos dos fármacos , Quinacrina/farmacologia , Vesículas Secretórias/metabolismo , Animais , Corantes Fluorescentes , Hepatócitos/metabolismo , Camundongos , Proteínas de Transporte de Nucleotídeos/metabolismo
8.
Int J Mol Sci ; 22(19)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34639002

RESUMO

Renal toxicity is a serious side effect that hinders the use of cisplatin, a commonly used and effective chemotherapeutic agent. Meanwhile, quinacrine is an FDA approved drug that has been stated for its anti-inflammatory effect. Thus, we investigated the ameliorative effect of quinacrine against cisplatin-induced renal toxicity. Single intraperitoneal (i.p.) 10 mg/kg cisplatin administration induced renal injury in rats. Our results showed that 10 mg/kg/day quinacrine decreased the mortality rate of rats from 46.15% (cisplatin group) to 12.5%, and significantly decreased renal tissue fibrosis, relative kidney to body weight ratio, serum creatinine and urea levels compared with the cisplatin group. Indeed, quinacrine significantly decreased renal malondialdehyde concentration and increased renal total antioxidant capacity, compared with the cisplatin group. Furthermore, quinacrine caused significant upregulation of renal sirtuin-1 (SIRT-1) with significant downregulation of intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-α (TNF-α). Moreover, quinacrine significantly blocked cisplatin-induced apoptosis, which was made evident by downregulating renal apoptotic proteins (BAX and p53) and upregulating the renal anti-apoptotic protein BCL2, compared with the cisplatin group. In conclusion, this study demonstrates, for the first time, that quinacrine alleviates cisplatin-induced renal toxicity via upregulating SIRT-1, downregulating inflammatory markers (ICAM-1 and TNF-α), reducing oxidative stress, and inhibiting apoptosis.


Assuntos
Cisplatino/efeitos adversos , Nefropatias/etiologia , Nefropatias/metabolismo , Quinacrina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose , Imuno-Histoquímica , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/diagnóstico , Nefropatias/tratamento farmacológico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos
9.
Biomed Pharmacother ; 139: 111707, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243615

RESUMO

Invasive ductal carcinoma (IDC) is the most recurrent cancer, accounting for 80% of all breast cancers worldwide. Originating from the milk duct, it eventually invades the fibrous tissue of the breast outside the duct, proliferation takes 1-2 months for each division. Quinacrine (QC), an FDA-approved small molecule, has been shown to have anti-cancer activity in numerous cancerous cell lines through diverse pathways; ultimately leading to cell death. Here, we have investigated the mode of action of QC in MCF7 cells. This study demonstrated the modulation of cellular cytoskeleton, such as the formation of distinct filopodial and lamellipodial structures and spikes, through the regulation of small-GTPases. We also observed that QC induces a signaling cascade by inducing apoptotic cell death by increasing ROS generation and altering HSP70 expression; which presumably involves ERK regulation. Our findings show that QC could be an attractive chemotherapeutic agent having a "shotgun" nature with potential of inducing different signaling pathways leading to apoptotic cell death. This opens new avenues for research on developing QC as an effective therapeutic agent for the treatment of invasive ductal carcinomas.


Assuntos
Carcinoma Ductal/tratamento farmacológico , Carcinoma Ductal/metabolismo , Citocromos c/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinacrina/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
J Pharmacol Exp Ther ; 379(1): 96-107, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34253645

RESUMO

In the wake of the COVID-19 pandemic, drug repurposing has been highlighted for rapid introduction of therapeutics. Proposed drugs with activity against SARS-CoV-2 include compounds with positive charges at physiologic pH, making them potential targets for the organic cation secretory transporters of kidney and liver, i.e., the basolateral organic cation transporters, OCT1 and OCT2; and the apical multidrug and toxin extruders, MATE1 and MATE2-K. We selected several compounds proposed to have in vitro activity against SARS-CoV-2 (chloroquine, hydroxychloroquine, quinacrine, tilorone, pyronaridine, cetylpyridinium, and miramistin) to test their interaction with OCT and MATE transporters. We used Bayesian machine learning models to generate predictions for each molecule with each transporter and also experimentally determined IC50 values for each compound against labeled substrate transport into CHO cells that stably expressed OCT2, MATE1, or MATE2-K using three structurally distinct substrates (atenolol, metformin and 1-methyl-4-phenylpyridinium) to assess the impact of substrate structure on inhibitory efficacy. For the OCTs substrate identity influenced IC50 values, although the effect was larger and more systematic for OCT2. In contrast, inhibition of MATE1-mediated transport was largely insensitive to substrate identity. Unlike MATE1, inhibition of MATE2-K was influenced, albeit modestly, by substrate identity. Maximum unbound plasma concentration/IC50 ratios were used to identify potential clinical DDI recommendations; all the compounds interacted with the OCT/MATE secretory pathway, most with sufficient avidity to represent potential DDI issues for secretion of cationic drugs. This should be considered when proposing cationic agents as repurposed antivirals. SIGNIFICANCE STATEMENT: Drugs proposed as potential COVID-19 therapeutics based on in vitro activity data against SARS-CoV-2 include compounds with positive charges at physiological pH, making them potential interactors with the OCT/MATE renal secretory pathway. We tested seven such molecules as inhibitors of OCT1/2 and MATE1/2-K. All the compounds blocked transport activity regardless of substrate used to monitor activity. Suggesting that plasma concentrations achieved by normal clinical application of the test agents could be expected to influence the pharmacokinetics of selected cationic drugs.


Assuntos
Antivirais/farmacologia , Proteínas de Transporte de Cátions Orgânicos/metabolismo , SARS-CoV-2/efeitos dos fármacos , Animais , Compostos de Benzalcônio/farmacologia , Células CHO , Cetilpiridínio/farmacologia , Cloroquina/análogos & derivados , Cloroquina/farmacologia , Cricetinae , Cricetulus , Naftiridinas/farmacologia , Proteínas de Transporte de Cátions Orgânicos/efeitos dos fármacos , Quinacrina/farmacologia , Tilorona/farmacologia
11.
Sci Rep ; 11(1): 12043, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103615

RESUMO

Alzheimer's disease (AD) is the most common type of dementia characterized by the abnormal accumulation of amyloid-ß (Aß) in the brain. Aß misfolding is associated with neuroinflammation and synaptic dysfunction, leading to learning and memory deficits. Therefore, Aß production and aggregation have been one of the most popular drug targets for AD. Failures of drug candidates regulating the aforementioned Aß cascade stimulated development of immunotherapy agents for clearance of accumulated Aß in the brain. Here, we report that quinacrine, a blood-brain barrier penetrating antimalarial chemical drug, dissociates Aß plaques in the brain of AD transgenic mice. When co-incubated with pre-formed Aß fibrils, quinacrine decreased thioflavin T-positive ß-sheets in vitro, on top of its inhibitory function on the fibril formation. We confirmed that quinacrine induced dissociation of high-molecular-weight Aß aggregates into low-molecular-weight species by dot blots in association with size cut-off filtrations. Quinacrine was then administered to adult 5XFAD transgenic mice via weekly intravenous injections for 6 weeks, and we found a significant reduction of Aß plaques and astrocytosis in their cortex and hippocampus. In western blots of quinacrine-administered mouse brains, amelioration of AD-related biomarkers, glial fibrillary acidic protein, postsynaptic protein 95, phosphorylated cAMP response element-binding protein, phosphorylated c-Jun N-terminal kinase were observed. Lastly, quinacrine-stimulated dissociation of misfolded aggregates induced recovery of synaptic function associated with Aß in excitatory post-synaptic current recordings of primary rat cortical neurons treated with Aß aggregates and quinacrine. Collectively, quinacrine can directly dissociate Aß fibrils and alleviate decreased synaptic functions.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/metabolismo , Quinacrina , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/genética , Placa Amiloide/tratamento farmacológico , Placa Amiloide/genética , Placa Amiloide/patologia , Quinacrina/farmacocinética , Quinacrina/farmacologia
12.
Regul Toxicol Pharmacol ; 124: 104968, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34062206

RESUMO

Quinacrine sterilization (QS) is a nonsurgical female method used by more than 175,000 women in over 50 countries. With FDA approval, QS is expected to be used by hundreds of millions of women. The negative international health consequences of the results of a 2-year rat study in 2010 by Cancel et al. in Regulatory Toxicology and Pharmacology (RTP) (56:156-165) are incalculable. S1C(R2) was ignored in this study, including the fundamental concept of maximum tolerated dose (MTD), which resulted in the use of massive doses (up to 35 times the MTD) which killed many of the rats and destroyed the uterus of survivors. The design of this rat study was built on the false assertion that this study mimics what happens in women. Cancel et al. (2010), concludes it "seems most likely" that genotoxicity was a major factor in the carcinogenicity observed, prompting the FDA to halt further research of QS. In RTP, McConnell et al. (2010), and Haseman et al. (2015), using the authors' data, definitively determined the carcinogenicity to be secondary to necrosis and chronic inflammation. Decisions made in the design, conduct, analysis, interpretation and reporting in this study lack scientific foundation. This paper explores these decisions.


Assuntos
Quinacrina/toxicidade , Projetos de Pesquisa/normas , Esterilização Reprodutiva/métodos , Testes de Toxicidade Crônica/normas , Animais , Confiabilidade dos Dados , Aprovação de Drogas , Feminino , Humanos , Dose Máxima Tolerável , Quinacrina/administração & dosagem , Ratos , Testes de Toxicidade Crônica/métodos , Estados Unidos , United States Food and Drug Administration
13.
Viruses ; 13(5)2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068686

RESUMO

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.


Assuntos
Proteases 3C de Coronavírus/efeitos dos fármacos , Quinacrina/farmacologia , Suramina/farmacologia , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Vacinas contra COVID-19/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Cisteína Endopeptidases/metabolismo , Reposicionamento de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Inibidores de Proteases/farmacologia , Quinacrina/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Suramina/metabolismo , Proteínas não Estruturais Virais
15.
Clin Infect Dis ; 73(8): 1517-1523, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34115100

RESUMO

BACKGROUND: Giardiasis failing nitroimidazole first-line treatment is an emerging problem in returning European travelers. We present data on the efficacy and tolerability of 2 second-line treatment regimens. METHODS: This prospective, open-label, multicenter study assessed the efficacy and tolerability of quinacrine monotherapy (100 mg 3 times per day for 5 days) and albendazole plus chloroquine combination therapy (400 mg twice daily plus 155 mg twice daily for 5 days) in nitroimidazole-refractory giardiasis. The defined end points were the clinical outcome, assessed at week 5 after treatment and the parasitological outcome, assessed using microscopy of 2 stool samples, ≥2 to ≤5 weeks after treatment. RESULTS: A total of 106 patients were included in the study. Quinacrine achieved clinical and parasitological cure in 81% (59/73) and 100% (56/56), respectively. Albendazole plus chloroquine achieved clinical and parasitological cure in 36% (12/33) and 48% (12/25), respectively. All patients (9/9) who clinically and parasitologically failed albendazole plus chloroquine treatment and opted for retreatment with quinacrine achieved clinical cure. Mild to moderate treatment-related adverse events were reported by 45% and 30% of patients treated with quinacrine and albendazole plus chloroquine, respectively. One patient treated with quinacrine developed severe neuropsychiatric side effects. The majority of nitroimidazole-refractory Giardia infections (57%) were acquired in India. CONCLUSIONS: Quinacrine was a highly effective treatment in nitroimidazole-refractory giardiasis, but patients should be cautioned on the low risk of severe neuropsychiatric adverse event. Albendazole plus chloroquine had a low cure rate in nitroimidazole-refractory giardiasis. Nitroimidazole-refractory giardiasis was primarily seen in travelers returning from India.


Assuntos
Antiprotozoários , Giardia lamblia , Giardíase , Nitroimidazóis , Albendazol/efeitos adversos , Antiprotozoários/efeitos adversos , Cloroquina/efeitos adversos , Giardíase/tratamento farmacológico , Humanos , Nitroimidazóis/efeitos adversos , Estudos Prospectivos , Quinacrina/efeitos adversos
16.
Travel Med Infect Dis ; 42: 102082, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34020030

RESUMO

BACKGROUND: Giardiasis is highly prevalent in children and is often mildly symptomatic. First-line treatment is metronidazole, but treatment failure is not uncommon. We describe a paediatric series, to identify risk factors for treatment failure and to analyse the safety and effectiveness of other treatment strategies. METHODS: Retrospective observational study, including children diagnosed with giardiasis from 2014 to 2019. Diagnosis was based on direct visualisation by microscopy after concentration using an alcohol-based fixative, antigen detection and/or DNA detection by polymerase chain reaction in stool. Treatment failure was considered when GI was detected 4 weeks after treatment. RESULTS: A total of 120 patients were included, 71.6% internationally adopted, median age 4.2 (2.3-7.3) years. Only 50% presented with symptoms, mainly diarrhoea (35%) and abdominal pain (14.1%); co-parasitism was frequent (45%). First-line treatment failure after a standard dose of metronidazole was 20%, lowering to 8.3% when a higher dose was administered (p < 0.001). Quinacrine was administered in 10 patients, with 100% effectiveness. Children <2 years were at higher risk of treatment failure (OR 3.49; 95% CI 1.06-11.53; p = 0.040). CONCLUSIONS: In children with giardiasis, treatment failure is frequent, especially before 2 years of age. Quinacrine can be considered as a second-line treatment. After treatment, eradication should be confirmed.


Assuntos
Giardíase , Criança , Pré-Escolar , Diarreia , Fezes , Giardíase/diagnóstico , Giardíase/tratamento farmacológico , Giardíase/epidemiologia , Humanos , Metronidazol/uso terapêutico , Quinacrina
17.
Sci Rep ; 11(1): 7434, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795785

RESUMO

We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.


Assuntos
Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Proteína-Arginina N-Metiltransferases/genética , Purina-Núcleosídeo Fosforilase/genética , Biomarcadores Tumorais , Transformação Celular Neoplásica/metabolismo , Deleção de Genes , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Estimativa de Kaplan-Meier , Mesotelioma Maligno/genética , Mesotelioma Maligno/mortalidade , Mesotelioma Maligno/patologia , Prognóstico , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Purina-Núcleosídeo Fosforilase/metabolismo , Quinacrina/farmacologia , Transcrição Genética
18.
Mol Neurobiol ; 58(7): 3405-3416, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33713017

RESUMO

Parkinson's disease is a neurodegenerative disorder characterised by nigrostriatal dopaminergic degeneration, and intracellular α-synuclein aggregation. Current pharmacological treatments are solely symptomatic so there is a need to identify agents that can slow or stop dopaminergic degeneration. One proposed class of therapeutics are neurotrophic factors which promote the survival of nigrostriatal dopaminergic neurons. However, neurotrophic factors need to be delivered directly to the brain. An alternative approach may be to identify pharmacological agents which can reach the brain to stimulate neurotrophic factor expression and/or their signalling pathways in dopaminergic neurons. BMP2 is a neurotrophic factor that is expressed in the human substantia nigra; exogenous BMP2 administration protects against dopaminergic degeneration in in vitro models of PD. In this study, we investigated the neurotrophic potential of two FDA-approved drugs, quinacrine and niclosamide, that are modulators of BMP2 signalling. We report that quinacrine and niclosamide, like BMP2, significantly increased neurite length, as a readout of neurotrophic action, in SH-SY5Y cells and dopaminergic neurons in primary cultures of rat ventral mesencephalon. We also show that these effects of quinacrine and niclosamide require the activation of BMP-Smad signalling. Finally, we demonstrate that quinacrine and niclosamide are neuroprotective against degeneration induced by the neurotoxins, MPP+ and 6-OHDA, and by viral-mediated overexpression of α-synuclein in vitro. Collectively, this study identifies two drugs, that are safe for use in patients' to 'are approved for human use, that exert neurotrophic effects on dopaminergic neurons through modulation of BMP-Smad signalling. This rationalises the further study of drugs that target the BMP-Smad pathway as potential neuroprotective pharmacotherapy for Parkinson's disease.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Neuritos/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Niclosamida/farmacologia , Quinacrina/farmacologia , alfa-Sinucleína/toxicidade , Animais , Proteína Morfogenética Óssea 2/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Neurônios Dopaminérgicos/metabolismo , Relação Dose-Resposta a Droga , Humanos , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , Degeneração Neural/prevenção & controle , Neuritos/metabolismo , Neuroproteção/fisiologia , Neurotoxinas/toxicidade , Niclosamida/uso terapêutico , Quinacrina/uso terapêutico , Ratos , Proteínas Smad/metabolismo
19.
PLoS One ; 16(3): e0248941, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33784323

RESUMO

Synthetic lethality is a successful strategy employed to develop selective chemotherapeutics against cancer cells. Inactivation of RAD52 is synthetically lethal to homologous recombination (HR) deficient cancer cell lines. Replication protein A (RPA) recruits RAD52 to repair sites, and the formation of this protein-protein complex is critical for RAD52 activity. To discover small molecules that inhibit the RPA:RAD52 protein-protein interaction (PPI), we screened chemical libraries with our newly developed Fluorescence-based protein-protein Interaction Assay (FluorIA). Eleven compounds were identified, including FDA-approved drugs (quinacrine, mitoxantrone, and doxorubicin). The FluorIA was used to rank the compounds by their ability to inhibit the RPA:RAD52 PPI and showed mitoxantrone and doxorubicin to be the most effective. Initial studies using the three FDA-approved drugs showed selective killing of BRCA1-mutated breast cancer cells (HCC1937), BRCA2-mutated ovarian cancer cells (PE01), and BRCA1-mutated ovarian cancer cells (UWB1.289). It was noteworthy that selective killing was seen in cells known to be resistant to PARP inhibitors (HCC1937 and UWB1 SYr13). A cell-based double-strand break (DSB) repair assay indicated that mitoxantrone significantly suppressed RAD52-dependent single-strand annealing (SSA) and mitoxantrone treatment disrupted the RPA:RAD52 PPI in cells. Furthermore, mitoxantrone reduced radiation-induced foci-formation of RAD52 with no significant activity against RAD51 foci formation. The results indicate that the RPA:RAD52 PPI could be a therapeutic target for HR-deficient cancers. These data also suggest that RAD52 is one of the targets of mitoxantrone and related compounds.


Assuntos
Recombinação Homóloga , Neoplasias/metabolismo , Neoplasias/patologia , Proteína Rad52 de Recombinação e Reparo de DNA/metabolismo , Proteína de Replicação A/metabolismo , Apoptose/efeitos dos fármacos , Proteína BRCA1/deficiência , Proteína BRCA1/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Doxorrubicina/farmacologia , Fluorescência , Ensaios de Triagem em Larga Escala , Recombinação Homóloga/efeitos dos fármacos , Humanos , Mitoxantrona/farmacologia , Ligação Proteica/efeitos dos fármacos , Quinacrina/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia
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