Tumour relapse, chemotherapy resistance, and metastasis continue to be unsolved issues in cancer therapy. A recent approach has been to scrutinise drugs used in the clinic for other illnesses and modify their structure to increase selectivity to cancer cells. Chloroquine (CQ) and hydroxychloroquine (HCQ), known antimalarials, have successfully treated autoimmune and neoplastic diseases. CQ and HCQ, well-known lysosomotropic agents, induce apoptosis, downregulate autophagy, and modify the tumour microenvironment. Moreover, they affect the Toll 9/NF-κB receptor pathway, activate stress response pathways, enhance p53 activity and CXCR4-CXCL12 expression in cancer cells, which would help explain their effects in cancer treatment. These compounds can normalise the tumourassociated vasculature, promote the activation of the immune system, change the phenotype of tumour-associated macrophages (from M2 to M1), and stimulate cancer-associated fibroblasts. We aim to review the historical aspects of CQ and its derivatives and the most relevant mechanisms that support the therapeutic use of CQ and HCQ for the treatment of cancer.
- MeSH
- antimalarika * farmakologie terapeutické užití MeSH
- chlorochin farmakologie terapeutické užití MeSH
- hydroxychlorochin * farmakologie terapeutické užití MeSH
- lidé MeSH
- lokální recidiva nádoru MeSH
- nádorové mikroprostředí MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In 2019 and 2021, the European League for Rheumatism (EULAR) jointly with the European Renal Association (ERA) and the Kidney Disease: Improving Global Outcomes (KDIGO), respectively, released updated guidelines on the management of lupus nephritis (LN). The Immunology Working Group of the ERA reviewed and compared both updates. Recommendations were either consistent or differences were of negligible clinical relevance for: indication for kidney biopsy, kidney biopsy interpretation, treatment targets, hydroxychloroquine dosing, first-line initial immunosuppressive therapy for active class III, IV (±V) LN, pregnancy in LN, LN in paediatric patients and LN patients with kidney failure. Relevant differences in the recommended management relate to the recognition of lupus podocytopathies, uncertainties in steroid dosing, drug preferences in specific populations and maintenance therapy, treatment of pure class V LN, therapy of recurrent LN, evolving alternative drug options and diagnostic work-up of thrombotic microangiopathy. Altogether, both documents provide an excellent guidance to the growing complexity of LN management. This article endeavours to prevent confusion by identifying differences and clarifying discrepancies.
- MeSH
- biopsie MeSH
- dítě MeSH
- hydroxychlorochin terapeutické užití MeSH
- imunosupresiva terapeutické užití MeSH
- ledviny patologie MeSH
- lidé MeSH
- membranózní glomerulonefritida * farmakoterapie MeSH
- nefritida při lupus erythematodes * diagnóza farmakoterapie patologie MeSH
- těhotenství MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Systémový lupus erythematodes (SLE) je autoimunitní onemocnění s rozmanitými projevy, jehož diagnostika může být nesnadná. Léčba vyžaduje multioborový přístup a pravidelný screening orgánových manifestací. V terapii SLE se uplatňují nefarmakologické postupy (fotoprotekce, nekouření, dostatek pohybu, zdravá strava), pilířem pak je farmakologická léčba, jejíž výběr se řídí charakteristikami pacienta, typem a závažností orgánového postižení, komorbiditami i preferencemi pacienta. Klíčovými farmaky jsou hydroxychlorochin, kortikosteroidy (při vzplanutí onemocnění a těžkém orgánovém postižení) a imunosupresiva (metotrexát, azathioprin, mykofenolát mofetil), z biologických léků pak je možné použít belimumab či anifrolumab. U pacientů se závažným orgánovým postižením či život ohrožujícím stavem jsou léky volby cyklofosfamid či rituximab.
Systemic lupus erythematosus (SLE) is an autoimmune disease with heterogeneous symptoms, whose diagnostics may not be easy. Treatment of SLE requires a multidisciplinary approach and a regular screening of organ manifestations. Therapy of SLE comprises nonpharmacological measures (photoprotection, nonsmoking, physical activity, healthy diet), the mainstay is pharmacological treatment, which is chosen according to the patient ́s characteristics, type and severity of organ damage, comorbidities as well as patient ́s preferences. The most important drugs are hydroxychloroquine, corticosteroids (in case of disease flare and severe organ damage) and immunosuppressants (methotrexate, azathioprine, mycophenolate mofetil), from the class of biological drugs, it is possible to use belimumab or anifrolumab. In patients with serious organ damage or lifethreatening condition, the treatment of choice includes cyclophosphamide or rituximab.
- Klíčová slova
- belimumab,
- MeSH
- glukokortikoidy farmakologie terapeutické užití MeSH
- humanizované monoklonální protilátky farmakologie terapeutické užití MeSH
- hydroxychlorochin farmakologie terapeutické užití MeSH
- imunosupresiva farmakologie terapeutické užití MeSH
- inhibitory kalcineurinu farmakologie terapeutické užití MeSH
- lidé MeSH
- rituximab farmakologie terapeutické užití MeSH
- systémový lupus erythematodes * farmakoterapie klasifikace patologie MeSH
- Check Tag
- lidé MeSH
A series of seventeen 4-chlorocinnamanilides and seventeen 3,4-dichlorocinnamanilides were characterized for their antiplasmodial activity. In vitro screening on a chloroquine-sensitive strain of Plasmodium falciparum 3D7/MRA-102 highlighted that 23 compounds possessed IC50 < 30 μM. Typically, 3,4-dichlorocinnamanilides showed a broader range of activity compared to 4-chlorocinnamanilides. (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-en-amide with IC50 = 1.6 μM was the most effective agent, while the other eight most active derivatives showed IC50 in the range from 1.8 to 4.6 μM. A good correlation between the experimental logk and the estimated clogP was recorded for the whole ensemble of the lipophilicity generators. Moreover, the SAR-mediated similarity assessment of the novel (di)chlorinated N-arylcinnamamides was conducted using the collaborative (hybrid) ligand-based and structure-related protocols. In consequence, an 'averaged' selection-driven interaction pattern was produced based in namely 'pseudo-consensus' 3D pharmacophore mapping. The molecular docking approach was engaged for the most potent antiplasmodial agents in order to gain an insight into the arginase-inhibitor binding mode. The docking study revealed that (di)chlorinated aromatic (C-phenyl) rings are oriented towards the binuclear manganese cluster in the energetically favorable poses of the chloroquine and the most potent arginase inhibitors. Additionally, the water-mediated hydrogen bonds were formed via carbonyl function present in the new N-arylcinnamamides and the fluorine substituent (alone or in trifluoromethyl group) of N-phenyl ring seems to play a key role in forming the halogen bonds.
Cryptococcus neoformans is an opportunistic fungal pathogen that can cause life-threatening invasive fungal infections. As its prevalence and drug resistance continue to rise, cryptococcosis requires new treatment options. Tapping into the potential antifungal effects of traditional drugs or combination therapy has become one of the options. This study was the first to examine the interaction of hydroxychloroquine (HCQ) and itraconazole (ITR) on Cryptococcus neoformans in vitro and in vivo. Our results showed that HCQ alone and in combination with ITR exhibited antifungal activity against C. neoformans planktonic cells. When HCQ was combined with ITR, the minimal inhibitory concentration (MIC) value of HCQ decreased to 32 μg/mL, and the MIC value of ITR decreased from 0.25 μg/mL to 0.06-0.25 μg/mL. The time-killing curve showed that the combined application of HCQ and ITR significantly shortened the killing time, dynamically defining the antifungal activity. The minimum biofilm clearance concentration (MBEC) of HCQ was only 32 μg/mL, which was significantly lower than the MIC of HCQ for planktonic cells. When combined with ITR, the MBEC of ITR decreased from 128 μg/mL to 2-1 μg/mL, and the MBEC of HCQ decreased from 32 μg/mL to 4 μg/mL, indicating a synergistic antifungal biofilm effect. In comparison to ITR alone, the combination of HCQ and ITR treatment increased the survival of C. neoformans-infected Galleria mellonella larvae and decreased the fungal burden of infected larvae. Mechanistic investigations revealed that HCQ might damage C. neoformans cell membranes, impact the structure of fungal cells, cause extracellular material leakage, and have a potent affinity for attaching to the C. neoformans genomic DNA. In conclusion, HCQ has potential clinical application in the treatment of cryptococcosis.
- MeSH
- antifungální látky farmakologie terapeutické užití MeSH
- Cryptococcus neoformans * MeSH
- hydroxychlorochin farmakologie terapeutické užití MeSH
- itrakonazol farmakologie MeSH
- kryptokokóza * farmakoterapie mikrobiologie MeSH
- mikrobiální testy citlivosti MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Hydroxychlorochin (HCQ) a chlorochin (CQ) jsou syntetická antimalarika s dlouhodobým ukotvením v terapii revmatických chorob. Celkově nízké riziko závažné HCQ/CQ toxicity zahrnuje především už po dekády známou retinální makulopatii, ale o kardiální toxicitě byly doposud k dispozici jenom sporadické informace. Zvýšenou pozornost ke kardiálnímu riziku HCQ/CQ terapie vyvolaly až nedávné zprávy o závažných arytmiích při prodloužení korigovaného QT intervalu (QTc) během experimentální HCQ medikace u infekce covid-19. Při HCQ/CQ terapii revmatických pacientů lze předpokládat rizikové prodloužení QTc intervalu zejména u nemocných s komorbiditou, především s arytmiemi a srdeční nedostatečností. Dlouhodobá léčba HCQ/ CQ může vést k restriktivní kardiomyopatii. HCQ/CQ kardiomyopatie je lyzozomová střádavá choroba, která se morfologicky vyznačuje nálezem zakřiveně lineárních myeloidních depozit při vyšetření endomyokardiální biopsie metodou elektronové mikroskopie. Formou krátkých případových studií je demonstrována HCQ retinální makulopatie, včetně fenoménu „býčí oko“, a magnetická rezonance u lyzozomové střádavé kardiomyopatie. Provedena analýza současných požadavků na optimální kontrolu kardiálního a očního rizika při HCQ/CQ terapii revmatických chorob a zvláště při dlouhodobé HCQ terapii u systémového lupus erythematodes.
Hydroxychloroquine (HCQ) and chloroquine (CQ) are synthetic antimalarials with a long-term stable position in the therapy of rheumatic diseases. Overall, the low risk of severe HCQ/CQ toxicity mainly includes retinal maculopathy, which has been known for decades, but only sporadic information has been available on cardiac toxicity. Increased attention to the cardiac risk of HCQ/CQ therapy has been prompted by recent reports of severe arrhythmias with prolongation of the corrected QT interval (QTc) during experimental HCQ medication in Covid-19 infection. With HCQ/CQ therapy of rheumatic patients, a risky prolongation of the QTc interval can be expected, especially in patients with comorbidities, especially arrhythmias and heart failure. Long-term treatment with HCQ/CQ can lead to restrictive cardiomyopathy. HCQ/CQ cardiomyopathy is a lysosomal storage disease, which is morphologically characterized by the finding of curved linear myeloid deposits during the examination of an endomyocardial biopsy by the electron microscopy method. HCQ retinal maculopathy, including the bull's eye phenomenon, and magnetic resonance imaging in lysosomal storage cardiomyopathy are demonstrated in the form of short case studies. An analysis of current requirements for optimal control of cardiac and ocular risk during HCQ/CQ therapy for rheumatic diseases and especially during long-term HCQ therapy for systemic lupus erythematosus was performed.
- MeSH
- antimalarika škodlivé účinky toxicita MeSH
- chlorochin * škodlivé účinky toxicita MeSH
- hydroxychlorochin * škodlivé účinky toxicita MeSH
- kardiomyopatie chemicky indukované MeSH
- lidé MeSH
- lyzozomální nemoci z ukládání chemicky indukované MeSH
- makulární degenerace chemicky indukované MeSH
- nežádoucí účinky léčiv MeSH
- revmatické nemoci * farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Due to the urgent need of innovation in the antimalarial therapeutic arsenal, a series of thirty-seven ring-substituted N-arylcinnamanilides prepared by microwave-assisted synthesis were subjected to primary screening against the chloroquine-sensitive strain of P. falciparum 3D7/MRA-102. The lipophilicity of all compounds was experimentally determined as the logarithm of the capacity factor k, and these data were subsequently used in the discussion of structure-activity relationships. Among the screened compounds, fourteen derivatives exhibited IC50 from 0.58 to 31 μM, whereas (2E)-N-(4-bromo-2-chlorophenyl)-3-phenylprop-2-enamide (24) was the most effective agent (IC50 = 0.58 μM). In addition, (2E)-N-[2,6-dibromo-4-(trifluoromethyl)- phenyl]-3-phenylprop-2-enamide (36), (2E)-N-[4-nitro-3-(trifluoromethyl)phenyl]-3-phenylprop- 2-enamide (18), (2E)-N-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide (23), and (2E)-3-phenyl-N-(3,4,5-trichlorophenyl)prop-2-enamide (33) demonstrated efficacy in the IC50 range from 2.0 to 4.3 μM, comparable to the clinically used standard chloroquine. The results of a cell viability screening performed using THP1-BlueTM NF-κB cells showed that none of these highly active compounds displayed any significant cytotoxic effect up to 20 μM, which makes them promising Plasmodium selective substances for further investigations.
- MeSH
- antagonisté kyseliny listové * MeSH
- antimalarika * farmakologie MeSH
- chlorochin farmakologie MeSH
- lidé MeSH
- tropická malárie * MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- axiální spondyloartritida diagnóza terapie MeSH
- dnavá artritida diagnóza etiologie MeSH
- hydroxychlorochin aplikace a dávkování terapeutické užití MeSH
- kongresy jako téma MeSH
- lidé MeSH
- osteoartróza terapie MeSH
- psoriatická artritida terapie MeSH
- revmatické nemoci * diagnóza terapie MeSH
- revmatoidní artritida komplikace terapie MeSH
- rituximab terapeutické užití MeSH
- systémová sklerodermie farmakoterapie MeSH
- systémový lupus erythematodes etiologie prevence a kontrola terapie MeSH
- vitamin D terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- zprávy MeSH
V decembri 2019 sa rozšíril do sveta z Číny nový typ koronavírusu, SARS-CoV-2, spôsobujúci ťažký akútny respiračný syndróm. Koronavírusy patria medzi obalené ssRNA vírusy a sú klasifikované do 4 rodov: Alphacoronavirus, Betacoronavirus, Gammacoronavirus a Deltacoronavirus. Predpokladá sa, že SARS-CoV-2 sa šíri primárne prostredníctvom osobného kontaktu cez väčšie respiračné kvapôčky. Tieto kvapôčky s vírusmi môžu byť priamo inhalované inými ľuďmi, resp. môžu pristáť na neživých povrchoch s možnosťou ďalšieho šírenia. Zistilo sa, že povrch oka je jednou zo vstupných brán pre infekciu. Ľudské oko má svoj vlastný renín-angiotenzínový systém s prítomnosťou ACE2 receptorov, na ktoré sa vírus viaže pomocou spike proteínu. Najbežnejšími prejavmi infekcie SARS-CoV-2 sú horúčka, kašeľ a dýchavičnosť. Viacero klinických diagnóz, ako konjunktivitída, uveitída, retinitída a neuritída boli a sú taktiež spájané s touto infekciou. Najčastejším oftalmologickým symptómom súvisiacim s ochorením COVID-19 je konjunktivitída. Niektoré štúdie naznačujú, že očné príznaky sa bežne vyskytujú u pacientov s ťažkou pneumóniou COVID-19 a že je možné detegovať vírusovú RNA zo spojivkového vaku týchto pacientov. V oftalmologickej praxi riešime nielen otázku liečby zápalov očných štruktúr v spojení s touto infekciou, ale aj celkový manažment návštev a kontrol pacientov rizikových a pozitívnych na koronavírusové ochorenie. Oftalmológovia by mohli potencionálne mať vyššie riziko vzniku infekcie SARS-CoV-2 v dôsledku osobnej komunikácie s pacientmi, častého vystavenia slzám a očnému sekrétu a používania prístrojov. Preto chceme poskytnúť pohľad na problém z pohľadu oftalmológa.
In December 2019, a novel coronavirus (CoV) epidemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged from China. Coronaviruses belong to enveloped ssRNA viruses and are classified into four genera: Alpha coronavirus, Beta coronavirus, Gamma coronavirus and Delta coronavirus. It is assumed that SARS-CoV-2 is spread primarily during a personal contact via bigger respiratory droplets. These droplets with viruses can be directly inhaled by other people or can lend on the surfaces with the possibility of further spreading. The ocular surface has been suggested as one of possible infection entries. Human eye has its own renin-angiotensin system with present ACE2 receptors, which bind the virus through spike protein. The most common symptoms of the SARS-CoV-2 infection are fever, cough and dyspnoea. Several clinical entities, such as conjunctivitis, anterior uveitis, retinitis, and optic neuritis have been associated with this infection. The most common ophthalmologic symptom associated with COVID-19 disease is conjunctivitis. Some studies indicate that eye symptoms are commonly present in patients with severe COVID-19 pneumonia and that it is possible to detect viral RNA from the conjunctival sac of these patients. In ophthalmologic praxis, we manage not only the therapy of the eye structures` inflammation in relation with this infection, but also the overall management of the visits and the supervision of the patients who are at risk and positive for coronavirus. Ophthalmologists could potentially have a higher risk of SARS-CoV-2 infection due to personal communication with the patients, frequent exposure to tears and eye secrets and the use of devices. We would like to provide an ophthalmologist`s perspective on this topic.
- MeSH
- chlorochin škodlivé účinky terapeutické užití MeSH
- COVID-19 * etiologie komplikace přenos MeSH
- dexamethason farmakologie terapeutické užití MeSH
- lidé MeSH
- oční nemoci * etiologie patologie terapie virologie MeSH
- přenos infekční nemoci prevence a kontrola MeSH
- virová konjunktivitida přenos MeSH
- vitamin D farmakologie terapeutické užití MeSH
- zdravotnický personál MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Introduction: Coronavirus pandemic is currently a global health concern with no established treatment guidelines. The aim of the present study was to determine the therapeutic effectiveness of hydroxychloroquine combined with azithromycin in patients with positive coronavirus disease 2019 (COVID-19) admitted to the hospital with severe dyspnea, as well as the incidence of occurrence of adverse effects.Methods: It was intended to utilize a retrospective clinical study of approximately 250 adult patients admitted to the ALSALAM Teaching Hospital in Mosul city with mild to moderate COVID-19 in order to evaluate treatment efficacy in combination with clinical and biochemical findings. Two groups were involved in the research. The first patient group consisted of 250 people who got hydroxychloroquine in conjunction with azithromycin, while the second untreated control group consisted of 100 individuals who received no medication as part of the research.Results: Baseline parameters (clinical and biochemical assays) did not vary substantially among the two groups. Patients in the treatment group were hospitalized at a rate of 30%, compared to 27% in the untreated control group (P<0.001). Between groups, there were no statistically significant changes in mortality,non-invasive oxygen demand, or hospitalization duration. Biochemical and Clinical outcomes were comparable between those receiving hydroxychloroquine with azithromycin and those do not receive any medication.Conclusion: This treatment regimen was shown to be not affective in mild to severe positve COVID-19 hospitalized patients and was associated with a small number of mild to moderate clinical adverse effects.
