Addressing male sexual and reproductive health in the wake of COVID-19 outbreak

Journal of Endocrinological Investigation, Год журнала: 2020, Номер 44(2), С. 223 - 231

Опубликована: Июль 13, 2020

The COVID-19 pandemic, caused by the SARS-CoV-2, represents an unprecedented challenge for healthcare. features a state of hyperinflammation resulting in "cytokine storm", which leads to severe complications, such as development micro-thrombosis and disseminated intravascular coagulation (DIC). Despite isolation measures, number affected patients is growing daily: June 12th, over 7.5 million cases have been confirmed worldwide, with more than 420,000 global deaths. Over 3.5 recovered from COVID-19; although this increasing day, great attention should be directed towards possible long-term outcomes disease. being trivial matter intensive care units (ICUs), erectile dysfunction (ED) likely consequence survivors, considering high transmissibility infection higher contagion rates among elderly men, worrying phenomenon large part patients.

Язык: Английский

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Combining L-Arginine with vitamin C improves long-COVID symptoms: The LINCOLN Survey

Pharmacological Research, Год журнала: 2022, Номер 183, С. 106360 - 106360

Опубликована: Июль 19, 2022

Язык: Английский

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Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors

Biomedicine & Pharmacotherapy, Год журнала: 2020, Номер 134, С. 111128 - 111128

Опубликована: Дек. 18, 2020

Phosphodiesterase 5 (PDE5) is one of the most well-studied phosphodiesterases (PDEs) that specifically targets cGMP typically generated by nitric oxide (NO)-mediated activation soluble guanylyl cyclase. Given crucial role through this cellular signaling pathway in a variety physiologically processes, pharmacological inhibition PDE5 has been demonstrated to have several therapeutic applications including erectile dysfunction and pulmonary arterial hypertension. While they are designed inhibit PDE5, inhibitors show different affinities specificities against all PDE subtypes. Additionally, shown induce allosteric structural changes protein. These mostly attributed their chemical structure and, therefore, binding interactions with catalytic domains. Therefore, understanding how these interact basis selectivity critically important for design novel, highly selective inhibitors. Here, we review its function regulated, discuss clinically available target phosphodiesterase 5, aiming better understand bases affinity specificity. We also indications potential repurposing wider range clinical applications.

Язык: Английский

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The neuropsychiatric manifestations of COVID-19: Interactions with psychiatric illness and pharmacological treatment

Biomedicine & Pharmacotherapy, Год журнала: 2021, Номер 135, С. 111200 - 111200

Опубликована: Янв. 1, 2021

The recent outbreak of the corona virus disease (COVID-19) has had major global impact. relationship between severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection and psychiatric diseases is great concern, with an evident link infections various central peripheral nervous system manifestations. Unmitigated neuro-inflammation been noted to underlie not only complications but also present in a range neuro-psychiatric illnesses. Several neurological disorders are characterized by immune-inflammatory states, while treatments for these have distinct anti-inflammatory properties effects. With inflammation being common contributing factor SARS-CoV-2, as well disorders, treatment either condition may affect progression other or alter response pharmacological treatment. In this review, we elucidate how viral could pre-existing conditions overall progress outcome SARS-CoV-2. We address whether any treatment-induced benefits potential adverse effects ultimately approach, considering underlying dysregulated neuro-inflammatory processes drug interactions. Finally, suggest adjunctive options SARS-CoV-2-associated symptoms.

Язык: Английский

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Beyond Erectile Dysfunction: cGMP-Specific Phosphodiesterase 5 Inhibitors for Other Clinical Disorders

The Annual Review of Pharmacology and Toxicology, Год журнала: 2022, Номер 63(1), С. 585 - 615

Опубликована: Окт. 7, 2022

Cyclic guanosine monophosphate (cGMP), an important intracellular second messenger, mediates cellular functional responses in all vital organs. Phosphodiesterase 5 (PDE5) is one of the 11 members cyclic nucleotide phosphodiesterase (PDE) family that specifically targets cGMP generated by nitric oxide-driven activation soluble guanylyl cyclase. PDE5 inhibitors, including sildenafil and tadalafil, are widely used for treatment erectile dysfunction, pulmonary arterial hypertension, certain urological disorders. Preclinical studies have shown promising effects inhibitors myocardial infarction, cardiac hypertrophy, heart failure, cancer anticancer-drug-associated cardiotoxicity, diabetes, Duchenne muscular dystrophy, Alzheimer's disease, other aging-related conditions. Many clinical trials with focused on potential cardiovascular, anticancer, neurological benefits. In this review, we provide overview current state knowledge their therapeutic indications various disorders beyond dysfunction.

Язык: Английский

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Post-COVID-19 Pulmonary Fibrosis

Cureus, Год журнала: 2022, Номер unknown

Опубликована: Март 2, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions worldwide with a high mortality rate due to lack of definitive treatment. Despite having wide range clinical features, distress (ARDS) emerged as the primary cause in these patients. Risk factors and comorbidities like advanced age limited lung function, pre-existing diabetes, hypertension, cardiovascular diseases, obesity have increased risk for severe COVID-19 infection. Rise inflammatory markers transforming growth factor β (TGF-β), interleukin-6 (IL-6), expression matrix metalloproteinase 1 7 (MMP-1, MMP-7), along collagen deposition at site injury, results extensive scarring fibrosis. Anti-fibrotic drugs, such Pirfenidone Nintedanib, potential treatment options post-COVID-19 pulmonary A transplant might be only life-saving current advances management COVID-19, there is still considerable knowledge gap long-term sequelae patients, especially concerning Follow up on trials research test efficacy various anti-inflammatory drugs needed prevent early

Язык: Английский

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Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives

Pharmaceuticals, Год журнала: 2023, Номер 16(9), С. 1266 - 1266

Опубликована: Сен. 6, 2023

Phosphodiesterase 5 (PDE5) inhibitors presented themselves as important players in the nitric oxide/cGMP pathway, thus exerting a profound impact on various physiological and pathological processes. Beyond their well-known efficacy treating male erectile dysfunction (ED) pulmonary arterial hypertension (PAH), plethora of studies have unveiled significance treatment myriad other diseases, including cognitive functions, heart failure, multiple drug resistance cancer therapy, immune systemic sclerosis others. This comprehensive review aims to provide an updated assessment crucial role played by PDE5 (PDE5-Is) disease-modifying agents taking limiting side effects into consideration. From medicinal chemistry discovery perspective, published PDE5-Is over last 10 years binding characteristics are systemically discussed, advancement properties is exposed. A persistent challenge encountered with these lies limited isozyme selectivity; considering this obstacle, also highlights breakthrough development recently reported allosteric inhibitors, which exhibit unparalleled level selectivity that was rarely achievable competitive inhibitors. The implications potential novel meticulously explored. Additionally, concept multi-targeted ligands critically evaluated relation inspecting broader spectrum molecular interactions effects. objective insight design potent, selective overview biological function, limitations, challenges, therapeutic potentials, undergoing clinical trials, future prospects emerging uses, guiding upcoming endeavors both academia industry within domain.

Язык: Английский

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Targeting the NO‐cGMP‐PDE5 pathway in COVID‐19 infection. The DEDALO project

Andrology, Год журнала: 2020, Номер 9(1), С. 33 - 38

Опубликована: Июнь 11, 2020

Abstract Background A pandemic outbreak of COVID‐19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into systemic disease, SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular liver function. Some clinical trials are testing biological drugs to limit immune system dysregulation, “cytokines storm,” that causes complications COVID‐19. The contraindications these their cost raise concerns over implications widespread availability. Objectives Numerous experimental studies have revealed role for nitric oxide (NO)‐cyclic GMP‐phosphodiesterase type 5 (PDE5) pathway modulating low‐grade inflammation patients metabolic diseases, offering protection. PDE5 inhibition favors an anti‐inflammatory response by activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. is highly expressed lungs, where its improves pulmonary complication severe disease. Materials methods We performed systematic review all evidence documenting any involvement NO‐cGMP‐PDE5 axis pathophysiology COVID‐19, presenting ongoing aimed at this axis, including our own “silDEnafil administration DiAbetic dysmetaboLic (DEDALO trial).” Results reviewed suggests inhibitors could offer new strategy managing (i) counteracting Ang‐II‐mediated downregulation AT‐1 receptor; (ii) acting on monocyte switching, thus pro‐inflammatory cytokines, interstitial infiltration vessel damage responsible alveolar hemorrhage‐necrosis; (iii) inhibiting transition smooth muscle cells mesenchymal artery, preventing thrombotic complications. Discussion Conclusion If presented herein should provide positive findings, low cost, wide availability temperature stability make them major resource combat developing countries.

Язык: Английский

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The Sexual Long COVID (SLC): Erectile Dysfunction as a Biomarker of Systemic Complications for COVID-19 Long Haulers

Sexual Medicine Reviews, Год журнала: 2021, Номер 10(2), С. 271 - 285

Опубликована: Ноя. 20, 2021

Язык: Английский

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Attenuation of clinical and immunological outcomes during SARS‐CoV‐2 infection by ivermectin

EMBO Molecular Medicine, Год журнала: 2021, Номер 13(8)

Опубликована: Июнь 25, 2021

Article12 July 2021Open Access Source DataTransparent process Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection by ivermectin Guilherme Dias de Melo orcid.org/0000-0003-0747-7760 Lyssavirus Epidemiology Neuropathology Unit, Institut Pasteur, Paris, France Search for more papers this author Françoise Lazarini orcid.org/0000-0001-5572-6982 Perception Memory CNRS UMR 3571, Florence Larrous orcid.org/0000-0003-0881-4263 Lena Feige Etienne Kornobis Biomics Technological Platform, Center Resources Research (C2RT), Bioinformatics Biostatistics Hub, Computational Biology Department, Sylvain Levallois orcid.org/0000-0002-5805-1092 Infection Inserm U1117, Agnès Marchio Nuclear Organization Oncogenesis Lauriane Kergoat orcid.org/0000-0002-5609-4398 David Hardy orcid.org/0000-0001-5874-4377 Experimental Thomas Cokelaer orcid.org/0000-0001-6286-1138 Pascal Pineau Marc Lecuit orcid.org/0000-0002-4491-1063 Division Infectious Diseases Tropical Medicine, Imagine, Université Necker-Enfants Malades University Hospital, AP-HP, Pierre-Marie Lledo Jean-Pierre Changeux orcid.org/0000-0003-0297-1583 Neuroscience Collège France, Hervé Bourhy Corresponding Author [email protected] orcid.org/0000-0002-2608-5589 Information Melo1, Lazarini2, Larrous1, Feige1, Kornobis3,4, Levallois5, Marchio6, Kergoat1, Hardy7, Cokelaer3,4, Pineau6, Lecuit5,8, Lledo2, Changeux9 *,1 1Lyssavirus 2Perception 3Biomics 4Bioinformatics 5Biology 6Nuclear 7Experimental 8Division 9Neuroscience *Corresponding author. Tel: +33 1 45 68 87 85; E-mail: EMBO Mol Med (2021)13:e14122https://doi.org/10.15252/emmm.202114122 PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments responses to feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract The devastating pandemic due emergence antigenic variants that jeopardize efficacy current vaccines create an urgent need comprehensive understanding pathophysiology COVID-19, contribution inflammation disease. It also warrants search immunomodulatory drugs could improve disease outcome. Here, we show standard doses (IVM), anti-parasitic drug with potential activities through cholinergic anti-inflammatory pathway, prevent deterioration, reduce olfactory deficit, limit upper lower respiratory tracts in SARS-CoV-2-infected hamsters. Whereas it has no effect on viral load airways infected animals, transcriptomic analyses lungs reveal IVM dampens type I interferon modulates several other inflammatory pathways. In particular, dramatically reduces Il-6/Il-10 ratio lung tissue promotes macrophage M2 polarization, which might account favorable presentation IVM-treated animals. Altogether, study supports use such as IVM, condition patients. SYNOPSIS caused SARS-CoV-2, induces pulmonary symptoms, severe cases can lead distress death. This shows modulation host's response using repurposed drug, independently load, strongly diminished score severity (including anosmia) observed golden brings proof-of-concept chemical therapy preserve modulating response, even without antiviral activity. is directly linked not necessarily load. A sex-dependent compartmentalized preventing deterioration reducing deficit. Ivermectin limits signaling pathways related I/III interferon, cytokines activation cells population lungs. reduced presentation. Ivermectin-treated animals presented polarization myeloid recruited lung. paper explained Problem COVID-19 than 3.5 million deaths 150 laboratory-confirmed worldwide since December 2019 (as May 2021). commonly about symptoms Different therapeutic approaches have been proposed fight but studies are still lacking. Results We report ivermectin, used at dose 400 µg/kg, protects hamsters from developing signs losing sense smell infection. treated exhibited specific presenting stimulation intracellular pathways, important reduction promoting These effects influenced sex, females exhibiting best Surprisingly, treatment did replication, non-treated similar amounts nasal cavity Impact results establish irrespective highlight critical role played host presence macrophages presentation, contributing better pathophysiology. then be considered promising agent against impact replication alleviating ensuing symptoms. Introduction Coronaviruses cause wide variety hosts. During ongoing causing coronavirus 19 (COVID-19), infection, frequently associated neurological anosmia ageusia. features over-responsiveness patients' immune system (Bhaskar et al, 2020; Han Qiu 2020). Consequently, there understand hallmarks find novel therapeutics or repurpose patients (Batalha macrocyclic lactone, commercially available prevents range endo- ectoparasites (Sajid 2006; Heidary Gharebaghi, efficient positive allosteric modulator α-7 nicotinic acetylcholine receptor (nAChR) (Krause 1998) ligand-gated ion channels, muscle glutamate (GluCl) worms (Hibbs Gouaux, 2011). Furthermore, shown exert humans 2020) under conditions known involve nAChR (Pavlov Tracey, 2012), though its underlying mechanisms yet established (Laing 2017). direct indirect interaction hypothesized, particular because sequence homologies between spike proteins ligands snake venom toxins (Changeux active beyond activity pathologies, cancer, allergy, infections Recently, reported status mice animal coronavirus, mouse hepatitis virus (MHV) (Arévalo vitro inhibition Vero/hSLAM (Caly 2020), albeit much higher concentrations (50- 100-fold) those clinically attainable (150–400 µg/kg) (Guzzo 2002; Bray Chaccour aim investigate pathogenesis model, Syrian hamster. species naturally permissive most reliable affordable model (Chan Muñoz-Fontela Moreover, was recently demonstrate importance lowering intranasal administration IFN progression (Hoagland Male female adult were intranasally inoculated 6 × 104 PFU [BetaCoV/France/IDF00372/2020]. inoculum size selected invariably causes symptomatic hamster, high incidence loads within 4 days post-inoculation (dpi) (de At time received single subcutaneous injection human setting, monitored over days. these although strong significant III ratio, along mostly sex-dependent, outcomes. Discussion outcome attenuated order outcome, assessed body weight, score, performance daily post-infection. hamster reproduces moderate-to-severe humans, phase lasting 5–6 post-infection followed complete recovery 2 weeks post-infection, death occurring. titers RNA elevated after 2–4 they drastically drop 7 Sia both sexes, showed decrease weight saline-treated (Fig EV1A). However, manner: Infected males significantly fully returned normal 1A). Remarkably, deficit (Figs 1B EV1B–D): 66.7% (12/18) hyposmia/anosmia, whereas only 22.2% (4/18) dysfunction EV1B–D). sex: 83.3% (10/12) 33.3% (4/12) females, while (2/6) (0/6; Figs Click here expand figure. Figure EV1. Complementary aspects olfaction test hamsters, A. Progression male mock-infected SARS-CoV-2-infected, saline µg/kg ivermectin. Symbols indicate median ± interquartile range. B. Curves represent percentage hidden (buried) food. C. visible (unburied) D. Summary status. Data information: Food finding assays performed 3 n = 6/group, except CoV_saline CoV_ivermectin, where 12/group. P value indicated bold when 0.05 threshold. Log-rank (Mantel–Cox) (B, C) Fisher's exact (D). obtained three independent experiments two females. data CoV_ivermectin groups (B) already Fig 1B. online Download figure PowerPoint 1. Clinical test, profile turbinates based cumulative 0–4 scale: ruffled fur; slow movements; apathy; absence exploration Olfactory food test. buried (dpi). Viral dpi. Ratio CPD (copy per droplets, normalized γ-actin Hprt reference gene relative expression) structural [N, nucleocapsid] non-structural [IP4: RdRp, RNA-dependent polymerase] expression determined digital droplet PCR (ddPCR) E. titer dpi expressed plaque-forming units (PFU)/g tissue. F. Cytokine chemokine transcripts Horizontal lines medians. Mann–Whitney (A, C–F) log-rank (B). M: F: each sex. See EV1 EV2 Appendix S1. [emmm202114122-sup-0004-SDataFig1.xlsx] Since anosmia/hyposmia, subsequently dose-response curve functions males: Lower (100 200 elicited EV2). As expected, EV2. different 400, 200, 100 Olfaction 12/group (CoV_saline 1) (CoV_ivermectin µg/kg). (C). does influence tract To evaluate tract, tested classical RT–qPCR 1C) highly sensitive technique (Suo 1D, S1). remained unaffected samples sexes. rate, evaluated transcription Finally, alter infectious 1E). illustrate detected vivo contrast previous suggesting inhibits vitro, far Therefore, action result replication. local hamsters' Anosmia typical symptom some differences (Han Xydakis Inflammation cavity, following sensory neurons deciliation, factor loss 2021), Cxcl10 implicated neurotoxic (Oliviero therefore possible particularly turbinates, primary target correlate score. aim, panel (Il-6, Il-10, Il-1β, Tnf-α, Ifn-β, Ifn-γ, Ifn-λ) chemokines (Cxcl10 Ccl5) assess Upon downregulation Il-6, key mediators prognostic (McElvaney 2020a), 1F), line their tests 1B). sex illustrated increase pro-inflammatory (Ifn-γ, Ifn-λ, 1F). No difference turbinates. Lung immunometabolism affected modulated attenuates pathology synapse-related genes further mode signs, comparative agnostic approach RNA-seq IVM. lungs, overall pattern, slightly KEGG 2A). number common dysregulated metabolic EV3) patients, "cytokine-cytokine interaction", "TNF pathway", "insulin resistance" (Dey Islam many response. profiles compared striking difference: Lungs 1,206 downregulated 1,428 upregulated genes, 36 51 males. GO enrichments representations EV4). 2. Transcriptomic Heatmaps showing differentially according calculated comparison * indicates Benjamini–Hochberg-adjusted P-value < same Color gradient represents log2 fold change comparing mock-infected. Complete listed Dataset Validation targets EV3-EV5. [emmm202114122-sup-0005-SDataFig2.xlsx] EV3. enrichment. enrichment analysis. Selected terms up- (CoV_saline) (mock_saline) samples. Only 20 highest plotted set. Circle sizes proportional set size, total terms. color corrected P-values. Terms identified sexes marked bold. EV4. ivermectin-treated (CoV_ivermectin) Several regulated IVM-tr

Язык: Английский

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