LitCovid-sentences  

PMC:7408073 / 95877-112683 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T463 0-2 Sentence denotes 8.
T464 3-56 Sentence denotes Hypothesizing Pharmacological Treatments for COVID-19
T465 57-167 Sentence denotes Based on the above described hypothesis, inhibition of ACE2 pathway might be beneficial for COVID-19 patients.
T466 168-428 Sentence denotes Indeed, the clinical picture as a whole is consistent with an ACE2 gain of function (possibly due to both circulating active forms of S1-sACE2 complexes and local forms of SARS-CoV-2-sACE2 complexes) rather than an ACE2 loss of function, as initially supposed.
T467 429-623 Sentence denotes Therefore, inhibition of ACE2/Ang (1–7)/MasR axis or other ACE2 pathways to restore ACE/ACE2 balance might be needed, at least in the first phases of the disease when hypoxia is not yet induced.
T468 624-765 Sentence denotes Different strategies could be pursued through ACE2 pathway inhibitors and/or MasR antagonists and/or renin inhibitors and/or metal chelators.
T469 766-971 Sentence denotes Several different molecules have been designed to specifically inhibit human ACE2 enzyme (both membrane bound and soluble forms) or human MasR signal transduction, but only a few have been studied in vivo.
T470 972-1118 Sentence denotes Some ACE2 pathway inhibitors have been widely used in mouse/rat models, as control of human and mouse ACE2 activity or in mouse models of colitis.
T471 1119-1411 Sentence denotes Thanks to mouse/rat in vivo experiments and clinical trial results in human participants it has been possible to infer toxicity/efficacy for some human ACE2 inhibitory molecules (MLN-4760/C16/GL1001/ORE1001, Dx600 and A779) that may be exploited to face this exceptionally dramatic situation.
T472 1412-1662 Sentence denotes Unfortunately, to my knowledge, only one (MLN-4760/C16/GL1001/ORE1001) of the ACE2-specific inhibitors has been tested in vivo in humans in a Phase I clinical trial long time ago (http://oreholdings.com/wp-content/uploads/2013/06/09.02.09-S-4-A.pdf).
T473 1663-1777 Sentence denotes Here, I have focused my attention on inhibitors of human ACE2 pathway that were consistently administered in vivo.
T474 1778-2154 Sentence denotes Making use of published reports in which human/rodent ACE2 pathway inhibitors were administered in vivo, I have hypothesized a possible therapeutic pharmacological intervention through an inhibition strategy of the RAS pathways for COVID-19 in patients experiencing both mild and critical, advanced and untreatable stages of the disease (the most problematic cases to manage).
T475 2156-2160 Sentence denotes 8.1.
T476 2161-2189 Sentence denotes Inhibition of ACE2: MLN-4760
T477 2190-2861 Sentence denotes Briefly, one of the best candidates to treat COVID-19 patients, but not to prevent viral entry, is the small synthetic molecule MLN-4760 (specific ACE2 inhibitor, also known as C16, GL1001 or ORE1001, [113]) for the following reasons:(1) It has been shown to bind/inhibit ACE2 enzymatic activity even at low/acidic pH (pH 6.5, [115]) typical of hypercapnia (as it might occur in lungs of COVID-19 patients) when human ACE2 activity is maximal [79]; nevertheless, it retains its inhibitory effects on soluble ACE2 bound to spike proteins [24], indicating that it is able to bind and inhibit ACE2 activity regardless ACE2 binding to SARS-CoV-2 particles or to S1 fragments.
T478 2862-3266 Sentence denotes (2) No significant adverse effects were described upon its chronic administration neither alone nor in combination with ACE2 activators (while inhibiting their activating effects) nor after inducing functional impairment of ACE2 activity in rodent experiments in vivo [52,117,118,122,183,184] nor in a clinical Phase I trial in humans (http://oreholdings.com/wp-content/uploads/2013/06/09.10.09-425.pdf);
T479 3267-3349 Sentence denotes (3) Its administration by different route is well described in rodents and humans.
T480 3350-3700 Sentence denotes In particular:(a) Chronic administration (about 4 weeks) of C-16/DLM-4760 in combination with ACE2 activating treatments was performed by daily intraperitoneal injection at a dose of 25mg/kg in distilled water (as a solution of 42 mg/mL) or 0.9% sterile saline (as a solution of 84 mg/mL using a 0.5-mL insulin syringe) freshly prepared [52,183,184].
T481 3701-4032 Sentence denotes (b) Alternatively, chronic administration (about 8 days) of GL1001/DLM-4760 disodium salt in combination with an ACE2 activating treatment was performed by subcutaneous injection (5mL/kg) containing up to a dose of 300 mg/kg, twice a day, formulated in a vehicle solution [15% 2-hydroxypropyl-β-cyclodextrin (HPBDC)/85% H2O] [122].
T482 4033-4118 Sentence denotes Subchronic doses of GL1001 indicate no adverse effects up to 1,000 mg/kg (see [122]).
T483 4119-4208 Sentence denotes (c) In humans ORE1001/GL1001/MLN-4760 was already proposed and tested in clinical trials.
T484 4209-4377 Sentence denotes Its pharmaceutical indication was for digestive tract inflammations (Inflammatory bowel disease, gastritis and colitis) that are correlated with overexpression of ACE2.
T485 4378-4454 Sentence denotes In a Phase I clinical testing up 14 days dosing, ORE1001 was well tolerated.
T486 4455-4539 Sentence denotes Subjects received drug (dosing up to 2100 mg) with no side adverse effects reported.
T487 4540-4677 Sentence denotes In particular, 47 subjects received single-dose from 2.1 to 2100 mg and 24 subjects received 14 day multiple doses from 50 mg to 1800 mg.
T488 4678-4767 Sentence denotes All doses were well tolerated, with no significant side effects including blood pressure.
T489 4768-4925 Sentence denotes Pharmacokinetics of orally administered capsules was consistent with once-daily dosing. (http://oreholdings.com/wp-content/uploads/2013/06/09.10.09-425.pdf).
T490 4926-5084 Sentence denotes 300 mg (active drug) oral capsules were used in a Phase Ib/IIa clinical trial that was, however, abandoned. (https://clinicaltrials.gov/ct2/show/NCT01039597).
T491 5085-5234 Sentence denotes (d) Finally, MLN-4760 was also administered (2.5 mg/kg per day) by nasal inhalation for 2–3 days in lung-infected mice by Pseudomonas bacteria [185].
T492 5235-5376 Sentence denotes Interestingly, the report underscores the role played by local concentration of molecules (ACE2) in modulating lung inflammation and disease.
T493 5377-5610 Sentence denotes For these reasons, in diseases involving respiratory tract, like SARS, inhalation treatment is preferable, even for the lower concentration (and hopefully lower toxicity) of MLN-4760 needed for this route of treatment administration.
T494 5611-5726 Sentence denotes Different routes of MLN-4760 treatment administration can be pursued depending on the hospital condition/expertise.
T495 5727-5889 Sentence denotes In this exceptionally critical situation, it could be delivered to critical untreatable patients as a controlled “compassionate use”, in particular by inhalation.
T496 5890-6089 Sentence denotes However, when, under hypoxic conditions, both arms of the RAS are upregulated, it might have a limited action and, by shifting the balance of ACE/ACE2 ratio in favour of ACE, might be even dangerous.
T497 6090-6301 Sentence denotes Instead, specific inhibition of ACE2 enzymatic activity might effectively work in preventing the establishment of positive feedback loops in COVID-19 patients who are suffering from mild symptoms of the disease.
T498 6302-6465 Sentence denotes MLN-4760 is sold by different companies, that, in case it works, could be encouraged to manufacture the molecule, actively contributing to face this global threat.
T499 6466-6613 Sentence denotes On the other hand, the drug could be also synthesized in University chemistry labs because, to my knowledge, is no longer under patent restriction.
T500 6614-7045 Sentence denotes MLN-4760, whose clinical development was abandoned after phase I trials (clinical name, ORE1001), is actually an interesting compound that could be useful for all patients in which a specific ACE2 upregulation is proven and associated to different (heart/lung/liver/intestine/kidney/immune system/blood/coagulation, etc.) pathological conditions related to ACE2 pathway downstream events, as it seems to occur in COVID-19 patients.
T501 7046-7442 Sentence denotes Although in blood of normal subjects sACE2 activity is undetectable because its catalytic activity in human plasma is masked by an endogenous inhibitor [116] and chronic ACE2 activation may be deleterious, some patients might need of sACE2 activity to better face an acute pathological condition, therefore a careful monitoring of clinical parameters should be performed during patient treatment.
T502 7444-7448 Sentence denotes 8.2.
T503 7449-7478 Sentence denotes Inhibition of Renin Activity:
T504 7479-7488 Sentence denotes Aliskiren
T505 7489-7596 Sentence denotes An alternative approach is to inhibit the RAS pathway at its origin by inhibiting renin enzymatic activity.
T506 7597-7810 Sentence denotes Regarding renin inhibitors, aliskiren is the sole compound in this class of drugs that was approved by the US Food and Drug Administration in March 2007 and commercialized for the management of hypertension [186].
T507 7811-7947 Sentence denotes Aliskiren may be used alone or in combination with other drugs to face COVID-19, in particular the severe forms of SARS-CoV-2 infection.
T508 7948-8053 Sentence denotes Indeed, in patients with severe symptoms of COVID-19 hypoxia might have upregulated both arms of the RAS.
T509 8054-8216 Sentence denotes Therefore, aliskiren might be a useful “tool” to reduce production of Ang I, the necessary fuel for both ACE and ACE2 hyperactivity and their detrimental effects.
T510 8217-8433 Sentence denotes Aliskiren treatment in rats has been shown to upregulate both AT1R and MasR expression probably as consequence of a compensation mechanism when both Ang II and Ang (1–7) ligands are reduced by renin inhibition [187].
T511 8434-8654 Sentence denotes Of particular interest in the context of SARS-CoV-2 infection, the treatment has been shown to reduce expression of both AT2R and ACE2, thus possibly performing a multiple action in inhibiting both arms of the RAS [187].
T512 8655-8771 Sentence denotes Similarly, cation chelating agents such as CaNa2EDTA or nicotianamine might also work, although at different levels.
T513 8773-8777 Sentence denotes 8.3.
T514 8778-8795 Sentence denotes Chelating Agents:
T515 8796-8805 Sentence denotes CaNa2EDTA
T516 8806-9084 Sentence denotes As already mentioned, chelating agents, by limiting zinc cellular availability, might influence hyperactivity, synthesis and conformation of both ACE2 and ACE, which may impair not only ACE2 (and ACE) enzymatic activity but also its availability on cell surface for viral entry.
T517 9085-9267 Sentence denotes For these reasons, chelating agents might be effective to counter SARS-CoV-2 infection, and in particular when (e.g., induced by hypoxia) both arms of the RAS are likely upregulated.
T518 9268-9459 Sentence denotes Differently from renin inhibitors, more chelating agents are commercially available and both classes of drugs might be administered, alone or in combination with other therapies for COVID-19.
T519 9460-9750 Sentence denotes Of note, these classes of drugs might be beneficial not only for SARS-CoV-2 infection but also for other disease in which both arms of the RAS (and of the inflammatory system) are upregulated, as for example ARDS, PAH and other pathologies associated to chronic hypoxia and cardiac failure.
T520 9751-10047 Sentence denotes Indeed, both Ang-II and Ang-(1–7) upregulation and a cytokine storm are common aspects in patients not only with ARDS and PAH but also with critical coronary artery disease [182], suggesting an upregulation of both arms of the RAS and of the inflammatory system in several different dysfunctions.
T521 10048-10151 Sentence denotes Notably, a number of clinical trials have indicated the utility of CaNa2EDTA in coronary heart disease.
T522 10152-10271 Sentence denotes It was believed that chelation therapy might alter plaque morphology and volume, or improve endothelial function [123].
T523 10272-10319 Sentence denotes However, the evidence was not convincing [123].
T524 10320-10425 Sentence denotes Future clinical trials on selected patients with both ACE and ACE2 upregulation might be more convincing.
T525 10426-10555 Sentence denotes It is clear that similar pathways of activation can lead to different outcomes depending on individual predisposition/background.
T526 10556-10774 Sentence denotes Therefore, future efforts to understand the genetic, morpho-physiological, environmental and lifestyle factors that individually affect the predisposition to a specific disease with a precision medicine must be pursed.
T527 10775-10946 Sentence denotes To avoid disrupting extracellular calcium levels, CaNa2EDTA formulation is typically employed as an antidote for lead poisoning or as an extracellular zinc chelator [123].
T528 10947-11088 Sentence denotes CaNa2EDTA is poorly absorbed in the gastrointestinal tract therefore can be preferentially administered by parenteral route or by inhalation.
T529 11089-11330 Sentence denotes Nevertheless, oral tablets (e.g., 250–500 mg/tablet) or suppositories of CaNa2EDTA might also work in reducing plasma zinc levels by inhibiting intestinal zinc absorption (the only physiological way of zinc uptake by the organism) [188,189].
T530 11331-11463 Sentence denotes In this regard, eight men showing elevated lead concentrations were given a seven-day course of CaNa2EDTA, 4 g/day in divided doses.
T531 11464-11599 Sentence denotes Oral CaNa2EDTA caused a rise in lead excretion within few hours, suggesting that orally administered drug was partially absorbed [188].
T532 11600-11744 Sentence denotes Importantly, the trial in the eight lead workers demonstrated that oral administration of CaNa2EDTA was safe and produced no side-effects [188].
T533 11745-12015 Sentence denotes However, the FDA-approved method for delivery of CaNa2EDTA in treatment of lead poisoning is intravenously or intramuscularly and the recommended dose for asymptomatic adults and pediatric patients with elevated blood lead levels is 1000 g/m2/day (~0,05 g/kg/day) [190].
T534 12016-12142 Sentence denotes CaNa2EDTA was usually administered for 5–10 days followed by an interval of at least 5–10 days before a second administration.
T535 12143-12201 Sentence denotes Unfortunately, intravenous administration is very painful.
T536 12202-12485 Sentence denotes Administration of CaNa2EDTA via nebulizer has also been pursued for inhalation therapy in pulmonary metal poisonings to protect lung tissue and reduce its systemic uptaken [123]; moreover, nebulized solutions containing EDTA have been proven safe, not inducing adverse effects [191].
T537 12486-12711 Sentence denotes For the sake of completeness, the unconventional methods for administering chelating agents such as rectal or inhalatory administration are not FDA approved methods for delivery and they have not been studied in detail [192].
T538 12712-12862 Sentence denotes CaNa2EDTA diffuses mainly in the extracellular fluids, where it is not significantly metabolized, and it is excreted rapidly by glomerular filtration.
T539 12863-12961 Sentence denotes The chelator has a half-life of 1.4 to 3 h in adults and is completely excreted within 24 h [123].
T540 12962-13043 Sentence denotes For all of the above reasons, CaNa2EDTA might be employed in therapy of COVID-19.
T541 13044-13298 Sentence denotes However, before beginning any therapy with medication, particularly in the case of new diseases (such as COVID-19) or new treatments, a careful patient selection for these new treatments is essential to prevent unnecessary toxicity (“first do not harm”).
T542 13300-13304 Sentence denotes 8.4.
T543 13305-13333 Sentence denotes Safety and Efficacy Concerns
T544 13334-13718 Sentence denotes Unfortunately, diseases of different aetiologies may present similar final dysfunction/alterations (e.g., cardiac dysfunction/lung alterations/thrombosis are induced by excessive activation of either AT1R or MasR/AT2R pathways, see Figure 1), while diseases with same aetiologies may present different final dysfunction/alterations depending on patients (COVID-19 is a clear example).
T545 13719-13931 Sentence denotes This confounding aspect of diseases can lead to erroneous interpretations, and only defining the correct and early molecular origin of diseases is possible to reach a successful outcome if a therapy is available.
T546 13932-14124 Sentence denotes In order to decide who to treat, and when to start treatment, it is important to define the entity of dysfunctions, probability of treatment success and probability to develop adverse effects.
T547 14125-14238 Sentence denotes To promptly intervene in order to prevent severe forms of COVID-19, we need early markers of disease progression.
T548 14239-14635 Sentence denotes To this regard, if plasma (free) Zn2+ (or total zinc/albumin molar ratio), albumin, IL-10, Ang (1–9), Ang (1–7), Ang (1–5) and/or bradykinin (1–7) will be proven to be reliable surrogate markers for ACE and/or ACE2 enzymatic activity in vivo, they could be exploited, together with circulating ACE and ACE2 activity evaluation, in order to decide who and when to start treating COVID-19 patients.
T549 14636-14734 Sentence denotes Alternatively, eosinopaenia and hypotension may be also exploited as signs of disease progression.
T550 14735-15161 Sentence denotes In any case, since the conditions of some patients can be critical, it is highly recommended to administer the minimal effective dose in order to reduce possible side effects, starting with low and increasing doses, while at the same time monitoring patient status and early signs of disease progression (e.g., blood pressure, eosinophil counts, molecular concentrations of the RAS peptides and other markers of inflammation).
T551 15162-15562 Sentence denotes The aim of the project was not necessarily to stop viral entry (the epithelial cells take already care of it shedding ACE2) but to block positive feedback loops that follow the cellular response to SARS-CoV-2 infection, which are likely the main cause of the severe symptoms associated with COVID-19, doing so, the disease might hopefully become like a simple flu, a spontaneously eradicable disease.
T552 15563-15693 Sentence denotes At the moment, I am alone in proposing these new and non-conventional therapeutic approaches that may or may not work on COVID-19.
T553 15694-15879 Sentence denotes In doing so, I have not only described a rationale/strategy to counter COVID-19, but also provided practical information to optimize the RAS inhibitors based on known experimental data.
T554 15880-16069 Sentence denotes Before any in vivo drug administration (e.g., ACE2 inhibitor), it has to be checked the biological activity (e.g., ACE2) that is affected by the drug, considering the possible side effects.
T555 16070-16248 Sentence denotes However, this is not always the case and, in some cases, patients are treated without a careful evaluation of the biological parameter that is modulated by the administered drug.
T556 16249-16461 Sentence denotes In this regard, I have tried to address all aspects of the RAS inhibition in detail because my main concern is that the use of these approaches in a wrong way may lead to a failure or even to deleterious effects.
T557 16462-16705 Sentence denotes That is why I have meticulously described all the steps before possible administration and provided the guideline suggestions and specific recommendations in order to increase the probability of success and to minimize the deleterious effects.
T558 16706-16806 Sentence denotes The readers are, however, expected and encouraged to debate and make their own optimized guidelines.