However, within the context of COVID-19 infection, effects on cell lines appear to be different. Zandvakili I, Conboy C, Ayed A, Cathcart-Rake E, Tefferi A. Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: A second experience. [8] The EUA was issued to Eli Lilly and Company. Based on this property, presumably, one of the important mechanisms of action of baricitinib in the treatment of rheumatoid arthritis is the inhibition of the IL-6 / JAK1 / JAK2 pathway. Clinical failure of dexamethasone (e.g., worsening hypoxemia and rising C-reactive protein despite dexamethasone). Ruxolitinib in adult patients with secondary haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial. [17], In a clinical trial of hospitalized patients with COVID-19, baricitinib, in combination with remdesivir, was shown to reduce time to recovery within 29 days after initiating treatment compared to patients who received a placebo with remdesivir. The primary concern involving the combination of dexamethasone and baricitinib is that excessive immunosuppression could increase the risk of opportunistic infections. [2] It acts as an inhibitor of janus kinase (JAK), blocking the subtypes JAK1 and JAK2. This is a valid concern which deserves further investigation. In ClinicalTrials.gov several studies are recruiting patients with COVID-19 pneumonia or cytokine storm to test ruxolitinib as single agent [e.g., NCT04362137, NCT04334044] or in combination with anakinra [NCT04366232], simvastatin … This is a multi-center, placebo-controlled RCT evaluating the effect of baricitinib when added to remdesivir (remdesivir plus placebo vs. remdesivir plus baricitinib).​5​  Patients weren’t allowed to receive steroid for treatment of COVID-19 (the trial was performed prior to publication of the RECOVERY trial). Baricitinib is not recommended for patients with severe hepatic or renal impairment (glomerular filtration rate <30 mL/min/1.73 m 2). 50% of the circulating baricitinib are bound to blood plasma proteins. Without baricitinib therapy, levels of C-reactive protein and IL-6 didn’t decrease over the first week of illness – whereas these levels dropped rapidly in the baricitinib group. Among patients not requiring oxygen at baseline, treatment with baricitinib reduced the development of hypoxemia (23% vs. 40%). [8] The median time to recovery from COVID-19 was seven days for baricitinib plus remdesivir and eight days for placebo plus remdesivir. This provides broader spectrum activity than inhibition of a single cytokine, potentially allowing JAK-inhibitors to be more effective than monoclonal antibodies. Tyrosine kinase 2, which belongs to the same enzyme family, is affected less (IC50 = 53 nM), and Janus kinase 3 far less (IC50 > 400 nM). Less common side effects included other infections such as herpes zoster, herpes simplex, urinary tract infections, and gastroenteritis. Morphine-6-glucuronide is responsible for approximately 85% of the response observed by morphine administration. Baricitinib is used to reduce pain, stiffness, and swelling in adults with rheumatoid arthritis after other treatments have failed. When you're done listening to the podcast. There are not thought to be any clinically significant pharmacokinetic drug interactions. Prediction of Transporter-Mediated Drug-Drug Interactions for Baricitinib. Janus kinases are intracellular enzymes that transmit signals arising from cytokine or growth factor receptor interactions on the cellular membrane to influence cellular processes of immune cell function and hematopoiesis. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. In the ACTT-2 trial, baricitinib caused a. Baricitinib has prothrombotic effects, causing a risk of venous thromboembolism of roughly 0.6 per one hundred patient-years among patients with rheumatoid arthritis. Should baricitinab be used in suspected or confirmed super added bacterial infection in Covid 19 insteadv of dexamethasone!! By blocking the actions of JAK1/2, baricitinib disrupts the activation of downstream … Treatment with baricitinib correlated with increases in lymphocyte count and decreases in C-reactive protein and IL-6 levels. Rodriguez-Garcia J, Sanchez-Nievas G, Arevalo-Serrano J, Garcia-Gomez C, Jimenez-Vizuete J, Martinez-Alfaro E. Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study. a different mode of action to the biological DMARDs. Beneficial impact of Baricitinib in COVID-19 moderate pneumonia; multicentre study. The baricitinib group showed more rapid improvement across a variety of clinical indices (e.g., oxygen saturation and various symptoms). Baricitinib, sold under the brand name Olumiant among others, is a drug for the treatment of rheumatoid arthritis (RA) in adults whose disease was not well controlled using RA medications called tumor necrosis factor (TNF) antagonists. Currently we lack prospective RCT-level evidence to answer this question. Greater systemic inflammation (e.g., C-reactive protein over ~100 mg/dL). Baricitinib restrains the immune dysregulation in patients with severe COVID-19. [6], Being metabolized only to a small extent, the substance has a low potential for interactions. Jorgensen S, Tse C, Burry L, Dresser L. Baricitinib: A Review of Pharmacology, Safety, and Emerging Clinical Experience in COVID-19. Baricitinib is mostly (75%) cleared by the kidneys with a half-life of about 6-9 hours. Specifically, due to improved treatment of the COVID-19 infection, JAK-inhibitors may actually improve some cytopenias. There were no differences in mortality. Ironically, 2 cases of acute pancreatitis were reported in the drug’s safety analysis [6, 7]. Consequently, the study cannot address the question of whether to use baricitinib in combination with steroid. Food in­take has no rel­e­vant in­flu­ence on the drug's phar­ma­co­ki­net­ics. For now, the following might be considered contraindications: Dexamethasone is currently the front-line immunomodulator therapy for hypoxemic patients with COVID-19 (based on established mortality benefit in the RECOVERY trial). In studies, inhibitors of the liver enzymes CYP3A4, CYP2C19, and CYP2C9, as well as the CYP3A4 inducer rifampicin, had no relevant influence on baricitinib concentrations in the bloodstream. According to the paper "mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication and the cytokine storm, and is associated with beneficial outcomes including in severely ill elderly patients". One would hope, in as much as it seems we’re running out of hospital beds…. This is an observational, multicenter study describing outcomes of hospitalized patients treated with baricitinib (4 mg/day for two weeks) versus hydroxychloroquine (both in combination with lopinavir/ritonavir).​6​  Steroid administration was not allowed. It reaches highest blood plasma levels after about an hour; in different individuals the time to reach this level ranges from 0.5 to 3 hours. This would be expected to reduce immobility and thereby, Patients with COVID-19 experience a prothrombotic state due to increased systemic inflammation. mechanism of action of baricitinib as an anti-cytokine and a poten-tial anti-viral agent. You’re doing pretty well when you’re safer than placebo. To date, most studies have focused on baricitinib due to its potential antiviral activity. The sub­stance is quickly ab­sorbed from the gut with an ab­solute bioavail­abil­ity of 79%. Implications regarding long-term functional endpoints are notable. Among patients with renal insufficiency, it should be dose-reduced: Probenecid inhibits baricitinib excretion by the kidney by about 50%. [6], As of August 2016[update], 31 clinical trials had been registered for baricitinib of which 24 had completed,[14] and 4 of 6 phase 3 trials had completed. It reaches high­est blood plasma lev­els after about an hour, in dif­fer­ent in­di­vid­u­als rang­ing from 0.5 to 3 hours. Severe renal failure (e.g., glomerular filtration rate <15 ml/min). [2][5], In February 2017, baricitinib was approved for use in the EU as a second-line therapy for moderate to severe active rheumatoid arthritis in adults, either alone or in combination with methotrexate. Since remdesivir probably has minimal effect on COVID-19, this trial is essentially a double-blind RCT investigating the use of baricitinib against COVID-19. Just about anything in life can cause liver test abnormalities, and this is true of medications. Given the trend in preventing supplemental oxygen need in ACCT-2 among inpatients, I would be curious if JAKIs are being considered/studied as a potential outpatient intervention to prevent hospitalization in those at risk/ with worsening course prior to requiring admission (as opposed to corticosteroids, which showed a trend towards harm in RECOVERY). [8], During pregnancy, the use of baricitinib is contraindicated. [20], In December 2016, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of baricitinib as a therapy for rheumatoid arthritis. I’m not familiar with RA biologics as I focus more on the Immuno-Oncology drugs, but here’s some info I’ve been able to find. To date, most research has focused on two classes of medications to treat this: JAK-inhibitors may offer a compromise between these two extremes: JAK inhibitors are relatively new medications. [8] The safety and effectiveness of this investigational therapy for use in the treatment of COVID-19 continues to be evaluated. Bronte V, Ugel S, Tinazzi E, et al. [6], An additive effect with other immunosuppressants cannot be excluded. Ruxolitinib for refractory/relapsed hemophagocytic lymphohistiocytosis. I really appreciate these PulmCrit posts. indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to [15][needs update], In April 2020, Lilly announced they were investigating the use of baricitinib for treating COVID-19 patients. Baricitinib is associated with an increased rate of infections such as upper respiratory tract infections compared to placebo (see section 4.8). It's a type of drug known as a Janus kinase JAK inhibitor. Nonetheless, this supports the utility of baricitinib. Area covered : We provide an overview of the mechanisms of action of baricitinib and its clinical implications in RA and other autoimmune diseases based on recent reports. Adequate supply of baricitinib to provide it to all patients who could potentially benefit. Thus, antiviral therapies generally have minimal effectiveness in this disease stage. These data support a role for JAK-STAT signaling in pain signaling and provide an opportunity to investigate the potential mechanism of action of baricitinib in joint pain. Baricitinib is a Janus kinase (JAK) inhibitor that reversibly inhibits Janus kinase 1 with a half maximal inhibitory concentration (IC50) of 5.9 nM and Janus kinase 2 with an IC50 of 5.7 nM. D’Alessio A, Del P, Bracchi F, et al. Via a signal transduction pathway involving STAT proteins, this ultimately modulates gene expression in immunological cells. However, it does lend further support to the concept that baricitinib provides benefit even when added to corticosteroid. Baricitinib is a JAK-inhibitor which blocks many of the cytokine pathways involved in hyperinflammation caused by COVID-19. This molecular mechanism of action suggests that baricitinib might inhibit cytokines central to the dysregulated innate and adaptive immune function observed in systemic lupus erythematosus. Would love your thoughts, please comment. At baseline, the groups were well matched and not very ill (inclusion required a saturation >92% on room air; patients were treated a median of seven days from symptom onset). [4], Despite widespread expectations that the FDA would approve baricitinib for rheumatoid arthritis,[21] in April 2017, the FDA issued a rejection, citing concerns about dosing and safety. In the next step, we explored the role of JAKs in human B cells differentiation. Neither baricitinib nor dexamethasone has been associated with an increase in opportunistic infection when utilized for COVID-19 patients. [8] For all of these endpoints, the effects were statistically significant. Baricitinib inhibits the activity of the selective JAK1 and JAK2 enzymes, interfering with the JAK-STAT signalling pathway. The use of baricitinib in COVID-19 is new, so it’s impossible to construct a definitive list of contraindications. This study has numerous limitations (e.g., lack of randomization and use of hydroxychloroquine as a control – although hydroxychloroquine is arguably an expensive placebo for COVID-19). [Figure 1][1] Figure 1 Representative still images from video recordings of animals during gait analysis at baseline (Top Panel), 3 Days post-CFA and vehicle treatment (Middle Panel) and 3 Days post-CFA with 10 … Another retrospective study similiarly suggested that the combination of ruxolitinib plus steroid was beneficial.​17​. Active severe infection (e.g., known tuberculosis or invasive fungal infection). I wonder how you and the time to do all this… JAK-inhibitors are small-molecule inhibitors which may be manufactured in bulk quantity and administered orally. We are the EMCrit Project, a team of independent medical bloggers and podcasters joined together by our common love of cutting-edge care, iconoclastic ramblings, and FOAM. ! A phase II placebo-controlled trial studied baricitinib in daily doses of 1 mg, 2 mg, 4 mg or 8 mg. It’s conceivable that by blunting the initial immune hyperactivation, baricitinib could also blunt the subsequent immunoparalysis phase. Baricitinib reduces intubation rate and accelerates recovery among COVID-19 patients. 3. Although these agents are currently expensive, over time their price is likely to decrease. He is an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont. In this study, we investigated the effects of the pharmacological modulation of the JAK cascade with baricitinib in an in vivo model of diet-induced metabolic alterations to evaluate the efficacy and mechanism of action of baricitinib to provide “proof of concept” evidence for the repurposing of JAK inhibitors in metabolic diseases. This could potentially reduce viral replication. Overall, it seems unlikely that baricitinib would cause clinically problematic venous thromboembolic disease (given considerations #2 and #3 above). In the context of rheumatoid arthritis, opportunistic infections are associated with lymphopenia. [8], In November 2020, the World Health Organization (WHO) updated its guideline on therapeutics for COVID-19 to include a conditional recommendation against the use of remdesivir, triggered by results from the WHO Solidarity trial. Baricitinib is one of the first once-daily oral selective JAK1 and JAK2 inhibitors for the treatment of rheumatoid arthritis (RA). However, discontinuation of baricitinib could theoretically lead to a resurgence of hyperinflammation. [2][5], In March 2020, the US FDA granted breakthrough therapy designation to baricitinib for the treatment of alopecia areata. - Mechanism of Action & Protocol. [8] The odds of clinical improvement at day 15 was higher in the baricitinib plus remdesivir group versus the placebo plus remdesivir group. JAK-inhibitors affect fewer pathways than steroid, potentially allowing JAK inhibitors to have a more favorable side effect profile (e.g., no myopathy or delirium). Baricitinib induced changes in gene expression, regardless of mechanism, by inhibiting JAK1 and JAK2 signalling. The safety profile was very good (with a reduction of infections seen in patients treated with baricitinib, and no significant difference in the risk of venous thromboembolism). [6], Less than 10% of the substance is metabolized to four different oxidation products by CYP3A4; the rest is left unchanged. MECHANISM OF ACTION. (explored above) suggests that baricitinib is beneficial among patients treated with steroid. Elimination half-life is 12.5 hours on average. Baricitinib is an inhibitor of JAK-1 and JAK-2, which may dampen proinflammatory cytokine signaling (figure above). Cao Y, Wei J, Zou L, et al. There was no significant difference in venous thromboembolic events between groups. More severe disease (e.g., patient on high-flow nasal cannula or mechanical ventilation). The usual dose of baricitinib for COVID-19 is 4 mg daily. Satarker S, Tom A, Shaji R, Alosious A, Luvis M, Nampoothiri M. JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy. Currently the decision may need to be personalized (e.g., incorporating individual aspects of the patient and multidisciplinary consultation). It’s likely that this is simply a result of avoiding intubation and thereby avoiding ventilator-associated pneumonia (VAP). Kalil A, Patterson T, Mehta A, et al. Secondary endpoints were more clinically meaningful and a bit more impressive: Baricitinib appeared to be safe. Wang J, Wang Y, Wu L, et al. Mechanism of action. Therefore, in patients receiving probenecid, the dose of baricitinib should be reduced by 50%.​12​ In the context of a baricitinib shortage, probenecid co-administration could be used to double the number of patients who could be treated with baricitinib. Baricitinib Inhibits Differentiation of B Cells to Plasmablasts As described above, inhibition of type-I IFN signaling is one of the most important mechanisms of action of JAK inhibitors on the human immune response. Much of the harm from infections is mediated by hyperactive inflammatory reactions. Mechanism of Action Baricitinib inhibits Janus kinase (JAK) enzymes, which are intracellular enzymes involved in stimulating hematopoiesis and immune cell function through a signaling pathway. The mechanism of action of baricitinib (BAR) in rheumatoid arthritis is understood to be via Janus k inase inhibition. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. However, this fear is probably overblown, for the following reasons: Currently, there is no simple answer regarding whether to add baricitinib to dexamethasone. Baricitinib has roughly two potential mechanisms of action against COVID-19: Baricitinib is an inhibitor of JAK-1 and JAK-2, which may dampen proinflammatory cytokine signaling (figure above). It is well absorbed, with a bioavailability of ~80%. Patients in the baricitinib group were significantly less likely to require ICU admission and less likely to die. Image courtesy of Ann Rheum Dis/NCBI. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. Upon administration, baricitinib binds to JAK1/2, which inhibits JAK1/2 activation and leads to the inhibition of the JAK-signal transducers and activators of transcription (STAT) signaling pathway. Informative as always. This decreases the production of inflammatory cytokines and may prevent an inflammatory response. Outpatient experience with baricitinib reveals that it causes a very small increase in venous thromboembolic events. Now why would I collect info that anyone could, only to copy and paste the data on Quora? [16], In November 2020, published research showed barcitinib was beneficial in treating COVID-19 patients. Ruxolitinib has recently demonstrated efficacy against hemophagocytic lymphohistiocytosis (HLH) in several case series, with an impressive efficacy/toxicity ratio.​1–4​ The application of JAK-inhibitors to other forms of hyperinflammation could open exciting new avenues into the treatment of critical illness. It’s also conceivable that it could relate to normalization of the immune system, thereby avoiding immunoparalysis. Multicenter RCT evaluating ruxolitinib for COVID-19, Jakinibs for hemophagocytic lymphohisticotyosis, IBCC – Sodium channel blocker toxicity (including tricyclic antidepressants), IBCC – Neuroleptic Malignant Syndrome (NMS). Baricitinib is an oral Janus kinase (JAK) inhibitor. EMCrit is a trademark of Metasin LLC. [3] European Union approval was granted in February 2017. [8], The data supporting the US FDA's Emergency Use Authorization (EUA) for baricitinib combined with remdesivir are based on a randomized, double-blind, placebo-controlled clinical trial (ACTT-2), which was conducted by the US National Institute of Allergy and Infectious Diseases (NIAID). Available data from Stepping et al. Posada M, Cannady E, Payne C, et al. The short half-life is both a strength and a weakness. The clinical question is thus whether baricitinib should be added in combination with dexamethasone. This site represents our opinions only. Dexamethasone 6 mg/day isn’t a very high dose of steroid (it’s equivalent to 40 mg prednisone). [18][19], In January 2016, Eli Lilly submitted a new drug application to the US Food and Drug Administration (FDA) for the approval of baricitinib to treat moderately-to-severely active rheumatoid arthritis. If a complication from baricitinib were to arise, the drug could be withdrawn rapidly. [8] The odds of a patient's condition progressing to death or being ventilated at day 29 was lower in the baricitinib plus remdesivir group versus the placebo plus remdesivir group. and Rodriguez-Garcia et al. Most notably, it suggests that baricitinib may be useful even among patients being treated with steroid (since 85% of patients were also treated with steroid). [8] Baricitinib is not authorized or approved as a stand-alone treatment for COVID-19. In contrast, serious infections were not more common for baricitinib than placebo in the randomised, controlled data. JAK inhibitors may cause lymphopenia, anemia, and neutropenia when used to treat rheumatoid arthritis. While baricitinib blocks a number of transporter proteins in vitro, clinically relevant interactions via this mechanism are considered very unlikely, except perhaps for the cation transporter SLC22A1 (OCT1). So the primary endpoint was statistically positive, but only with a small difference. Baricitinib is a small-molecule agent which is available in tablet form. Baricitinib inhibits AP2-associated protein kinase 1 (AAK-1), … Baricitinib (LY3009104; INCB028050) is a selective and orally bioavailable JAK1 and JAK2 inhibitor with IC50s of 5.9 nM and 5.7 nM, respectively. Substantial immune dysfunction (e.g., AIDS, TNF-inhibitors, chemotherapy). Ahmed A, Merrill S, Alsawah F, et al. There is no free lunch. What Are Some Side Effects That I Need to Call My Doctor About Right away? Serum autoantibodies and complement were not altered by baricitinib treatment, suggesting that the mechanism of action of baricitinib in SLE may be primarily through an anti-inflammatory effect. [8] The trial followed patients for 29 days and included 1,033 patients with moderate or severe COVID-19; 515 patients received baricitinib plus remdesivir, and 518 patients received placebo plus remdesivir. This is true of any immunomodulatory therapy (e.g., steroid, tocilizumab). 4 Morphine and its metabolites act as agonists of the mu and kappa opioid receptors. Whether to add baricitinib on top of dexamethasone remains controversial, given a lack of direct RCT-level evidence. Pregnancy (little human data; some evidence of toxicity in animals). Baricitinib, also known as Olumiant, is used to treat rheumatoid arthritis. However, further evidence is needed to establish this. This decision may be made for each individual patient, possibly with the help of rheumatology consultation. 50% of the cir­cu­lat­ing baric­i­tinib are bound t… [6], Baricitinib is a Janus kinase (JAK) inhibitor that reversibly inhibits Janus kinase 1 with a half maximal inhibitory concentration (IC50) of 5.9 nM and Janus kinase 2 with an IC50 of 5.7 nM. [citation needed], CCS(=O)(=O)N1CC(C1)(CC#N)N2C=C(C=N2)C3=C4C=CNC4=NC=N3, InChI=1S/C16H17N7O2S/c1-2-26(24,25)22-9-16(10-22,4-5-17)23-8-12(7-21-23)14-13-3-6-18-15(13)20-11-19-14/h3,6-8,11H,2,4,9-10H2,1H3,(H,18,19,20), Janus kinase inhibitor § Mechanism of action, National Institute of Allergy and Infectious Diseases, Committee for Medicinal Products for Human Use, "Baricitinib (Olumiant) Use During Pregnancy", "Drug Approval Package: Olumiant (baricitinib)", "Olumiant- baricitinib tablet, film coated", "Coronavirus (COVID-19) Update: FDA Authorizes Drug Combination for Treatment of COVID-19", "Xeljanz- tofacitinib tablet, film coated Xeljanz XR- tofacitinib tablet, film coated, extended release", "FDA approves Xeljanz for rheumatoid arthritis", "Inrebic- fedratinib hydrochloride capsule", "Eli Lilly to study baricitinib for Covid-19 treatment", "JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality", "A living WHO guideline on drugs for covid-19", "Lilly and Incyte Announce Submission of NDA to FDA for Oral Once-Daily Baricitinib for Treatment of Moderate-to-Severe Rheumatoid Arthritis", "We don't know when (exactly) Lilly will announce the FDA's baricitinib decision, but watch out for the looming pricing squabble", "The FDA shot down a new rheumatoid arthritis drug — and the companies that make the drug are tumbling", "Surprise FDA Rejection Will Sting This Biotech", "Lilly Receives FDA Breakthrough Therapy Designation for Baricitinib for the Treatment of Alopecia Areata", "Baricitinib as rescue therapy in a patient with COVID-19 with no complete response to sarilumab", "Baricitinib: A Review of Pharmacology, Safety, and Emerging Clinical Experience in COVID-19", "Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19", "JAK Inhibition as a New Treatment Strategy for Patients with COVID-19", "Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients", "Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19", Methoxy polyethylene glycol-epoetin beta (CERA/Mircera), Granulocyte macrophage colony-stimulating factor, Interferon alpha (interferon alfa, IFN-α), FMS-like tyrosine kinase 3 ligand (FLT3L), Leukemia/leukocyte inhibitory factor (LIF), https://en.wikipedia.org/w/index.php?title=Baricitinib&oldid=1018495444, Articles containing unverified chemical infoboxes, Articles containing potentially dated statements from August 2016, All articles containing potentially dated statements, Wikipedia articles in need of updating from April 2020, All Wikipedia articles in need of updating, Articles with unsourced statements from March 2020, Creative Commons Attribution-ShareAlike License, This page was last edited on 18 April 2021, at 10:48. Figure 3 shows genes whose expression changed based on baricitinib’s inhibition of JAK1 and JAK2 signalling and the most significantly baricitinib-induced changed genes. Online Medical Education on Emergency Department (ED) Critical Care, Trauma, and Resuscitation, December 31, 2020 by Josh Farkas 4 Comments.