Immune thrombocytopenia: options and new perspectives.

Immune thrombocytopenia is a haematological, autoimmune disorder characterized by elevated platelet demolition due to the presence of antiplatelet autoantibodies derived from B cells and to an irregular, deficient process of platelets production in bone marrow. In this review, after a brief presentation of 'old' strategies used nowadays yet, we focused on new drugs used in the treatment of immune thrombocytopenia and their mechanism of action and posology, basing on the last scientific literature. The observation that CoViD-19 can be associated with immune thrombocytopenia is also put in evidence. Particular attention will be dedicated on the concept that the ideal treatment should represent a solution not only for the failure of normal processes of production and survival of platelets, but also it should improve quality of life of patients, with minimum adverse events. Anyway, despite enormous advances of the last years, further investigations are necessary in order to define scrupulously long-term efficacy of new molecules proposed.

Antiviral Activity of Pyrimidine Containing Compounds: Patent Review.

Viruses are still the most prevalent infectious pathogens on a worldwide scale, with many of them causing life-threatening illnesses in humans. Influenza viruses, because of their significant morbidity and mortality, continue to pose a major threat to human health. According to WHO statistics, seasonal influenza virus epidemics are predicted to cause over 2 million severe illness cases with high death rates yearly. The whole world has been suffering from the COVID-19 epidemic for two years and is still suffering so far, and the deaths from this virus have exceeded three million cases. Because the great majority of viral infections do not have a specific medication or vaccination, discovering novel medicines remains a vital task. This review covers reports in the patent literature from 1980 to the end of 2021 on the antiviral activities of pyrimidine moieties. The patent database, SciFinder, was used to locate patent applications. A large variety of pyrimidine molecules have been produced and tested for antiviral activity over the last decade. These molecules were reported to inhibit a wide range of viruses, including influenza virus, respiratory syncytial virus, rhinovirus, dengue virus, herpes virus, hepatitis B and C, and human immunodeficiency virus. The cytotoxicity of the developed pyrimidine derivatives was tested in almost all reported studies and the selectivity index was calculated to show the selectivity and safety of such molecules. From the remarkable activity of pyrimidine compounds as antivirals for several dangerous viruses, we expect that these derivatives will be used as potent drugs in the very near future.

The third dose of mRNA SARS-CoV-2 vaccines enhances the spike-specific antibody and memory B cell response in myelofibrosis patients.

Vaccination against SARS-CoV-2 using mRNA-based vaccines has been highly recommended for fragile subjects, including myelofibrosis patients (MF). Available data on the immune responsiveness of MF patients to mRNA SARS-CoV-2 vaccination, and the impact of the therapy with the JAK inhibitor ruxolitinib, are still fragmented. Here, we profile the spike-specific IgG and memory B-cell response in MF patients, treated or not with ruxolitinib, after the second and the third dose of SARS-CoV-2 BNT162b2 (BioNTech) and mRNA-1273 (Moderna) vaccines. Plasma and peripheral blood mononuclear cells samples were collected before vaccination, post the second and the third doses and tested for spike-specific antibodies, ACE2/RBD antibody inhibition binding activity and spike-specific B cells. The third vaccine dose significantly increased the spike-specific IgG titers in both ruxolitinib-treated and untreated patients, and strongly enhanced the percentage of subjects with antibodies capable of in vitro blocking ACE2/RBD interaction, from 50% up to 80%. While a very low frequency of spike-specific B cells was measured in blood 7 days after the second vaccination dose, a strong and significant increase was elicited by the third dose administration, generating a B cell response similar to the one detected in healthy controls. Despite the overall positive impact of the third dose in MF patients, two patients that were under active concomitant immunosuppressive treatment at the time of vaccination, and a patient that received lymphodepleting therapies in the past, remained low responders. The third mRNA vaccine dose strongly increases the SARS-CoV-2 specific humoral and B cell responses in MF patients, promoting a reactivation of the immune response similar to the one observed in healthy controls.

Design of novel pyrimidine based remdesivir analogues with dual target specificity for SARS CoV-2: A computational approach.

As the world undergone unpreceded time of tragedy with the corona virus, many researchers have raised to showcase their scientific contributions in terms of novel configured anti-viral drugs until now. Herein, we designed pyrimidine based nucleotides and assessed for the binding capability with SARS-CoV-2 viral replication targets of nsp12 RNA-dependent RNA polymerase and Mpro main protease. Molecular docking studies showed all the designed compounds to possess good binding affinity, with a few compounds which outperforms the control drug remdesivir GS-5743 and its active form GS-441524. Further molecular dynamics simulation studies confirmed their stability and preservation of the non-covalent interactions. Based on the present findings Ligand2-BzV_0Tyr, ligand3-BzV_0Ura, and ligand5-EeV_0Tyr showed good binding affinity with Mpro, whereas, ligand1-BzV_0Cys and Ligand2-BzV_0Tyr showed good binding affinity with RdRp, thus could act as potential lead compounds against SARS-CoV-2, which needs further validation studies. In particular, Ligand2-BzV_0Tyr could be more beneficial candidate with the dual target specificity for Mpro and RdRp.

A pharmacokinetic drug-drug interaction study between rosuvastatin and emvododstat, a potent anti-SARS-CoV-2 (COVID-19) DHODH (dihydroorotate dehydrogenase) inhibitor.

A therapeutic agent that targets both viral replication and the hyper-reactive immune response would offer a highly desirable treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) management. Emvododstat (PTC299) was found to be a potent inhibitor of immunomodulatory and inflammation-related processes by the inhibition of dihydroorotate dehydrogenase (DHODH) to reduce SARS-CoV-2 replication. DHODH is the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. This drug interaction study was performed to determine whether emvododstat was an inhibitor of breast cancer resistance protein (BCRP) transporters in humans. Potential drug-drug interactions (DDIs) between emvododstat and a BCRP transporter substrate (rosuvastatin) were investigated by measuring plasma rosuvastatin concentrations before and after emvododstat administration. There was no apparent difference in rosuvastatin plasma exposure. The geometric means of maximum plasma rosuvastatin concentrations (Cmax ) were 4369 (rosuvastatin) and 5141 pg/mL (rosuvastatin + emvododstat) at 4 h postdose. Geometric mean rosuvastatin area under the concentration-time curve (AUC) from time 0 to the last measurable plasma concentration was 45 616 and 48 975 h·pg/mL when administered alone and after 7 days of b.i.d. emvododstat dosing, respectively. Geometric least squares mean ratios for Cmax and AUC were approximately equal to 1. Overall, administration of multiple doses of 100 mg emvododstat b.i.d. for 7 days in combination with a single dose of rosuvastatin was safe and well tolerated. Emvododstat can be safely administered with other BCRP substrate drugs. Hence, pharmacokinetic DDI mediated via BCRP inhibition is not expected when emvododstat and BCRP substrates are coadministered.

Ruxolitinib and methylprednisolone for treatment of patients with relapsed/refractory multiple myeloma.

Although Janus kinase (JAK) inhibitors have demonstrated efficacy for treating autoimmune disorders and myeloproliferative neoplasms, their efficacy in treating other types of cancer has not been clearly demonstrated. We evaluated oral ruxolitinib (15 mg twice daily) with oral methylprednisolone (40 mg every other day) for multiple myeloma (MM) patients with progressive disease who had received a proteasome inhibitor, lenalidomide, glucocorticosteroids and three or more prior regimens. All of the planned 29 patients had been enrolled with follow-up until 28 April 2022. Median lines of prior therapy were 6 (range 3-12). Cytogenetics and fluorescent in situ hybridization were evaluable in 28 patients; 9 (32%) and 17 (70%) patients showed high-risk cytogenetics and/or 1q+, respectively. The overall response rate was 31%. The median duration of response was 13.1 (range 2.8-22.0) months. Median progression-free survival rate was 3.4 (range 0.5-24.6) months, Overall, the treatment was well tolerated. The combination of ruxolitinib and methylprednisolone demonstrated significant clinical activity among previously heavily-treated MM patients, and responses were achieved among patients who had high-risk cytogenetics. This is the first clinical study to show activity of JAK inhibitors in combination with steroids for MM patients and expands the potential use of these drugs to those with cancers other than myeloproliferative neoplasms.

Positioning of tofacitinib in treatment of ulcerative colitis: a global perspective.

INTRODUCTION: Tofacitinib has emerged as a useful drug for the treatment of ulcerative colitis (UC). AREAS COVERED: There is an unmet need for cost-effective, non-immunogenic drugs with a safe adverse effect profile to treat patients with ulcerative colitis. In the present review, we evaluate the available literature to inform the appropriate positioning of tofacitinib in the current drug landscape and identify subsets where its use should be done with caution. EXPERT OPINION: Tofacitinib is helpful in the treatment of patients where the standard conventional or biological therapies have failed or were not tolerated. With lower costs of the generic drug than the biologicals (or biosimilars), it could be an important therapy in low- to middle-income countries. The risk of infections, especially Herpes Zoster and tuberculosis, needs to be addressed before initiation. Tofacitinib should be avoided in patients with venous thromboembolism and cardiovascular disease risk factors. Due to limited evidence, the use is not recommended in pregnancy, while it should be used with caution in elderly citizens. Future trials should look into the head-to-head comparison of tofacitinib with biologicals. The role of tofacitinib in acute severe colitis needs evaluation with comparative trials with current standards of care.

Synthesis and Molecular Docking Study of Novel Pyrimidine Derivatives against COVID-19.

A novel series of pyrido[2,3-d]pyrimidines; pyrido[3,2-e][1,3,4]triazolo; and tetrazolo[1,5-c]pyrimidines were synthesized via different chemical transformations starting from pyrazolo[3,4-b]pyridin-6-yl)-N,N-dimethylcarbamimidic chloride 3b (prepared from the reaction of o-aminonitrile 1b and phosogen iminiumchloride). The structures of the newly synthesized compounds were elucidated based on spectroscopic data and elemental analyses. Designated compounds are subjected for molecular docking by using Auto Dock Vina software in order to evaluate the antiviral potency for the synthesized compounds against SARS-CoV-2 (2019-nCoV) main protease M pro. The antiviral activity against SARS-CoV-2 showed that tested compounds 7c, 7d, and 7e had the most promising antiviral activity with lower IC50 values compared to Lopinavir, "the commonly used protease inhibitor". Both in silico and in vitro results are in agreement.

Efficacy and Safety of Pacritinib vs Placebo for Patients With Severe COVID-19: A Phase 2 Randomized Clinical Trial.

Importance: The morbidity and mortality associated with COVID-19 remain high despite advances in standard of care therapy, and the role of anti-inflammatory agents that inhibit the interleukin 6/JAK2 pathway is still being elucidated. Objective: To evaluate the efficacy and safety of the oral JAK2/IRAK1 inhibitor pacritinib vs placebo in the treatment of adults with severe COVID-19. Design, Setting, and Participants: This phase 2, double-blind, placebo-controlled, randomized clinical trial enrolled hospitalized adult patients with severe COVID-19 at 21 centers across the US between June 2020 and February 2021, with approximately 1.5 months of safety follow-up per patient. Data analysis was performed from September 2021 to July 2022. Interventions: Patients were randomized 1:1 to standard of care plus pacritinib (400 mg per os on day 1 followed by 200 mg twice daily on days 2-14) vs placebo, for 14 days. Main Outcomes and Measures: The primary end point was death or need for invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) by day 28. All-cause mortality and safety were also assessed. Results: A total of 200 patients were randomized to pacritinib (99 patients; 56 men [56.6%]; median [range] age, 60 [19-87] years) or placebo (101 patients; 64 men [63.4%]; median [range] age 59 [28-94] years). The percentage requiring supplementary oxygen was 99.0% (98 patients) in the pacritinib group vs 98.0% (99 patients) in the placebo group. The percentage who progressed to IMV, ECMO, or death was 17.2% (17 patients) in the pacritinib group vs 22.8% (23 patients) in the placebo group (odds ratio, 0.62; 95% CI, 0.28-1.35; P = .23). Among patients with elevated interleukin 6, the rate was 17.5% (11 of 63 patients) in the pacritinib group vs 30.4% (21 of 96 patients) in the placebo group. The adverse event rate was similar for pacritinib vs placebo (78.1% [75 patients] vs 80.2% [81 patients]), with no excess in infection (14.6% [14 patients] vs 19.8% [20 patients]), bleeding (8.3% [8 patients] vs 10.9% [11 patients]), or thrombosis (8.3% [8 patients] vs 7.9% [8 patients]). Rates of grade 3 or higher adverse events were lower with pacritinib than placebo (29.2% [28 patients] vs 40.6% [41 patients]). Conclusions and Relevance: The study did not meet its primary end point in patients with severe COVID-19. Subgroup analyses may indicate specific populations with hyperinflammation that could benefit from pacritinib, although further clinical trials would be needed to confirm these effects. Trial Registration: ClinicalTrials.gov Identifier: NCT04404361.

Discovery and mechanism of action of Thonzonium bromide from an FDA-approved drug library with potent and broad-spectrum inhibitory activity against main proteases of human coronaviruses.

Although the effective drugs or vaccines have been developed to prevent the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), their efficacy may be limited for the viral evolution and immune escape. Thus, it is urgently needed to develop the novel broad-spectrum antiviral agents to control the coronavirus disease 2019 (COVID-19) global pandemic. The 3C-like protease (3CLpro) is a highly conserved cysteine proteinase that plays a pivotal role in processing the viral polyprotein to create non-structural proteins (nsps) for replication and transcription of SARS-CoV-2, making it an attractive antiviral target for developing broad-spectrum antiviral agents against SARS-CoV-2. In this study, we identified Thonzonium bromide as an inhibitor of SARS-CoV-2 3CLpro with an IC50 value of 2.04 ± 0.25 µM by fluorescence resonance energy transfer (FRET)-based enzymatic inhibition assay from the FDA-approved drug library. Next, we determined the inhibitory activity of Thonzonium bromide analogues against SARS-CoV-2 3CLpro and analyzed their structure-activity relationship (SAR). Interestingly, Thonzonium bromide showed better inhibitory activity than other analogues. Further fluorescence quenching assay, enzyme kinetics analysis, circular dichroism (CD) analysis and molecular docking studies showed that Thonzonium bromide inhibited SARS-CoV-2 3CLpro activity by firmly occupying the catalytic site and inducing conformational changes of the protease. In addition, Thonzonium bromide didn't exhibit inhibitory activity on human chymotrypsin C (CTRC) and Dipeptidyl peptidase IV (DPP-IV), indicating that it had a certain selectivity. Finally, we measured the inhibitory activities of Thonzonium bromide against 3CLpro of SARS-CoV, MERS-CoV and HCoV-229E and found that it had the broad-spectrum inhibitory activity against the proteases of human coronaviruses. These results provide the possible mechanism of action of Thonzonium bromide, highlighting its potential efficacy against multiple human coronaviruses.

Combinations of Host- and Virus-Targeting Antiviral Drugs Confer Synergistic Suppression of SARS-CoV-2.

Three directly acting antivirals (DAAs) demonstrated substantial reduction in COVID-19 hospitalizations and deaths in clinical trials. However, these agents did not completely prevent severe illness and are associated with cases of rebound illness and viral shedding. Combination regimens can enhance antiviral potency, reduce the emergence of drug-resistant variants, and lower the dose of each component in the combination. Concurrently targeting virus entry and virus replication offers opportunities to discover synergistic drug combinations. While combination antiviral drug treatments are standard for chronic RNA virus infections, no antiviral combination therapy has been approved for SARS-CoV-2. Here, we demonstrate that combining host-targeting antivirals (HTAs) that target TMPRSS2 and hence SARS-CoV-2 entry, with the DAA molnupiravir, which targets SARS-CoV-2 replication, synergistically suppresses SARS-CoV-2 infection in Calu-3 lung epithelial cells. Strong synergy was observed when molnupiravir, an oral drug, was combined with three TMPRSS2 (HTA) oral or inhaled inhibitors: camostat, avoralstat, or nafamostat. The combination of camostat plus molnupiravir was also effective against the beta and delta variants of concern. The pyrimidine biosynthesis inhibitor brequinar combined with molnupiravir also conferred robust synergistic inhibition. These HTA+DAA combinations had similar potency to the synergistic all-DAA combination of molnupiravir plus nirmatrelvir, the protease inhibitor found in paxlovid. Pharmacodynamic modeling allowed estimates of antiviral potency at all possible concentrations of each agent within plausible therapeutic ranges, suggesting possible in vivo efficacy. The triple combination of camostat, brequinar, and molnupiravir further increased antiviral potency. These findings support the development of HTA+DAA combinations for pandemic response and preparedness. IMPORTANCE Imagine a future viral pandemic where if you test positive for the new virus, you can quickly take some medicines at home for a few days so that you do not get too sick. To date, only single drugs have been approved for outpatient use against SARS-CoV-2, and we are learning that these have some limitations and may succumb to drug resistance. Here, we show that combinations of two oral drugs are better than the single ones in blocking SARS-CoV-2, and we use mathematical modeling to show that these drug combinations are likely to work in people. We also show that a combination of three oral drugs works even better at eradicating the virus. Our findings therefore bode well for the development of oral drug cocktails for at home use at the first sign of an infection by a coronavirus or other emerging viral pathogens.

Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma.

BACKGROUND: Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma. METHODS: We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed. RESULTS: Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group. CONCLUSIONS: Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).

Pazopanib Is a Potential Treatment for Coronavirus-Induced Lung Injuries.

Severe acute respiratory syndrome coronavirus 2, responsible for the severe acute respiratory syndrome known as COVID-19, has rapidly spread in almost every country and devastated the global economy and health care system. Lung injury is an early disease manifestation believed to be a major contributor to short- and long-term pathological consequences of COVID-19, and thus drug discovery aiming to ameliorate lung injury could be a potential strategy to treat COVID-19 patients. By inducing a severe acute respiratory syndrome-like pulmonary disease model through infecting A/J mice with murine hepatitis virus strain 1 (MHV-1), we show that i.v. administration of pazopanib ameliorates acute lung injuries without affecting MHV-1 replication. Pazopanib reduces cell apoptosis in MHV-1-infected lungs. Furthermore, we also identified that pazopanib has to be given no later than 48 h after the virus infection without compromising the therapeutic effect. Our study provides a potential treatment for coronavirus-induced lung injuries and support for further evaluation of pazopanib in COVID-19 patients.

Tofacitinib in paediatric dermatoses: a narrative review.

Tofacitinib has revolutionized the treatment of numerous dermatological conditions in different age groups. However, evidence for its effectiveness, safety and tolerability in the paediatric population is limited. We performed a literature search, which showed that oral tofacitinib is a reliable option in refractory juvenile dermatomyositis, severe alopecia areata, atopic dermatitis and psoriasis. Topical tofacitinib is an effective option in vitiligo and halo naevus. The risk-benefit ratio should be assessed prior to consideration of this molecule. In this narrative review, we have attempted to present a summary of the evidence of using tofacitinib (oral and topical) in paediatric dermatoses.

Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern.

The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently transmitted, more virulent, and more able to escape naturally acquired and vaccine-induced immunity. Recently, the protease inhibitor Paxlovid® and the polymerase inhibitor molnupiravir, both targeting mutant-prone viral components, were approved for high-risk COVID-19 patients. Nevertheless, effective therapeutics to treat COVID-19 are urgently needed, especially small molecules acting independently of VoCs and targeting genetically stable cellular pathways which are crucial for viral replication. Pamapimod is a selective inhibitor of p38 Mitogen-Activated Protein Kinase alpha (p38 MAPKα) that has been extensively clinically evaluated for the treatment of rheumatoid arthritis. Signaling via p38 has recently been described as a key pathway for the replication of SARS-CoV-2. Here, we reveal that the combination of pamapimod with pioglitazone, an anti-inflammatory and approved drug for the treatment of type 2 diabetes, possesses potent and synergistic activity to inhibit SARS-CoV-2 replication in vitro. Both drugs showed similar antiviral potency across several cultured cell types and similar antiviral activity against SARS-CoV-2 Wuhan type, and the VoCs Alpha, Beta, Gamma, Delta, and Omicron. These data support the combination of pamapimod and pioglitazone as a potential therapy to reduce duration and severity of disease in COVID-19 patients, an assumption currently evaluated in an ongoing phase II clinical study.