piperidines and Enterovirus-Infections

Rituximab is a well-established component of treatment regimens for B-cell non-Hodgkin lymphoma. Rituximab binds the CD20 antigen on the surface of B lymphocytes, causing an enhanced clearance of malignant and benign B cells. Thus, rituximab leads to depletion of normal B lymphocytes as well, which can cause substantial immunodeficiency. Ibrutinib inhibits the Bruton tyrosine kinase and thereby B-cell activity. It is used for the treatment of different B-lymphocyte malignancies, such as mantle cell lymphoma. Recently, the combination of both drugs has been tested in various clinical scenarios.. We present a case of disseminated enterovirus infection resulting from combined rituximab and ibrutinib maintenance treatment in a 57-year-old Caucasian patient. with mantle cell lymphoma. Initially presenting with myositis symptoms, further diagnostic investigation revealed myocarditis, enteritis, myeloencephalitis, and hepatitis. These organ manifestations led to potentially life-threatening complications such as rhabdomyolysis, delirium, and heart rhythm disturbances. After treatment with high-dose intravenous immunoglobulins, virus clearance was achieved and organ functions could be restored.. This case emphasizes the risk of combined therapy with rituximab/ibrutinib for severe immune-related side effects with the necessity of continuous patient monitoring. High-dose intravenous therapy should be considered as treatment for severe enterovirus infection. In severe enterovirus infections, we recommend subtyping for the development of efficient preventive and therapeutic strategies.

Topics: Adenine; Adult; Antigens, CD20; Enterovirus Infections; Humans; Lymphoma, Mantle-Cell; Middle Aged; Piperidines; Rituximab

Antivirals against enterovirus 71 (EV71) are urgently needed. We demonstrate that the novel enteroviral protease inhibitor (PI) SG85 and capsid binder (CB) vapendavir efficiently inhibit the in vitro replication of 21 EV71 strains/isolates that are representative of the different genogroups A, B, and C. The PI rupintrivir, the CB pirodavir, and the host-targeting compound enviroxime, which were included as reference compounds, also inhibited the replication of all isolates. Remarkably, the CB compound pleconaril was devoid of any anti-EV71 activity. An in silico docking study revealed that pleconaril-unlike vapendavir and pirodavir-lacks essential binding interactions with the viral capsid. Vapendavir and SG85 (or analogues) should be further explored for the treatment of EV71 infections. The data presented here may serve as a reference when developing yet-novel inhibitors.

Topics: Antiviral Agents; Benzimidazoles; Capsid; Capsid Proteins; Drug Resistance, Viral; Enterovirus A, Human; Enterovirus Infections; Isoxazoles; Molecular Docking Simulation; Oximes; Phenylalanine; Piperidines; Protease Inhibitors; Protein Binding; Pyridazines; Pyrrolidinones; Sulfonamides; Valine; Virus Replication

A series of substituted heteroaromatic piperazine and piperidine derivatives were found through virtual screening based on the structure of human enterovirus 71 capsid protein VP1. The preliminary biological evaluation revealed that compounds 8e and 9e have potent activity against EV71 and Coxsackievirus A16 with low cytotoxicity.

Topics: Animals; Antiviral Agents; Capsid Proteins; Chlorocebus aethiops; Enterovirus A, Human; Enterovirus Infections; Humans; Piperazines; Piperidines; Vero Cells

Intranasal (i. n.) infection with 10 LD50 of Sindbis virus caused acute encephalomyelitis and death in ABD2F1 mice 3-7 days post infection (p.i.). Histologic lesions were found in the CNS, pancreas. liver, parotid glands, exorbital lacrimal glands, lymphoid organs and kidneys. Repeated oral administration of the anticholinergic anti-Parkinson drug Norakin protected infected animals from death in a dose-dependent manner when treatment was started prior to but not after virus inoculation. The maximum protective effect was achieved when the drug was administered twice daily at doses of 2.5 or 5.0 mg/kg body mass for at least 56 hr; single injections of the full daily dose were ineffective. Daily doses of greater than or equal to 25 mg/kg body mass had a reduced protective effect or failed to prevent mortality. Administration of Norakin up to doses of 300 mg/kg body mass per day to noninfected ABD2F1 mice were tolerated without obvious clinical or histological signs of illness over a period of 104 hr. Replication of sindbis virus in BHK 21/C13 cells was not inhibited by Norakin concentrations up to 10 micrograms/ml. In Mengo virus-infected mice Norakin did not exert any protective effect within the range of 1.25-50.0 mg/kg body mass when treatment started 1 hr before infection and has been continued twice daily over a period of 104 hr.

Topics: Animals; Antiparkinson Agents; Antiviral Agents; Cells, Cultured; Cricetinae; Enterovirus Infections; Mengovirus; Mice; Piperidines; Sindbis Virus; Togaviridae Infections; Virus Replication

Mengo virus has been described to cause, in dependence on the virus dose, lethal panencephalomyelitis and exocrine pancreatitis in mice after i.p. inoculation. Two immunosuppressive agents, cyclophosphamide and 1,3-bis(piperidinomethyl)-5-ethyl-5-phenyl-barbituric acid (ZIMET 176/68), were shown to potentiate Mengo virus infection as demonstrated by histopathology and enhanced mortality. Organotropism of Mengo virus did not change under the drug treatment. However, the histological lesions in brain, spinal cord and pancreas failed to exhibit any inflammatory reaction in case of cyclophosphamide, due to its antiphlogistic properties. Considering the mode of action of the drugs employed and the pathogenesis of Mengo virus infection in mice, it is concluded that in the system used both cyclophosphamide and ZIMET 176/68 exert their potentiating effects by interfering with primary virus-macrophage interaction.

Topics: Animals; Barbiturates; Brain; Cyclophosphamide; Enterovirus Infections; Immunosuppressive Agents; Lymphopenia; Mengovirus; Mice; Pancreas; Piperidines; Spinal Cord; Spleen

The effects of cyclophosphamide and 1,3-(piperidinomethyl)-5-phenyl-5-ethylbarbituric acid on certain flavi- and enterovirus infections in mice were studied. Differential enhancement of mortality rates after extraneural and, less markedly, intracerebral virus inoculation was noted. While depression of humoral and/or cell-mediated immunity is considered to be responsible for the effects observed in flavivirus infections, impaired function of the reticuloendothelial system seems to contribute mainly to the potentiation of Mengo virus infection by the immunodepressants used.

Topics: Animals; Arbovirus Infections; Barbiturates; Cyclophosphamide; Dengue; Disease Models, Animal; Encephalitis Viruses, Tick-Borne; Enterovirus Infections; Immunosuppressive Agents; Mengovirus; Mice; Piperidines; West Nile Fever