Low-dose oral administration of human interferon alpha can control the development of Theileria parva infection in cattle

Parasitology ◽  
1990 ◽  
Vol 101 (2) ◽  
pp. 201-209 ◽  
Author(s):  
A. S. Young ◽  
A. C. Maritim ◽  
D. P. Kariuki ◽  
D. A. Stagg ◽  
J. M. Wafula ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Oral Treatment ◽  
Human Interferon ◽  
Theileria Parva ◽  
Once Daily ◽  
Treatment Groups ◽  
Control Calf ◽  
Dose Oral ◽  
Homologous Challenge

Two natural human interferon alpha preparations, (nHuIFN-μ [Cantell]) and (Nhuifn-μ [ISI]), were used for the oral treatment of cattle experimentally infected with Theileria parva parva. In the first experiment, 8 Friesian bulls were inoculated with a 1 in 10 dilution of a sporozoite stabilate of T. p. parva (Marikebuni) stock. Four of the cattle were treated daily with 1 international unit/kg body weight (i.u./kg bwt) of nHuIFN-μ (Cantell) from day –2 to day 8 p.i. None of the 4 calves given IFN developed clinical theileriosis, but 3 of the 4 control calves died of theileriosis while the fourth had a mild infection. Three of 4 treated calves and the 1 surviving control calf developed a detectable antibody response to T. p. parva schizont antigen but, on challenged with a 10-fold higher dose of stabilate, the surviving control animal and only 1 of the 4 treated calves proved to be immune. In a second experiment, 4 groups of 4 calves were inoculated with the same stabilate dilution. Three treatment groups were given either 1 i.u. nHuIFN-μ (Cantell), 1 i.u. nHuIFN-μ (ISI), or 10 i.u. nHuIFN-μ (ISI)/kg bwt from day –2 to day 8 p.i. once daily and the fourth group were controls. Clinical theileriosis occurred in 2 controls, 2 calves given 10 i.u. nHuINF-μ (ISI), 1 calf given 1 i.u. nHuIFN-μ (ISI) and no calves given 1 i.u. nHuIFN-μ (Cantell)/kg bwt. Of these, 2, 1, 0 and 0 cattle died in the respective groups. All the surviving cattle proved to be immune on homologous challenge with 10-fold higher dose of stabilate except the 2 cattle which did not develop high antibody responses. A third experiment using an undiluted challenge of T. p. parva (Muguga) sporozoite stabilate (10α) on 8 steers. Four steers were treated with 1 i.u. nHuIFN-α (Cantell)/kg bwt and 4 were controls. All calves developed acute theileriosis and the experiment was terminated. Cells of the C2 lymphoblastoid cell line, infected with T. p. parva (Muguga) schizonts, were cultured in vitro with various concentrations (0-01-100 i.u./ml) of nHuIFN-a (Cantell). The IFN appeared to have no effect on host cell or parasite developmental variables when compared to untreated control cultures.

Abstract 10210: Effects of Chronic Treatment With the Phosphodiesterase-5 Inhibitors Sildenafil and Tadalafil on Platelet Aggregation in Patients With Eisenmenger Syndrome

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Nair Y Maeda ◽  
Mariana M Clavé ◽  
Sonia M Mesquita ◽  
Sergio P Bydlowski ◽  
Antonio A Lopes
Keyword(s):  
Platelet Count ◽  
Platelet Aggregation ◽  
Platelet Activation ◽  
Oral Treatment ◽  
Impedance Method ◽  
Treatment Groups ◽  
Phosphodiesterase 5 Inhibitors ◽  
Hemodynamic Improvement ◽  
Phosphodiesterase 5

Background: Patients with pulmonary arterial hypertension (PAH) associated with the Eisenmeger syndrome (ES) frequently have decreased platelet counts and aggregation. This is probably due to chronic endogenous platelet activation and consumption associated with hypoxemia and blood hyperviscosity, with "exhausted" platelets present in circulation. When platelets are analyzed in vitro, decreased response to aggregation inducing agents is generally observed. Purpose: Since phosphodiesterase-5 inhibitors (PDE-5Is) are frequently used in the management of PAH, we investigated, the effects of sildenafil and tadalafil on in vitro platelet aggregation (PA) in adults with ES. Methods: Twenty-three naïve patients aged 28 (22-47) years (median and interquartile range) were randomly assigned to oral treatment with sildenafil (20mg t.i.d., N=11) or tadalafil (single daily dose of 40mg, N=12). Baseline spO 2 , Ht, Hb level and platelet count were 87% (80-92%), 52% (49-60%), 17 (16-20)g/dL and 205 (158-248) x 10 3 pl/μL, respectively. Data were collected at baseline, 90 and 180 days of treatment. Whole blood PA was analyzed by the impedance method. Results are expressed as percent normal. Results: Treatment with PDE-5Is resulted in decrease Ht and Hb level (p<0.001), but no change in platelet count. When patients analyzed as a whole (N=23), ADP-induced PA was 44% (23-91%), 54% (23-87%) and 71% (42-124%) respectively at baseline, 90 and 180 days (p=0.029). Collagen-induced PA was 55% (23-138%), 96% (67-162%) and 146% (62-187%), respectively (p=0.041). When treatment groups were investigated separately at 180 days, collagen-induced PA was 2.7 (1.1-11.1) times baseline in sildenafil-treated patients, and 1.8 (0.6-4.2) times baseline in the tadalafil group. ADP-induced PA was 2.2 (1.3-4.8) times baseline in the sildenafil , but 1.0 (0.7-3.6) time baseline for tadalafil. Conclusion: In ES patients, PDE-5Is therapy is associated with improvement of PA. This may be due to decelerated endogenous platelet activation associated with hemodynamic improvement. However, particularly for sildenafil, some patients may become transiently at a higher risk of thrombotic events, as PA increases far above normal levels.

The effects of human interferon-alpha upon in vitro canine immune responses

1988 ◽  
Vol 19 (3-4) ◽  
pp. 185-196 ◽  
Author(s):  
Steven Krakowka ◽  
Joseph M. Cummins ◽  
Susan S. Ringler
Keyword(s):  
Immune Responses ◽  
Interferon Alpha ◽  
Human Interferon

scholarly journals Oral treatment of transmissible gastroenteritis with natural human interferon alpha: A field study

1995 ◽  
Vol 45 (3-4) ◽  
pp. 355-360 ◽  
Author(s):  
Joseph M. Cummins ◽  
Richard E. Mock ◽  
Bradford W. Shive ◽  
Steven Krakowka ◽  
Alan B. Richards ◽  
...  
Keyword(s):  
Field Study ◽  
Interferon Alpha ◽  
Oral Treatment ◽  
Human Interferon ◽  
Transmissible Gastroenteritis

scholarly journals Synergistic Interferon Alpha-based Drug Combinations Inhibit SARS-CoV-2 and other viral Infections in Vitro

2021 ◽  
Author(s):  
Aleksandr Ianevski ◽  
Rouan Yao ◽  
Eva Zusinaite ◽  
Laura Lello ◽  
Sainan Wang ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Influenza A ◽  
Viral Infections ◽  
Human Lung ◽  
Therapeutic Potential ◽  
A549 Cells ◽  
Drug Dose ◽  
Human Interferon ◽  
Lung Epithelial

Abstract There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. In the present study, we found that recombinant human interferon-alpha (IFNa) triggered cell intrinsic and extrinsic antiviral responses and reduced replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human lung epithelial Calu-3 cells. However, IFNa alone was insufficient to completely abolish SARS-CoV-2 replication. Combinations of IFNa with camostat, remdesivir, EIDD-2801, cycloheximide or convalescent serum showed strong synergy and effectively inhibited SARS-CoV-2 infection. Additionally, we demonstrated synergistic antiviral activity of IFNa2a with pimodivir against influenza A virus (FluAV) infection in human lung epithelial A549 cells, as well as of IFNa2a with lamivudine against human immunodeficiency virus 1 (HIV-1) infection in human TZM-bl cells. Our results indicate that IFNa2a-based combinational therapies help to reduce drug dose and improve efficacy in comparison with monotherapies, making them attractive targets for further pre-clinical and clinical development.

The Novel Potent Pan-Deacetylase (DAC) Inhibitor, Panobinostat (LBH589), Markedly Enhances the Anti-Myeloma Effects of Chemotherapy In Vitro and In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2520-2520
Author(s):  
Richard A. Campbell ◽  
Eric Sanchez ◽  
Jeffrey Steinberg ◽  
Michael Share ◽  
Joseph Wang ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Low Dose ◽  
Liposomal Doxorubicin ◽  
Single Agent ◽  
Mouse Serum ◽  
Once Daily ◽  
Treatment Groups

Abstract Deacetylase (DAC) inhibitors represent a new class of anti-cancer therapeutics that inhibit DAC enzymes and have been shown to have multiple effects in tumor cell lines including decreased oncoprotein expression (Bcr-Abl, HER-2), decreased angiogenesis, induction of apoptosis, induction of cell-cycle arrest, and decreased tumor cell motility and invasion. Panobinostat (LBH589), a novel cinnamic hydroxamic acid analogue with potent histone DAC inhibitor activity, has recently been shown to have the potential to treat a wide range of solid and hematological malignancies including multiple myeloma (MM). In this study, we first evaluated the in vitro anti-MM effects of panobinostat alone and in combination with doxorubicin or melphalan using the MM cell lines RPMI8226, U266 and MM1S. Cells treated with the combinations of panobinostat + doxorubicin and panobinostat + melphalan showed marked synergistic anti-MM effects as determined by measuring proliferation with the MTS assay compared to treatment with single agent and untreated cells. Next, we evaluated the anti-MM effects of panobinostat alone and in these combinations in vivo using one of our SCID-hu mouse models of human MM, LAGλ-1. Each SCID mouse was implanted with a 2.0 - 4.0 mm3 LAGλ-1 into the left superficial gluteal muscle. In our panobinostat single agent study, tumors were allowed to grow for 7 days at which time human IgG levels were detectable in the mouse serum, and mice were blindly assigned into panobinostat treatment groups. Panobinostat was administered via intraperitoneal (i.p.) injection once daily five times per week at 5, 10 and 20 mg/kg. Control mice were given sterile normal saline as vehicle. Mice receiving panobinostat showed marked inhibition of tumor growth (10 mg/kg, P &lt; 0.003; 20 mg/kg, P &lt; 0.009) and reduction of paraprotein levels (10 mg/kg, P &lt; 0.0025; 20 mg/kg, P &lt; 0.015) compared to mice receiving vehicle. Next, we evaluated the combination of low-dose panobinostat (5 mg/kg) with low doses of either liposomal doxorubicin (1 mg/kg) or melphalan (3 mg/kg) i.p. in mice bearing LAGλ-1. Tumors were allowed to grow for 10 days at which time human IgG levels were detectable in the mouse serum, and mice were blindly assigned into treatment groups. Panobinostat was administered as above, and liposomal doxorubicin was injected once daily for three consecutive days weekly and melphalan once weekly. Mice treated with the combination of panobinostat + liposomal doxorubicin showed markedly smaller tumors and reduced hIgG levels compared to treatment with the DAC inhibitor alone, and treatment with liposomal doxorubicin as a single agent produced no anti-MM effects. Mice bearing LAGλ-1 treated with the combination of low-dose panobinostat + low-dose melphalan also showed markedly smaller tumors and decreased hIgG levels compared to treatment with panobinostat alone whereas mice receiving melphalan alone showed similar results to vehicle-treated animals. These promising results support the further clinical development of panobinostat and suggest that combining this DAC inhibitor with low-dose chemotherapy (liposomal doxorubicin or melphalan) may enhance the efficacy of this novel agent for the treatment of MM patients.

scholarly journals The Fungal Cyp51 Inhibitor VT-1129 Is Efficacious in an Experimental Model of Cryptococcal Meningitis

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
Edward P. Garvey ◽  
Stephen R. Brand ◽  
Xin Xu ◽  
...  
Keyword(s):  
Cryptococcal Meningitis ◽  
Survival Benefit ◽  
Oral Treatment ◽  
Immunocompromised Patients ◽  
Once Daily ◽  
Content Type ◽  
Fungal Burden ◽  
The Brain

ABSTRACTCryptococcal meningitis is a significant cause of morbidity and mortality in immunocompromised patients. VT-1129 is a novel fungus-specific Cyp51 inhibitor with potentin vitroactivity againstCryptococcusspecies. Our objective was to evaluate thein vivoefficacy of VT-1129 against cryptococcal meningitis. Mice were inoculated intracranially withCryptococcus neoformans. Oral treatment with VT-1129, fluconazole, or placebo began 1 day later and continued for either 7 or 14 days, and brains and plasma were collected on day 8 or 15, 1 day after therapy ended, and the fungal burden was assessed. In the survival study, treatment continued until day 10 or day 28, after which mice were monitored off therapy until day 30 or day 60, respectively, to assess survival. The fungal burden was also assessed in the survival arm. VT-1129 plasma and brain concentrations were also measured. VT-1129 reached a significant maximal survival benefit (100%) at a dose of 20 mg/kg of body weight once daily. VT-1129 at doses of ≥0.3 mg/kg/day and each dose of fluconazole significantly reduced the brain tissue fungal burden compared to that in the control after both 7 and 14 days of dosing. The fungal burden was also undetectable in most mice treated with a dose of ≥3 mg/kg/day, even ≥20 days after dosing had stopped, in the survival arm. In contrast, rebounds in fungal burden were observed with fluconazole. These results are consistent with the VT-1129 concentrations, which remained elevated long after dosing had stopped. These data demonstrate the potential utility of VT-1129 to have a marked impact in the treatment of cryptococcal meningitis.

scholarly journals In Vivo Activities of Evernimicin (SCH 27899) against Vancomycin-Susceptible and Vancomycin-Resistant Enterococci in Experimental Endocarditis

2000 ◽  
Vol 44 (10) ◽  
pp. 2733-2739 ◽  
Author(s):  
Maria Souli ◽  
Claudie Thauvin-Eliopoulos ◽  
George M. Eliopoulos
Keyword(s):  
Continuous Infusion ◽  
Once Daily ◽  
Treatment Groups ◽  
Final Density ◽  
Vancomycin Resistant Enterococci ◽  
Potential Efficacy ◽  
Vancomycin Resistant ◽  
To Receive

ABSTRACT To assess the potential efficacy of evernimicin (SCH 27899) against serious enterococcal infections, we used a rat model of aortic valve endocarditis established with either a vancomycin-susceptibleEnterococcus faecalis or a vancomycin-resistantEnterococcus faecium strain. Animals infected with either one of the test strains were assigned to receive no treatment (controls) or 5-day therapy with one of the following regimens: evernimicin 60-mg/kg of body weight intravenous (i.v.) bolus once daily, 60-mg/kg i.v. bolus twice daily (b.i.d.), 60 mg/kg/day i.v. by continuous infusion, or 120 mg/kg/day i.v. by continuous infusion. These regimens were compared with vancomycin at 150 mg/kg/day. In animals infected with E. faecalis, evernimicin at 120 mg/kg/day by continuous infusion significantly reduced bacterial counts in vegetations (final density, 5.75 ± 3.38 log10CFU/g) compared with controls (8.51 ± 1.11 log10CFU/g). In animals infected with 0.5 ml of an 8 × 107-CFU/ml inoculum of the vancomycin-resistant E. faecium, both 60-mg/kg bolus once a day and b.i.d. dose regimens of evernimicin were very effective (viable counts, 3.45 ± 1.44 and 3.81 ± 1.98 log10 CFU/g, respectively). Vancomycin was unexpectedly active against infections induced with that inoculum. In animals infected with a 109-CFU/ml inoculum of the vancomycin-resistant E. faecium, the evernimicin 60-mg/kg i.v. bolus b.i.d. reduced viable counts in vegetations compared with controls (6.27 ± 1.63 versus 8.34 ± 0.91 log10 CFU/g; P < 0.05), whereas vancomycin was ineffective. Although resistant colonies could be selected in vitro, we were not able to identify evernimicin-resistant clones from cardiac vegetations. An unexplained observation from these experiments was the great variability in final bacterial densities within cardiac vegetations from animals in each of the evernimicin treatment groups.

scholarly journals 4'-Fluorouridine is a broad-spectrum orally efficacious antiviral blocking respiratory syncytial virus and SARS-CoV-2 replication

2021 ◽  
Author(s):  
Julien Sourimant ◽  
Carolin Lieber ◽  
Megha Aggarwal ◽  
Robert Cox ◽  
Josef Wolf ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Broad Spectrum ◽  
Rna Virus ◽  
Oral Treatment ◽  
The Elderly ◽  
Virus Infections ◽  
Once Daily ◽  
Syncytial Virus ◽  
Well Differentiated

The COVID-19 pandemic has underscored the critical need for broad-spectrum therapeutics against respiratory viruses. Respiratory syncytial virus (RSV) is a major threat to pediatric patients and the elderly. We describe 4'-fluorouridine (4'-FlU, EIDD-2749), a ribonucleoside analog that inhibits RSV, related RNA viruses, and SARS-CoV-2 with high selectivity index in cells and well-differentiated human airway epithelia. Polymerase inhibition in in vitro RdRP assays established for RSV and SARS-CoV-2 revealed transcriptional pauses at positions i or i+3/4 post-incorporation. Once-daily oral treatment was highly efficacious at 5 mg/kg in RSV-infected mice or 20 mg/kg in ferrets infected with SARS-CoV-2 WA1/2020 or variant-of-concern (VoC) isolate CA/2020, initiated 24 or 12 hours after infection, respectively. These properties define 4'-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2 and related RNA virus infections.

scholarly journals Efficient treatment of experimental cerebral malaria by an artemisone-SMEDDS system: impact of application route and dosing frequency

2021 ◽  
Author(s):  
Johanna Zech ◽  
Nadeen Salaymeh ◽  
Nicholas H. Hunt ◽  
Karsten Mäder ◽  
Jacob Golenser
Keyword(s):  
Cerebral Malaria ◽  
Oral Treatment ◽  
Aqueous Solubility ◽  
Intranasal Delivery ◽  
Experimental Cerebral Malaria ◽  
Efficient Treatment ◽  
Once Daily ◽  
Dosing Frequency ◽  
The Impact

Artemisone (ART) has been successfully tested in vitro and in animal models against several diseases. However, its poor aqueous solubility and limited chemical stability are serious challenges. We developed a self-microemulsifying drug delivery system (SMEDDS) that overcomes these limitations. Here, we demonstrate the efficacy of this formulation against experimental cerebral malaria in mice and the impact of its administration using different routes (gavage, intranasal delivery and parenteral injections) and frequency on the efficacy of the treatment. The minimal effective oral dose was 20 mg/kg. We found that splitting a dose of 20 mg/kg ART given every 24 hours, by administering two doses of 10 mg/kg each every 12 hours, was highly effective and gave far superior results compared to 20 mg/kg once daily. We obtained the best results with nasal treatment, oral treatment was ranked second and the least effective route of administration was intraperitoneal injection. A complete cure of experimental cerebral malaria could be achieved through choosing the optimal route of application, dose and dosing interval. Altogether, the developed formulation combines easy manufacturing with high stability, and is a successful and very versatile carrier for the delivery of ART in treatment of human severe malaria.

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