BISTABILITY AND LONG-TERM CURE IN A WITHIN-HOST MODEL OF HEPATITIS C

2011 ◽  
Vol 19 (04) ◽  
pp. 533-550 ◽  
Author(s):  
SWATI DEBROY ◽  
BENJAMIN M. BOLKER ◽  
MAIA MARTCHEVA
Keyword(s):  
Hepatitis C ◽  
Term Treatment ◽  
Clinical Settings ◽  
Duration Of Treatment ◽  
Short Term Treatment ◽  
Biologically Relevant ◽  
Ode Models ◽  
Permanent Cure ◽  
Extinction Threshold ◽  
Parameter Values

Treatment of hepatitis C virus (HCV) is lengthy, expensive and fraught with side-effects, succeeding in only 50% of treated patients. In clinical settings, short-term treatment response (so-called sustained virological response (SVR)) is used to predict prolonged viral suppression. Although ordinary differential equation (ODE) models for within-host HCV infection have illuminated the mechanisms underlying treatment with interferon (IFN) and ribavirin (RBV), they have difficulty producing SVR without the introduction of an external extinction threshold. Here we show that bistability in an existing ODE model of HCV, which occurs when infected hepatocytes proliferate sufficiently faster than uninfected hepatocytes, can produce SVR without an external extinction threshold under biologically relevant conditions. The model can produce all clinically observed patient profiles for realistic parameter values; it can also be used to estimate the efficacy and/or duration of treatment that will ensure permanent cure for a particular patient.

scholarly journals Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 in Vitro

2021 ◽  
Author(s):  
Karen A. Gammeltoft ◽  
Yuyong Zhou ◽  
Carlos R. Duarte Hernandez ◽  
Andrea Galli ◽  
Anna Offersgaard ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
Viral Suppression ◽  
Term Treatment ◽  
Short Term ◽  
Short Term Treatment ◽  
Direct Acting Antiviral ◽  
Human Lung Carcinoma

Antivirals targeting SARS-CoV-2 could improve treatment of COVID-19. We evaluated efficacy of clinically relevant hepatitis C virus (HCV) NS3 protease inhibitors (PI) against SARS-CoV-2 and their interactions with remdesivir, the only direct-acting antiviral approved for COVID-19 treatment. HCV PI showed differential potency in short-term treatment assays based on detection of SARS-CoV-2 Spike protein in VeroE6 cells. Linear PI boceprevir, telaprevir and narlaprevir had 50% effective concentrations (EC50) of ∼40 μM. Among macrocyclic PI, simeprevir had the highest (EC50 15 μM) and glecaprevir the lowest (EC50 >178 μM) potency, with paritaprevir, grazoprevir, voxilaprevir, vaniprevir, danoprevir and deldeprevir in between. Acyclic PI asunaprevir and faldaprevir had EC50 of 72 and 23 μM, respectively. ACH-806, inhibiting the HCV NS4A protease cofactor, had EC50 of 46 μM. Similar and slightly increased PI potencies were found in human hepatoma Huh7.5 cells and human lung carcinoma A549-hACE2 cells, respectively. Selectivity indexes based on antiviral and cell viability assays were highest for linear PI. In short-term treatments, combination of macrocyclic but not linear PI with remdesivir showed synergism in VeroE6 and A549-hACE2 cells. Longer-term treatment of infected VeroE6 and A549-hACE2 cells with 1-fold EC50 PI revealed minor differences in barrier to SARS-CoV-2 escape. Viral suppression was achieved with 3- to 8-fold EC50 boceprevir or 1-fold EC50 simeprevir or grazoprevir, but not boceprevir, in combination with 0.4- to 0.8-fold EC50 remdesivir; these concentrations did not lead to viral suppression in single treatments. This study could inform development and application of protease inhibitors for optimized antiviral treatments of COVID-19.

scholarly journals Arrhythmic safety of hydroxychloroquine in COVID-19 patients from different clinical settings

EP Europace ◽  
2020 ◽  
Vol 22 (12) ◽  
pp. 1855-1863 ◽  
Author(s):  
Alessio Gasperetti ◽  
Mauro Biffi ◽  
Firat Duru ◽  
Marco Schiavone ◽  
Matteo Ziacchi ◽  
...  
Keyword(s):  
Intensive Care ◽  
Term Treatment ◽  
Hospital Treatment ◽  
Clinical Settings ◽  
Qtc Interval ◽  
Qtc Prolongation ◽  
Short Term Treatment ◽  
Therapy Regimen ◽  
Qtc Interval Prolongation ◽  
Overall Mortality

Abstract Aims The aim of the study was to describe ECG modifications and arrhythmic events in COVID-19 patients undergoing hydroxychloroquine (HCQ) therapy in different clinical settings. Methods and results COVID-19 patients at seven institutions receiving HCQ therapy from whom a baseline and at least one ECG at 48+ h were available were enrolled in the study. QT/QTc prolongation, QT-associated and QT-independent arrhythmic events, arrhythmic mortality, and overall mortality during HCQ therapy were assessed. A total of 649 COVID-19 patients (61.9 ± 18.7 years, 46.1% males) were enrolled. HCQ therapy was administrated as a home therapy regimen in 126 (19.4%) patients, and as an in-hospital-treatment to 495 (76.3%) hospitalized and 28 (4.3%) intensive care unit (ICU) patients. At 36–72 and at 96+ h after the first HCQ dose, 358 and 404 ECGs were obtained, respectively. A significant QT/QTc interval prolongation was observed (P < 0.001), but the magnitude of the increase was modest [+13 (9–16) ms]. Baseline QT/QTc length and presence of fever (P = 0.001) at admission represented the most important determinants of QT/QTc prolongation. No arrhythmic-related deaths were reported. The overall major ventricular arrhythmia rate was low (1.1%), with all events found not to be related to QT or HCQ therapy at a centralized event evaluation. No differences in QT/QTc prolongation and QT-related arrhythmias were observed across different clinical settings, with non-QT-related arrhythmias being more common in the intensive care setting. Conclusion HCQ administration is safe for a short-term treatment for patients with COVID-19 infection regardless of the clinical setting of delivery, causing only modest QTc prolongation and no directly attributable arrhythmic deaths.

Meta-analysis of double-blind placebo-controlled trials of antidepressants and benzodiazepines for patients with panic disorders

1991 ◽  
Vol 21 (4) ◽  
pp. 991-998 ◽  
Author(s):  
Greg Wilkinson ◽  
Matteo Balestrieri ◽  
Mirella Ruggeri ◽  
Cesario Bellantuono
Keyword(s):  
Active Treatment ◽  
Meta Analysis ◽  
Term Treatment ◽  
Controlled Trials ◽  
Clinical Settings ◽  
Short Term ◽  
Short Term Treatment ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Panic Disorders

SYNOPSISMeta-analysis of 19 double-blind placebo-controlled trials of antidepressants (N = 13) and benzodiazepines (N = 6) for patients with panic disorders showed that active treatment had 25% greater success rate than placebo over a mean duration of 14 weeks. There were no statistically significant differences observed between treatment sub-groups (antidepressants – mean duration 16 weeks; and benzodiazepines – mean duration 7 weeks). On this basis antidepressants and benzodiazepines prescribed in clinical settings are likely to be equally effective in the short-term treatment of people with panic disorders.

Placebo controlled studies in acute schizophrenia – an issue of concern

1994 ◽  
Vol 9 (4) ◽  
pp. 165-173 ◽  
Author(s):  
A Delini-Stula ◽  
D Berdah-Tordjman
Keyword(s):  
Scientific Evidence ◽  
A Priori ◽  
Term Treatment ◽  
Drop Out ◽  
Assessment Instruments ◽  
Duration Of Treatment ◽  
Short Term Treatment ◽  
Improvement Rate ◽  
Acute Schizophrenia ◽  
Reported Data

SummaryPlacebo controlled studies in patients suffering from exacerbation eg acute productive episode of schizophrenia and performed in the period between 1963-1993 are reviewed and analysed with respect to study designs; size of studies; improvement rate under placebo and drop-outs due to inefficacy under placebo. The aim of the analysis was to find out if the reported data permit some realistic estimates for a priori assumptions needed for proper planning of such studies, particularly in view of the numerous ethical and other difficulties which their performance encounters in the practice. Literature research revealed a rather limited number of rigorous, placebo-controlled, monotherapy studies (without intermittent or concomitant additional neuroleptics) in acute schizophrenia. Across comparison of findings from these studies was difficult due to differences in duration of treatment, assessment instruments and criteria of efficacy which illustrated a lack of methodological standards for studies in this indication. The improvement rate under placebo, if measured by Clinical Global Assessment (CGI) appeared, however, not to exceed 25%, whereas BPRS score reduction as efficacy criterion mostly provided higher response rates (up to 40%). Of interest however, is the finding that the response rate to conventional neuroleptics at the end of 4-6 weeks of treatment in some studies hardly exceeded 40%. The most sensitive measure of placebo effect seemed to be the drop-out rate due to inefficacy (up to 100%) and it is suggested to consider this measure and the survival analysis approach in designing future studies. The review demonstrated many unresolved methodological problems in testing antipsychotic drugs in acute schizophrenia and, particularly, the need of scientific evidence of validity and sensitivity of measures of antipsychotic efficacy. The findings reported up to now do not offer cues for rational estimates of the effect size differences between placebo and active drugs after short-term treatment in acute schizophrenia.

scholarly journals Comparison of antihyperglycemic effects of creatine and metformin in type II diabetic patients

2009 ◽  
Vol 32 (6) ◽  
pp. 322 ◽  
Author(s):  
B Rocic ◽  
N Bedernjak Bajuk ◽  
P Rocic ◽  
D S Weber ◽  
J Boras ◽  
...  
Keyword(s):  
Term Treatment ◽  
Type Ii ◽  
Short Term ◽  
Duration Of Treatment ◽  
Short Term Treatment ◽  
C Peptide ◽  
Study Results ◽  
Type Ii Diabetics ◽  
Upper Level

Purpose: To compare the antihyperglycemic effects of metformin and creatine in recently detected type II diabetics in a short-term clinical study. Methods: In a 14 day simmetrically randomized crossover study, recently detected type II diabetics received either creatine (2x3 g/day) or metformin (2x500 mg/day) for five days, followed by two days of washout, followed by cross-over to the opposite treatment for the next five days. Fasting and post-prandial (-15, 60, 90, 120, 180 and 240 min) blood glucose, insulin, c-peptide, creatine and lactate were measured every other day for the duration of treatment, and HbA1c only at the begining and at the end of the study. Results: Both creatine and metformin decreased glucose concentrations to similar levels at all time points vs. basal glucose values [-15, 60, 90, 120, 180, and 240 min]: 11.1±0.75 vs 9.1±0.55a vs 8.8±0.59b, 14.4±0.6 vs 12.9±0.47a vs 13.1±0.55a, 14.8±0.58 vs 13.0±0.46b vs 13.3±0.55a, 14.1±0.6 vs 11.9±0.42b vs 12.5±0.51a, 12.2±0.6 vs 9.6±0.36c vs 9.9±0.38c, and 10.1±0.47 vs 7.8±0.36c vs 8.4±0.4b; (aP < 0.05; bP < 0.01; cP < 0.001 vs. basal glucose values). Neither treatment altered insulin, c-peptide, or HbA1c. Lactate varied during the day, but never reached the upper level of the safety reference range. Conclusion: Short-term treatment with creatine and metformin elicits similar glucose lowering effects in recently detected type II diabetics. Further studies are necessary to determine the effect of creatine on long-term glucose and insulin regulation. Purpose: To compare the antihyperglycemic effects of metformin and creatine in recently detected type II diabetics in a short-term clinical study. Methods: In a 14 day simmetrically randomized crossover study, recently detected type II diabetics received either creatine (2x3 g/day) or metformin (2x500 mg/day) for five days, followed by two days of washout, followed by cross-over to the opposite treatment for the next five days. Fasting and post-prandial (-15, 60, 90, 120, 180 and 240 min) blood glucose, insulin, c-peptide, creatine and lactate were measured every other day for the duration of treatment, and HbA1c only at the begining and at the end of the study. Results: Both creatine and metformin decreased glucose concentrations to similar levels at all time points vs. basal glucose values [-15, 60, 90, 120, 180, and 240 min]: 11.1±0.75 vs 9.1±0.55a vs 8.8±0.59b, 14.4±0.6 vs 12.9±0.47a vs 13.1±0.55a, 14.8±0.58 vs 13.0±0.46b vs 13.3±0.55a, 14.1±0.6 vs 11.9±0.42b vs 12.5±0.51a, 12.2±0.6 vs 9.6±0.36c vs 9.9±0.38c, and 10.1±0.47 vs 7.8±0.36c vs 8.4±0.4b; (aP < 0.05; bP < 0.01; cP < 0.001 vs. basal glucose values). Neither treatment altered insulin, c-peptide, or HbA1c. Lactate varied during the day, but never reached the upper level of the safety reference range. Conclusion: Short-term treatment with creatine and metformin elicits similar glucose lowering effects in recently detected type II diabetics. Further studies are necessary to determine the effect of creatine on long-term glucose and insulin regulation.

Sustained Response After Short-Medium-Term Treatment With Eltrombopag In Patients With ITP

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2323-2323 ◽  
Author(s):  
Tomás José González-López ◽  
José Ramón González-Porras ◽  
Maryam Arefi ◽  
Erik De Cabo ◽  
Blanca Sanchez Gonzalez ◽  
...  
Keyword(s):  
Platelet Count ◽  
Disease Onset ◽  
Term Treatment ◽  
Additional Treatment ◽  
Concomitant Treatment ◽  
Short Term ◽  
Duration Of Treatment ◽  
Short Term Treatment ◽  
Platelet Counts ◽  
Specific Subset

Abstract Introduction Eltrombopag is an oral, non-peptide thrombopoietic receptor-agonist (TPO-RA). In chronic immune thrombocytopenic purpura (ITP) randomized–controlled trials proved to be effective, safe and well tolerated with reported response rates of 59%-88%. When eltrombopag is discontinued, platelet counts usually return to baseline within 2 weeks. However, certain patients may be able to discontinue TPO-RA and still maintain platelet counts above baseline without additional treatment. We report here 12 patients who presented sustained responses after discontinuing eltrombopag without substituting additional anti-ITP therapy. Patients and Methods Primary ITP was defined as a platelet count < 100 x 109/L in the absence of other causes or disorders that may be associated with thrombocytopenia. Patients received daily oral eltrombopag, at a starting dose of 50 mg/day adjusting the dose as needed up to a maximum of 75 mg/day based on the patient’s platelet count. Successful discontinuation of eltrombopag treatment was defined as a platelet count of 30,000/μl and 20,000/μl above initial baseline for at least 6 months off eltrombopag without substituting additional anti-ITP therapy. Results Our patients were 4 males and 8 females, with a mean disease onset age of 55 years (range, 28–79 years). The median time from diagnosis to eltrombopag start was 24 months (range, 1-480). 5 cases had ITP since less than 1 year. The median prior number of therapies was 5 (range, 1-7). All patients were refractory to corticosteroids. Six patients had received rituximab: Patient (P) 1, P2, P3, P6, P7 and P8. Seven patients were splenectomized. Three patients (P2, P6 and P8) who failed to respond to romiplostim were switched to eltrombopag. One romiplostim responder (P12) switched to eltrombopag because patient request. The median platelet count before starting treatment was 7 x 109/L (range, 1-97 x 109/l). At start, concomitant treatment was administered in 4 patients: P2, P3 and P9 corticosteroids. P5, intravenous immunoglobulin. The median maximum platelet count during treatment was 482 x109/l (range, 251-858 x109/l). One patient had a transient increase in leukocyte count reaching 12x109/L. The median duration of treatment was 5 months (range, 1-13) (Fig 1A): only one month in three patients. Nine patients stopped treatment due to platelets higher than 250 x 109/l. Initial stop of eltrombopag in P2 was failed because of low platelet counts and eltrombopag was reinitiated. After 8 months of re-treatment, eltrombopag could be stopped with no other treatments needed for over 6 months. In P1, P10 and P11 eltrombopag was stopped at 140, 178 and 138 x109/L platelets, respectively. After a median follow-up of 7 months (range, 6 – 20 months), ten patients maintain a platelet count greater than 100 x 109/L (Fig 1B) without any anti-ITP treatment. Discussion The possibility of eltrombopag cessation in a specific subset of patients has emerged. Recently, a prospective ongoing study has demonstrated that approximately 1/3 of patients (5 of 15) appear able to successful elective discontinuation of eltrombopag after 2 or more years of treatment. Nevertheless we have showed that the remission of ITP is feasible after short term treatment with eltrombopag (3 patients treated for only 1 month). Repeated short-term use of eltrombopag in chronic ITP has been reported. Patient P2 could succesfully reintroduce eltrombopag after initial treatment stop. In our data no factors predict which patients may discontinue eltrombopag. Disclosures: San Miguel: Jansen, Celgene Corporation, Onyx, Novartis, Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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