scholarly journals Safety assessment of a new anti-tuberculosis drug in silico and with the participation of healthy volunteers

2022 ◽  
pp. 42-47
Author(s):  
A. Yu. Savchenko ◽  
G. V. Ramenskaya ◽  
V. G. Kukes ◽  
M. S. Burenkov ◽  
B. V. Shilov
Keyword(s):  
Clinical Study ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
In Silico ◽  
Safety Assessment ◽  
Study Drug ◽  
Open Label ◽  
Good Tolerability ◽  
Carcinogenic Effect ◽  
Clinical Safety

Relevance. In connection with the increase in the number of cases of multidrug-resistant tuberculosis (MDR-TB), the search for new anti-tuberculosis drugs (ATD) is necessary. The assessment of its effect on the human body outside the aspect of the therapeutic effect is one of the main directions in the development of anti-TB drugs.Aim. Evaluation of the possible toxicity of thiosonide, a new domestic anti-TB drug, combining a consistent study of this side of the drug using a bioinformatics approach and an analysis of the results of a clinical safety study.Methods. The bioinformatic assessment was carried out using web services and models to predict the toxicity of thiosonide. The safety assessment in relation to healthy volunteers was carried out as part of a clinical study according to the protocol: «An open-label study of the pharmacokinetics, safety and tolerability of the drug thiozonide, capsule 100 mg with a single dose of increasing doses by various groups of healthy volunteers.» (2013, Permit No. 187 to conduct a clinical trial dated March 22, 2013, issued by the Ministry of Health of the Russian Federation).Results. Potential unwanted targets were identified, the predicted activity value for which was greater than 7. The results obtained indicate the likelihood of the effect of thiosonide on these protein targets and, possibly, the ability of the latter to cause side effects associated with changes in the activity of these molecules. The cytotoxic and carcinogenic effect of thiosonide is not predicted. During a clinical study, the drug thiosonide showed good tolerance and safety, since the identified adverse events did not show a definite or reliable relationship with the study drug. The resolution of all adverse events was complete, and dose escalation did not affect the number, severity of AEs and association with the study drug.Conclusion. The safety analysis of thiosonide demonstrated its good tolerability both during in silico assessment and in a study with the participation of healthy volunteers.

scholarly journals Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study of the Penetration of a Monoclonal Antibody Combination (ASN100) Targeting Staphylococcus aureus Cytotoxins in the Lung Epithelial Lining Fluid of Healthy Volunteers

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Zoltan Magyarics ◽  
Fraser Leslie ◽  
Johann Bartko ◽  
Harald Rouha ◽  
Steven Luperchio ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
Dose Escalation ◽  
Human Study ◽  
Epithelial Lining ◽  
Open Label ◽  
Double Blind ◽  
Epithelial Lining Fluid ◽  
Double Blind Placebo

ABSTRACT ASN100 is a novel antibody combination of two fully human IgG1(κ) monoclonal antibodies (MAbs), ASN-1 and ASN-2, which neutralize six Staphylococcus aureus cytotoxins, alpha-hemolysin (Hla) and five bicomponent leukocidins. We assessed the safety, tolerability, and serum and lung pharmacokinetics of ASN100 in a randomized, double-blind, placebo-controlled single-dose-escalation first-in-human study. Fifty-two healthy volunteers were enrolled and randomized to receive either ASN-1, ASN-2, a combination of both MAbs (ASN100), or a corresponding placebo. Thirty-two subjects in the double-blind dose escalation portion of the study received ASN-1 or ASN-2 at a 200-, 600-, 1,800-, or 4,000-mg dose, or placebo. Eight subjects received both MAbs simultaneously in a 1:1 ratio (ASN100) at 3,600 or 8,000 mg, or they received placebos. Twelve additional subjects received open-label ASN100 at 3,600 or 8,000 mg to assess the pharmacokinetics of ASN-1 and ASN-2 in epithelial lining fluid (ELF) by bronchoalveolar lavage fluid sampling. Subjects were monitored for 98 days (double-blind cohorts) or 30 days (open-label cohorts) for safety assessment. No dose-limiting toxicities were observed, and all adverse events were mild and transient, with only two adverse events considered possibly related to the investigational product. ASN100 exhibited linear serum pharmacokinetics with a half-life of approximately 3 weeks and showed detectable penetration into the ELF. No treatment-emergent anti-drug antibody responses were detected. The toxin neutralizing potency of ASN100 in human serum was confirmed up to 58 days postdosing. The favorable safety profile, ELF penetration, and maintained functional activity in serum supported the further clinical development of ASN100.

Effectiveness and Safety of Rizatriptan Benzoate 10 mg in the Treatment of Migraine Headaches

2010 ◽  
Vol 2 ◽  
pp. CMT.S4670
Author(s):  
Michel Aubé ◽  
Fridon Chouha ◽  
Julie Vaillancourt ◽  
John Sampalis
Keyword(s):  
Adverse Events ◽  
Real Life ◽  
Study Drug ◽  
Pain Severity ◽  
Open Label ◽  
Serious Adverse Events ◽  
Over The Counter ◽  
Rizatriptan Benzoate ◽  
Migraine Headaches ◽  
Real Life Setting

Background Patients that do not achieve therapeutic response with over the counter non-triptan medications may benefit from triptan-based treatments. Objective Phase I V, open-label, multi-center, prospective cohort study assessing the effectiveness of rizatriptan in the management of migraines for patients that have not responded to non-triptan treatment. Methods Patients were treated with one rizatriptan (MAXALT RPD®) 10 mg wafer at the onset of each migraine attack and were assessed after a minimum of one and a maximum of two consecutive headache episodes. Outcome measures included self-reported assessments (severity and duration of migraine headache) and the Migraine ACT questionnaire. Results A total of 369 patients were enrolled, of which 291 and 215 reported one and two attacks, respectively. For the first and second attacks, 47.2% and 53.9% of patients reported complete resolution of pain while 73.6% and 77.0% reported pain severity reduction within two hours of onset. Mean (SD) pain severity score (four-point Likert scale) during the 488 migraine episodes was reduced significantly ( P < 0.001) from 2.56 (0.49) at onset to 1.91 (0.85) at 30, 1.31 (1.00) at 60 and 0.84 (1.00) at 120 minutes. Similar improvements were observed for changes in Migraine ACT questionnaire scores. No treatment-related serious adverse events were reported. The most frequently reported non-serious adverse events that were attributed to the study drug were dizziness (2.2%), chest discomfort (1.1%), nausea (1.1%), and somnolence (0.8%). Conclusion In a real-life setting, rizatriptan benzoate 10 mg is effective and safe in the treatment of acute migraine headaches in patients who do not respond to non-triptan treatment.

A phase II study of single agent mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in patients with diffuse large cell B-cell (DLBCL) and follicular (FL) lymphomas.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8535-8535 ◽  
Author(s):  
Michael Crump ◽  
Charalambos Andreadis ◽  
Sarit E. Assouline ◽  
David Rizzieri ◽  
Amanda Copeland ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Hdac Inhibitor ◽  
Single Agent ◽  
Objective Response ◽  
Study Drug ◽  
Clinical Activity ◽  
Duration Of Treatment ◽  
Open Label ◽  
Cardiac Symptoms

8535 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single-agent activity in Hodgkin’s lymphoma and in AML and MDS (in combination with 5-azacitidine). More than 430 patients have been treated to date. Methods: This open-label, phase II trial enrolled patients with DLBCL and FL. Patients received mocetinostat at doses ranging from 70-110 mg 3x/wk every 28 days. Anticancer activity, safety, pharmacokinetics and pharmacodynamics were evaluated. Results: Sixty-nine patients with DLBCL (n=41) and FL (n=28) were enrolled for treatment at starting doses of 85-110 mg. Median age was 62 years (range: 32 to 81). Median duration of treatment was ~3 months (range: <1 to 24). Objective response rate in DLBCL and FL, respectively, was 7/41 (17%; including 2 unconfirmed PRs) and 3/28 (11%; including 1 CR). Median time to response was 2.0 mos (range 1.7-21.0) and 5.3 mos (range 4.3-6.0) respectively. Stable disease was achieved by 13/41 (32%) and 14/28 (50%), respectively, for a disease control rate of 49% and 61%, respectively. Mean duration of SD in patients with DBLCL was ~4.5 mos (range 2-12 mos), with 10 patients remaining stable for ≥3 mos. Among FL patients, mean duration of SD was approximately 4.1 mos (range 1.7-13 mos), with 9 patients remaining stable for ≥3 mos. The FL CR occurred in a 62-year-old female with paratracheal, subcarinal and portal target lesions who achieved a PR after 4 cycles and CR after 12 cycles that persisted through the remaining 4 mos on study. Study drug was discontinued for adverse events in 19/69 (28%). Fatigue, weight loss or anorexia were most common (n=4 each). A total of 26 drug-related SAEs were reported among 12 patients (17%; 1-6 events per pt). There were no drug related deaths. Enrollment is complete and final data will be presented. Conclusions: Single-agent mocetinostat has activity in DLBCL and FL. Fatigue, gastrointestinal, and cardiac symptoms are the most common adverse events resulting in discontinuation of dosing. Based on the acceptable tolerability and clinical activity further development is warranted. Clinical trial information: NCT00359086.

scholarly journals A Randomized Phase 2 Study of Long-Acting TransCon GH vs Daily GH in Childhood GH Deficiency

2017 ◽  
Vol 102 (5) ◽  
pp. 1673-1682 ◽  
Author(s):  
Pierre Chatelain ◽  
Oleg Malievskiy ◽  
Klaudziya Radziuk ◽  
Ganna Senatorova ◽  
Magdy O. Abdou ◽  
...  
Keyword(s):  
Adverse Events ◽  
Gh Deficiency ◽  
Area Under The Curve ◽  
Study Drug ◽  
Height Velocity ◽  
Controlled Study ◽  
Open Label ◽  
Safety And Efficacy ◽  
Treatment Naïve ◽  
Long Acting

Abstract Context: TransCon Growth Hormone (GH) (Ascendis Pharma) is a long-acting recombinant sustained-release human GH prodrug in development for children with GH deficiency (GHD). Objective: To compare the pharmacokinetics, pharmacodynamics, safety, and efficacy of weekly TransCon GH to that of daily GH in prepubertal children with GHD. Design: Randomized, open-label, active-controlled study of three doses of weekly TransCon GH versus daily Genotropin (Pfizer). Setting: Thirty-eight centers in 14 European countries and Egypt. Patients: Prepubertal male and female treatment-naïve children with GHD (n = 53). Interventions: Subjects received one of three TransCon GH doses (0.14, 0.21, or 0.30 mg GH/kg/wk) or Genotropin 0.03 mg GH/kg/d for 26 weeks. Main Outcome Measures: GH and insulinlike growth factor-1 (IGF-1) levels, growth, adverse events, and immunogenicity. Results: Both GH maximum concentration and area under the curve were similar following TransCon GH or Genotropin administration at comparable doses. A dose response was observed, with IGF-1 standard deviation scores increasing into the normal range for all three TransCon GH doses. Annualized mean height velocity for the three TransCon GH doses ranged from 11.9 cm to 13.9 cm, which was not statistically different from 11.6 cm for Genotropin. Adverse events were mild to moderate, and most were unrelated to the study drug. Injection site tolerance was good. One TransCon GH subject developed a low-titer, nonneutralizing antibody response to GH. Conclusions: The results suggest that long-acting TransCon GH is comparable to daily Genotropin for GH (pharmacokinetics) and IGF-1 (pharmacodynamics) levels, safety, and efficacy and support advancement into phase 3 development.

Efficacy and Safety of a Combination of Cinnarizine and Dimenhydrinate in the Treatment of Vertigo

2018 ◽  
Vol 3 (01) ◽  
Author(s):  
Dr. Mayuresh Kiran ◽  
Mr. Lalit Pawaskar
Keyword(s):  
Clinical Study ◽  
Adverse Events ◽  
Calcium Antagonists ◽  
Safety Assessment ◽  
Channel Blocker ◽  
Medical Condition ◽  
Age Group ◽  
Efficacy And Safety ◽  
Efficacy Assessment ◽  
Antihistaminic Drug

Introduction and Background: Vertigo is a medical condition where a person feels as he/ she or the objects around them are moving when they are stable and not moving. Antihistamines, Calcium antagonists, histamine analogs (eg, betahistine derivatives), diuretics, neuroleptics as well as other psychotherapeutic drugs, corticosteroids agents and hemorheologics can be used for the treatment of Vertigo. Combination of Cinnarizine which is a selective calcium-channel blocker and Dimenhydrinate which is an H 1 antihistaminic drug can be used in combination for the treatment of vertigo. This clinical study was conducted to evaluate the efficacy and safety of combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg in patients of vertigo of age group 18 to 65 years. Methodology: Out of total 216 patients, 168 completed the study. Efficacy assessment was made by analysing the reduction in vertigo symptom score (VSS). Safety assessment was made by analysing the adverse events experienced by the patient or observed by the investigator during trial. Results: Reduction in VSS from 7.277 (baseline) to 3.975 (day 3) and 0.987 (day 5). At visit 2 and visit 3 there was reduction of 45.373 % and 86.426 % in mean VSS score. Conclusion: A combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg is safe and efficacious in the treatment of vertigo.

scholarly journals A Double-Blind, Randomized, Crossover Comparative Study for Evaluating the Clinical Safety of Ephedrine Alkaloids-Free Ephedra Herb Extract (EFE)

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Hiroshi Odaguchi ◽  
Mariko Sekine ◽  
Sumiko Hyuga ◽  
Toshihiko Hanawa ◽  
Keika Hoshi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Comparative Study ◽  
Study Drug ◽  
Pharmacological Effects ◽  
Double Blind ◽  
Clinical Safety ◽  
Ephedra Herb ◽  
Stage 1 ◽  
Prior Administration ◽  
Herb Extract

Ephedra Herb is an important crude drug; it is used in various Traditional Japanese Medicine (Kampo) formulations. Its significant pharmacological effects have been believed to be attributed to ephedrine and pseudoephedrine, which sometimes induce adverse effects. On the other hand, it has been reported that some of these pharmacological effects are not dependent on ephedrine or pseudoephedrine. Ephedrine alkaloids-free Ephedra Herb extract has been newly developed. It has been reported to have analgesic, anti-influenza, and antimetastatic effects. This clinical trial was aimed at verifying the noninferiority of EFE’s safety compared to that of Ephedra Herb extract (EHE) in humans. This was a single-institution, double-blinded, randomized, two-drug, two-stage, crossover comparative study. Twelve healthy male subjects were equally and randomly allocated into two groups: prior administration of EFE (EFE-P) and prior administration of EHE (EHE-P). In Stage 1, EFE and EHE were orally administered to the EFE-P and EHE-P groups, respectively, for six days. After a 4-week washout period, Stage 2 was initiated wherein the subjects were given a study drug different from Stage 1 study drug for six days. Eleven adverse events with a causal relationship to the study drugs (EHE: 8; EFE: 3) were noted; all events were mild in severity. With regard to the incidence of adverse events, EHE and EFE administration, respectively, accounted for 4 cases (out of 12 subjects, similarly below) and 1 case of increased pulse rate (p=0.32) and 3 cases and 1 case of insomnia (p=0.59). Further, there was one case of hot flashes (p=1.00) due to EFE administration and one case of dysuria (p=1.00) due to EHE administration. There were no significant differences in the incidences of adverse events between EHE administration and EFE administration. Therefore, we concluded that EFE is not inferior to EHE in terms of safety.

scholarly journals Safety, Tolerability, and Pharmacokinetics of Intravenous Oseltamivir: Single- and Multiple-Dose Phase I Studies with Healthy Volunteers

2012 ◽  
Vol 56 (9) ◽  
pp. 4729-4737 ◽  
Author(s):  
Barbara J. Brennan ◽  
Brian Davies ◽  
Georgina Cirrincione-Dall ◽  
Peter N. Morcos ◽  
Anna Beryozkina ◽  
...  
Keyword(s):  
Phase I ◽  
Healthy Volunteers ◽  
Multiple Dose ◽  
Unmet Need ◽  
Oral Medication ◽  
Oseltamivir Carboxylate ◽  
Open Label ◽  
Two Phase ◽  
Double Blind ◽  
Good Tolerability

ABSTRACTThere is an unmet need for an intravenous (i.v.) neuraminidase inhibitor, particularly for patients with severe influenza who cannot take oral medication. Two phase I pharmacokinetic and safety studies of i.v. oseltamivir were carried out in healthy volunteers. The first was an open-label, randomized, four-period, two-sequence, single-dose trial of 100 mg, 200 mg, and 400 mg oseltamivir i.v. over 2 h and a 75-mg oral dose of oseltamivir. The second was a double-blind, placebo-controlled, parallel-group, multiple-dose study in which participants were randomized to 100 mg or 200 mg oseltamivir or placebo (normal saline) i.v. over 2 h every 12 h for 5 days. Exposure to the active metabolite oseltamivir carboxylate (OC) after dosing achieved with 100 mg oseltamivir administered i.v. over 2 h was comparable to that achieved with 75 mg administered orally. Single i.v. doses of oseltamivir up to 400 mg were well tolerated with no new safety signals. Multiple-dose data confirmed good tolerability of 100 mg and 200 mg oseltamivir and showed efficacious OC exposures with 100 mg i.v. over 2 h twice daily for 5 days. These results support further exploration of i.v. oseltamivir as an influenza treatment option for patients unable to take oral medication.

scholarly journals A phase I, randomized, single-dose pharmacokinetic study comparing sb8 (bevacizumab biosimilar) with reference bevacizumab in healthy volunteers

2020 ◽  
Vol 86 (4) ◽  
pp. 567-575 ◽  
Author(s):  
Donghoon Shin ◽  
Yoon Jung Lee ◽  
Jihye Choi ◽  
Dahyoung Lee ◽  
Minjeong Park ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
Neutralizing Antibodies ◽  
Study Drug ◽  
The European Union ◽  
Double Blind ◽  
Time Curve ◽  
Single Dose Study ◽  
Primary Endpoints

Abstract Purpose To compare pharmacokinetics, safety, tolerability, and immunogenicity between SB8, a bevacizumab biosimilar, and the European Union (EU) and United States (US) reference products (bevacizumab-EU, bevacizumab-US). Methods In this randomized, double-blind, parallel-group, and single-dose study, healthy volunteers were randomized to receive a 3 mg/kg dose of SB8, bevacizumab-EU, or bevacizumab-US via intravenous infusion. Primary endpoints were area under the concentration–time curve from time zero to infinity (AUCinf) and to the last quantifiable concentration (AUClast), and maximum observed serum concentration (Cmax). Bioequivalence was achieved if 90% confidence intervals (CIs) for the ratios of the geometric least squares means (LSMeans) of primary endpoints were within the predefined bioequivalence margins of 80.00–125.00%. Safety and immunogenicity were also investigated. Results The 90% CIs for the geometric LSMean ratios of AUCinf, AUClast and Cmax were all within the prespecified bioequivalence margins. Geometric LSMean ratios for SB8/bevacizumab-EU, SB8/bevacizumab-US and bevacizumab-EU/bevacizumab-US were 88.01%, 88.48% and 100.54% for AUCinf, 88.65%, 89.08% and 100.49% for AUClast and 99.59%, 101.15% and 101.56% for Cmax, respectively. Incidence of treatment-emergent adverse events (TEAEs) across treatment groups was comparable (SB8: 50.0%, bevacizumab-EU: 37.5%, bevacizumab-US: 53.8%). Most TEAEs were mild and considered as not related to the study drug. No deaths or treatment discontinuations due to adverse events occurred. Incidence of anti-drug antibodies was also comparable between all groups and no neutralizing antibodies were detected. Conclusion This study demonstrated pharmacokinetic bioequivalence and similar safety and immunogenicity profiles of SB8 to both reference products, bevacizumab-EU and bevacizumab-US, and of bevacizumab-EU to bevacizumab-US. Clinicaltrials.gov identifier NCT02453672 (submitted date); EudraCT number: 2015-001,026-41.

scholarly journals Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma

2014 ◽  
Vol 4 (2) ◽  
pp. e182-e182 ◽  
Author(s):  
D S Siegel ◽  
P Richardson ◽  
M Dimopoulos ◽  
P Moreau ◽  
C Mitsiades ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Adverse Events ◽  
Study Drug ◽  
Maximum Tolerated Dose ◽  
Laboratory Studies ◽  
Open Label ◽  
Adverse Experiences ◽  
Previously Treated ◽  
Dose Escalating

Abstract The addition of vorinostat to lenalidomide/dexamethasone represents a novel combination therapy in multiple myeloma (MM), informed by laboratory studies suggesting synergy. This was a phase I, multicenter, open-label, non-randomized, dose-escalating study in patients with relapsed or relapsed and refractory MM. Clinical evaluation, electrocardiogram, laboratory studies and adverse events were obtained and assessed. The maximum-tolerated dose was not reached owing to a non-occurrence of two dose-limiting toxicities per six patients tested at any of the dosing levels. Patients tolerated the highest dose tested (Level 5) and this was considered the maximum administered dose: at 400 mg vorinostat on days 1–7 and 15–21, 25 mg lenalidomide on days 1–21 and 40 mg dexamethasone on days 1, 8, 15 and 22, per 28-day cycle. Drug-related adverse events were reported in 90% of patients serious adverse experiences were reported in 45% of the patients and 22% of all patients had adverse experiences considered, possibly related to study drug by the investigators. A confirmed partial response or better was reported for 14/30 patients (47%) evaluable for efficacy, including 31% of patients previously treated with lenalidomide. Vorinostat in combination with lenalidomide and dexamethasone proved tolerable with appropriate supportive care, with encouraging activity observed.

scholarly journals The CECARI Study: Everolimus (Certican®) Initiation and Calcineurin Inhibitor Withdrawal in Maintenance Heart Transplant Recipients with Renal Insufficiency: A Multicenter, Randomized Trial

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Jan Van Keer ◽  
David Derthoo ◽  
Olivier Van Caenegem ◽  
Michel De Pauw ◽  
Eric Nellessen ◽  
...  
Keyword(s):  
Adverse Events ◽  
Renal Insufficiency ◽  
Heart Transplant ◽  
Statistical Significance ◽  
Group Versus ◽  
Study Drug ◽  
Major Adverse Cardiovascular Events ◽  
Transplant Recipients ◽  
Open Label ◽  
Heart Transplant Recipients

In this 3-year, open-label, multicenter study, 57 maintenance heart transplant recipients (>1 year after transplant) with renal insufficiency (eGFR 30–60 mL/min/1.73 m2) were randomized to start everolimus with CNI withdrawal (N=29) or continue their current CNI-based immunosuppression (N=28). The primary endpoint, change in measured glomerular filtration rate (mGFR) from baseline to year 3, did not differ significantly between both groups (+7.0 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p=0.18). In the on-treatment analysis, the difference did reach statistical significance (+9.4 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p=0.047). The composite safety endpoint of all-cause mortality, major adverse cardiovascular events, or treated acute rejection was not different between groups. Nonfatal adverse events occurred in 96.6% of patients in the everolimus group and 57.1% in the CNI group (p<0.001). Ten patients (34.5%) in the everolimus group discontinued the study drug during follow-up due to adverse events. The poor adherence to the everolimus therapy might have masked a potential benefit of CNI withdrawal on renal function.

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