scholarly journals Novel Long-Acting Ropeginterferon Alfa-2b: Pharmacokinetics, Pharmacodynamics, and Safety in a Phase I Clinical Trial

2021 ◽  
Author(s):  
Yi-Wen Huang ◽  
Chung-Wei Tsai ◽  
Albert Qin ◽  
Jane Fang ◽  
Chingleou Teng ◽  
...  
Keyword(s):  
Dose Level ◽  
Geometric Mean ◽  
Dose Range ◽  
Healthy Male ◽  
Recombinant Interferon ◽  
Mean Values ◽  
Branched Polyethylene ◽  
Subcutaneous Dose ◽  
Long Acting ◽  
Related Increase

AIM Ropeginterferon alfa-2b is a new site-specific conjugated 40 kDa branched polyethylene-glycol recombinant interferon (IFN). The aim of the study was to determine its safety, pharmacokinetics (PK) and pharmacodynamic (PD). METHODS Ropeginterferon alfa-2b was evaluated first in human in 48 healthy male volunteers after a single dose subcutaneous injection by either 24, 48, 90, 180, 225, 270mcg of the product or 180mcg of marketed pegylated (peg)-IFN alfa-2a. Within each dosing group, 6 subjects received ropeginterferon alfa-2b and 2 subjects received peg-IFN alfa-2a. RESULTS Dose-related increases in ropeginterferon alfa-2b PK parameters (Cmax, AUC, and AUC0-t) were observed over the dose range 24 to 270mcg. The geometric mean values for these PK parameters of ropeginterferon alfa-2b were higher than that of peg-IFN alfa-2a at the 180mcg dose level of 176%, 166%, and 182%, respectively. Mean PD parameters (Emax, Tmax, and AUC0-t) for ropeginterferon alfa-2b increased with dose for both biomarkers neopterin and 2’, 5’-OAS. Ropeginterferon alfa-2b has similar PD profiles as peg-IFN alfa-2a. The treatment related adverse events are similar between the two study drugs, but the overall incidence was numerically lower for ropeginterferon alfa-2b (83%) than peg-IFN alfa-2a (100%) at the 180mcg dose level. CONCLUSIONS Single subcutaneous dose of Ropeginterferon alfa-2b of up to 270mcg is safe and well tolerated. It displays dose related increase in PK and PD parameters, potentially less frequent injection, and better safety profiles. Ropeginterferon alfa-2b is being developed for diseases in which previous peg-IFN use has been limited by side effects.

HAEMATO-BIOCHEMICAL AND IMMUNOLOGICAL CHANGES IN EXPERIMENTALLY INDUCED ACETAMIPRID TOXICITY IN SWISS ALBINO MICE

2016 ◽  
Vol 12 (1) ◽  
Author(s):  
D.T. Fefar ◽  
Ankita N. Brahmbhatt ◽  
B.P. Joshi ◽  
D.J. Ghodasara
Keyword(s):  
Dose Level ◽  
Significant Rise ◽  
High Dose ◽  
Cell Mediated Immunity ◽  
Swiss Albino Mice ◽  
Mean Values ◽  
Group Iii ◽  
Treatment Groups ◽  
Immunological Effects ◽  
Albino Mice

A study was conducted on 5 weeks old 64 (32 male and 32 female) Swiss albino mice to assess the haemato-biochemical and immunological effects of acetamiprid. All the male and female mice were randomly divided into eight different groups. The groups I (male) and II (female) served as controls whereas remaining groups served as treatment groups and were administered acetamiprid at the daily dose rate of 20, 10, 5 mg/kg body weight in males(Group III, V, VII) and females (Group IV, VI,VIII),respectively for 28 days. After 28 days treatment, blood samples were collected for hematological, biochemical as well as immunological analysis. There was significant decrease in haematological parameters like Hb, TEC, TLC, neutrophils and lymphocytes count in high dose groups and revealed potential adversity of acetamiprid at rates of 20 mg/kg/day on haematopoetic system of mice. A dose dependent significant rise in mean values of AST and ALT was observed in treatment groups, whereas there was significant decrease in total protein and albumin and increase in BUN in high and mid dose treated groups, irrespective of sex of mice. Dinitroflurobenzene (DNFB) test conducted to assess the cell mediated immunity revealed the toxic effect of acetamiprid on cell mediated immunity of mice at dose level of 10 mg/kg/day. The mice of high dose group revealed a significant decrease in HA titer and indicated the immunotoxic potential of acetamiprid at dose level of 20 mg/kg/day.

scholarly journals Safety and Immunogenicity of a Novel Staphylococcus aureus Vaccine: Results from the First Study of the Vaccine Dose Range in Humans

2010 ◽  
Vol 17 (12) ◽  
pp. 1868-1874 ◽  
Author(s):  
Clayton Harro ◽  
Robert Betts ◽  
Walter Orenstein ◽  
Eun-Jeong Kwak ◽  
Howard E. Greenberg ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Response ◽  
Adverse Events ◽  
Immune Responses ◽  
Geometric Mean ◽  
Dose Range ◽  
Vaccine Dose ◽  
Double Blind Study ◽  
Mean Concentration ◽  
Positive Immune Response

ABSTRACT Merck V710 is a novel vaccine containing the conserved Staphylococcus aureus iron surface determinant B shown to be protective in animal models. A phase I, multicenter, double-blind study of the dose range was conducted to assess the immunogenicity and safety of an adjuvanted liquid formulation of V710. A total of 124 adults (18 to 55 years of age) were randomized 1:1:1:1 to receive one 0.5-ml intramuscular injection of V710 (5 μg, 30 μg, or 90 μg) or saline placebo. A positive immune response was defined as at least a 2-fold increase in IsdB-specific IgG levels from baseline levels. Local and systemic adverse events were assessed for 5 and 14 days, respectively, following vaccination. Positive immune responses were detected in 12 (67%) of the 18 subjects in the groups receiving 30 and 90 μg V710 tested at day 10. At day 14, a significantly greater proportion of subjects manifested a positive immune response with higher geometric mean concentrations in the V710 30-μg (86%; geometric mean concentration of 116 μg/ml) and 90-μg (87%; geometric mean concentration of 131 μg/ml) dose groups than in the V710 5-μg (29%; geometric mean concentration of 51 μg/ml) or placebo (4%; geometric mean concentration of 23 μg/ml) groups. Immune responses were durable through day 84. Subjects <40 and ≥40 years of age had comparable immune responses. The most common adverse events were injection-site pain, nausea, fatigue, and headache, usually of mild intensity. No immediate reactions or serious adverse events were reported. In this first study of V710 in humans, a single 30-μg or 90-μg dose was more immunogenic than the 5-μg dose or placebo. Immune responses were evident by 10 to 14 days after vaccination in most responders.

scholarly journals The local antibody response to R.S. virus infection in the respiratory tract

1974 ◽  
Vol 72 (1) ◽  
pp. 111-120 ◽  
Author(s):  
R. Scott ◽  
P. S. Gardner
Keyword(s):  
Virus Infection ◽  
Respiratory Tract ◽  
Acute Phase ◽  
Respiratory Infections ◽  
Geometric Mean ◽  
High Titre ◽  
Virus Infections ◽  
Mean Values ◽  
Neutralizing Activity ◽  
Tract Infections

SUMMARYNasopharyngeal secretions were taken during the acute phase of illness from 66 infants and children admitted to hospital with lower respiratory tract infections. Second secretions were taken, after an interval of 7 days, from 33 of these patients. A significant increase in neutralizing activity to R.S. virus was demonstrated in the nasopharyngeal secretions of patients in response to severe R.S. virus infection. Seventeen out of 25 patients (68%) with R.S. virus infections developed a rise in secretory neutralizing titre, compared with only 1 out of 8 patients (13%) with respiratory infections not involving R.S. virus.A high titre of secretory neutralizing activity was found more often in the acute phase of illness in patients with R.S. virus infections, especially bronchiolitis, than in patients with respiratory infections not involving R.S. virus. Fifteen out of 34 patients (44%) with R.S. virus bronchiolitis were found to possess a neutralizing titre of 1/4 or more in their first secretions, compared with 4 out of 12 patients (33%) with R.S. virus infections other than bronchiolitis and 3 out of 20 patients (15%) with respiratory infections not involving R.S. virus.A quantitative analysis of the immunoglobulins present in the secretions indicated that IgA was the only immunoglobulin consistently present at a detectable concentration. The geometric mean values of IgA, IgM and IgG in the secretions examined were found to be 22·3, 4·3 and 5·3 mg./lOO ml. respectively.The neutralizing activity against R.S. virus, present in the secretions, was shown to be due to specific IgA antibody. This was accomplished by removing the neutralizing activitv in two secretions bv absorotion with anti-IaA serum.

scholarly journals Health-Related Effects of Home Nebulization With Glycopyrronium on Difficult-to-Treat Asthma: Post-Hoc Analyses of an Observational Study (Preprint)

2020 ◽  
Author(s):  
Deepak Talwar ◽  
Salil Bendre
Keyword(s):  
Adverse Events ◽  
Asthma Control ◽  
Inhaled Corticosteroids ◽  
Moderate Intensity ◽  
Serious Adverse Events ◽  
Female Ratio ◽  
Mean Values ◽  
Control Score ◽  
Long Acting ◽  
Post Hoc

BACKGROUND Bronchial asthma remains a clinical enigma with poorly controlled symptoms or exacerbations despite regular use of inhaled corticosteroids. Home nebulization offers a simplified solution for the delivery of rescue and maintenance bronchodilators, which is especially true for patients with frequent exacerbations during management of uncontrolled or difficult-to-treat asthma. OBJECTIVE We aimed to assess the clinical impact and outcomes associated with home nebulization—delivered long-acting bronchodilators for uncontrolled or difficult-to-treat asthma. METHODS This observational, concurrent study was conducted with 60 patients at 2 centers during November 2018. Statistical analyses for prebronchodilator forced expiratory volume in one second (FEV1) and Global Initiative for Asthma (GINA) asthma control score in patients on long-acting bronchodilators and corticosteroids were conducted, with two-tailed <i>P</i> values &lt;.05 considered statistically significant. RESULTS Per protocol analyses (53/60) for consecutive cases receiving home nebulization with long-acting bronchodilators and corticosteroids were conducted. The baseline demographics included a male-to-female ratio of 30:23 and mean values of the following: age, 60.3 years (SD 11.8 years); weight, 64 kg (SD 16.8 kg); FEV1, 43% (SD 16%); GINA asthma control score, 3.0 points (SD 0.8 points); serum eosinophil level, 4% (SD 3%); fractional exhaled nitric oxide (FeNO), 12.1 ppb (SD 6 ppb). Of the patients, 100% (53/53) had uncontrolled symptoms, 69.8% (37/53) had prior exacerbations, 100% (53/53) used formoterol/budesonide, and 75.5% (40/53) used glycopyrronium. The per protocol group (n=53) had significantly improved mean prebronchodilator FEV1 (23.7%, SD 29.8%; 0.46 L, SD 0.58 L; <i>P</i>&lt;.001) and GINA asthma control score (2.1 points, SD 0.8 points, <i>P</i>&lt;.001). At baseline, patients (n=40) receiving glycopyrronium/formoterol/budesonide (25/20/500 mcg) nebulization admixture had the following mean values: prebronchodilator FEV1, 38% (SD 15%); GINA asthma control score, 3.0 points (SD 0.8 points); reversibility, 12% (SD 6%); peripheral eosinophil level, 4% (SD 3%); FeNO, 12 ppb (SD 5.7 ppb). In the post hoc analyses, these patients had significantly improved mean prebronchodilator FEV1 of 27.7% (SD 26.2%; 0.54 L, SD 0.51 L; <i>P</i>&lt;.001) at 8 weeks compared with baseline. At baseline, patients (n=13) receiving formoterol/budesonide (20/500 mcg) nebulization had the following mean values: FEV1, 55% (SD 12%); GINA asthma control score, 3.0 points (SD 1.2 points); reversibility, 14% (SD 7%); serum eosinophil level, 4% (SD 3%); FeNO, 13.3 ppb (SD 6.8 ppb). In the post hoc analyses, these patients showed a significant improvement in prebronchodilator FEV1 of 11.2% (SD 13.1%; 0.22 L, SD 0.25 L; <i>P</i>&lt;.001) from baseline. Breathlessness of mild to moderate intensity was reported by 10 cases (10/53, 18.9%), with no other treatment-emergent adverse events or serious adverse events. CONCLUSIONS Home nebulization remains a viable option for symptomatic difficult-to-treat asthma cases with frequent use of rescue medications. Glycopyrronium as add-on therapy offers a synergistic response in patients on corticosteroids with difficult-to-treat asthma. CLINICALTRIAL Clinical Trial Registry of India CTRI/2018/11/016319; https://tinyurl.com/y78cctm3

SERUM IMMUNOGLOBULINS: I. LEVELS IN NORMAL CHILDREN AND IN UNCOMPLICATED CHILDHOOD ALLERGY

PEDIATRICS ◽  
1968 ◽  
Vol 41 (3) ◽  
pp. 600-611
Author(s):  
Rebecca H. Buckley ◽  
Susan C. Dees ◽  
W. Michael O'Fallon
Keyword(s):  
Statistical Analysis ◽  
Geometric Mean ◽  
Serum Concentrations ◽  
Normal Children ◽  
Mean Values ◽  
Serum Immunoglobulins ◽  
Normal Individuals ◽  
Contrast Analysis ◽  
Relationship Of ◽  
The Relationship

In 201 normal individuals from infancy to adulthood, serum concentrations of immunoglobulins G, A, and M are presented as geometric mean values (mg/l00 ml) and as percents of adult mean values for each of these proteins. A statistical analysis revealed a significant relationship between age and both IgG and IgA concentrations up to ages 6 and 7 years. No correlation was present between age and immunoglobulin concentrations beyond that time, suggesting that the adult concentrations of IgG and IgA are normally reached and maintained after ages 6 and 7 years. In contrast, analysis of the IgM data suggested that the adult value is reached by age 1 year. No truly significant differences were found in immunoglobulin concentrations which could be attributed to sex. Significantly higher concentrations of IgG were found in normal Negro than in normal Caucasian subjects after age 6 years, but no significant differences were found below this age for IgG or at any age for IgA and IgM. Similarly determined serum immunoglobulins in 85 allergic children, selected because they had no complicating illnesses, were compared with the normal group according to the age of the child. No significant differences were found in concentrations of either IgG or IgA. Some differences were found in IgM, but these were small and were primarily associated with the relationship of IgM to age in the allergic group.

In vivo biological response to recombinant interferon-gamma during a phase I dose-response trial in patients with metastatic melanoma.

1990 ◽  
Vol 8 (6) ◽  
pp. 1070-1082 ◽  
Author(s):  
J M Kirkwood ◽  
M S Ernstoff ◽  
T Trautman ◽  
G Hebert ◽  
Y Nishida ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Dose Response ◽  
Dose Range ◽  
Cell Subset ◽  
Optimal Dosage ◽  
Antitumor Effects ◽  
Ifn Gamma ◽  
Recombinant Interferon ◽  
Wide Range

Interferon-gamma (IFN gamma), as produced by recombinant DNA technology, has shown a wide range of immunomodulatory activity in vitro and in vivo. Clinical studies have attempted to establish a dose-response relationship to define optimal dosage ranges for induction of effector cell function and host response in patients with cancer. We conducted a randomized trial to test the in vivo biologic activity of five daily dosages ranging from 3 to 3,000 micrograms/m2, administered by daily 2-hour bolus injection or by continuous infusion for 14 days. We demonstrate comparable immunobiologic effects of recombinant IFN gamma (rIFN gamma; Biogen, Inc, Cambridge, MA) administered by these two schedules at the various dosages tested, and have defined a relationship of dose to biologic response over this 3-log10 dose range. Oligo 2'5' adenylate synthetase (2'5'As) induction, natural-killer (NK) cell activity, and T-cell subset distribution (heightened T helper/suppressor ratio) showed the most consistent treatment-associated changes and the greatest immunobiologic effects at dosages of 300 to 1,000 micrograms/m2. Mononuclear cell DR and DQ antigen expression showed no consistent dose-related treatment effect. The relevance of the phenotypic, functional, and enzymologic effects observed in this trial to any clinical antitumor effects of IFN gamma in cancer therapy must now be established.

Effect of Sodium-Transport Inhibitors on Bronchial Reactivity in Vivo

1990 ◽  
Vol 79 (4) ◽  
pp. 325-330 ◽  
Author(s):  
Alan J. Knox ◽  
John R. Britton ◽  
Anne E. Tattersfield
Keyword(s):  
Confidence Intervals ◽  
Sodium Transport ◽  
Geometric Mean ◽  
Normal Subjects ◽  
Bronchial Reactivity ◽  
Mean Values ◽  
Doubling Dose ◽  
The Difference

1. We have recently shown that ouabain, an inhibitor of Na+/K+-adenosine triphosphatase, causes contraction of bovine and human airways in vitro, and that amiloride causes relaxation and inhibits receptor-operated contraction in bovine trachealis. 2. To determine whether such drugs alter bronchial reactivity in vivo, we have studied the effect of oral digoxin (an inhibitor of Na+/K+-adenosine triphosphatase) and oral and inhaled amiloride on bronchial reactivity to histamine in three double-blind, placebo-controlled studies. 3. Histamine reactivity was measured as the provocative dose causing a 20% reduction in the forced expiratory volume in 1 s (PD20FEV1) or, when normal subjects were included, the provocative dose causing a 35% reduction in the specific airways conductance (PD35sGaw); the results are given as geometric mean values. 4. In study 1, 13 atopic asthmatic subjects were given 20 mg of oral amiloride or placebo on separate days. Two hours after the drug, the geometric mean PD20FEV1 for histamine was 0.43 μmol after amiloride and 0.54 μmol after placebo (95% confidence intervals for the difference: 0.9 to −0.2 doubling doses of histamine; P = 0.2). 5. In study 2, six normal and 24 atopic asthmatic men inhaled 10 ml of 10−2 mol/l amiloride or diluent control in a crossover study. The mean values of PD35sGaw for histamine immediately after inhalation of amiloride and placebo were 3.0 μmol and 4.3 μmol, respectively, in the normal subjects (95% confidence intervals for the difference: −0.53 to 1.52 doubling doses, P = 0.2), and 0.33 μmol and 0.29 μmol in the asthmatic subjects (95% confidence intervals for the difference: −0.95 to 0.57 doubling doses; P = 0.6). 6. In study 3, 24 atopic asthmatic men were treated for 7 days with placebo or oral digoxin (1.5 mg loading dose plus 0.25 mg twice daily for 6 days). The PD20FEV1 for histamine was measured before, 12 h after the loading dose and on day 7 of treatment. The change in PD20FEV1 did not differ significantly after digoxin and placebo, after either 1 day's treatment [mean (95% confidence intervals) difference: 0.56 doubling dose (−0.37 to 1.5 doubling dose)] or 7 day's treatment [mean (95% confidence intervals) difference: 0.3 doubling dose (−1.23 to 1.8 doubling doses)]. 7. Although our work in vitro has suggested that membrane sodium transport may play an important role in determining airway smooth muscle contractility, we have been unable to demonstrate any effect of the sodium-transport inhibitors amiloride and digoxin on histamine reactivity in these studies.

scholarly journals Weed Classification for Site-Specific Weed Management Using an Automated Stereo Computer-Vision Machine-Learning System in Rice Fields

Plants ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 559
Author(s):  
Mojtaba Dadashzadeh ◽  
Yousef Abbaspour-Gilandeh ◽  
Tarahom Mesri-Gundoshmian ◽  
Sajad Sabzi ◽  
José Luis Hernández-Hernández ◽  
...  
Keyword(s):  
Weed Management ◽  
Rice Field ◽  
Vision System ◽  
Geometric Mean ◽  
Texture Features ◽  
Learning System ◽  
Metaheuristic Algorithms ◽  
Test Set ◽  
Site Specific ◽  
Mean Values

Site-specific weed management and selective application of herbicides as eco-friendly techniques are still challenging tasks to perform, especially for densely cultivated crops, such as rice. This study is aimed at developing a stereo vision system for distinguishing between rice plants and weeds and further discriminating two types of weeds in a rice field by using artificial neural networks (ANNs) and two metaheuristic algorithms. For this purpose, stereo videos were recorded across the rice field and different channels were extracted and decomposed into the constituent frames. Next, upon pre-processing and segmentation of the frames, green plants were extracted out of the background. For accurate discrimination of the rice and weeds, a total of 302 color, shape, and texture features were identified. Two metaheuristic algorithms, namely particle swarm optimization (PSO) and the bee algorithm (BA), were used to optimize the neural network for selecting the most effective features and classifying different types of weeds, respectively. Comparing the proposed classification method with the K-nearest neighbors (KNN) classifier, it was found that the proposed ANN-BA classifier reached accuracies of 88.74% and 87.96% for right and left channels, respectively, over the test set. Taking into account either the arithmetic or the geometric means as the basis, the accuracies were increased up to 92.02% and 90.7%, respectively, over the test set. On the other hand, the KNN suffered from more cases of misclassification, as compared to the proposed ANN-BA classifier, generating an overall accuracy of 76.62% and 85.59% for the classification of the right and left channel data, respectively, and 85.84% and 84.07% for the arithmetic and geometric mean values, respectively.

scholarly journals ATIM-24. DOSE FINDING AND DOSE EXPANSION TRIAL OF D2C7 IMMUNOTOXIN (D2C7-IT) ADMINISTERED INTRATUMORALLY VIA CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMA (MG)

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi6-vi6
Author(s):  
Annick Desjardins ◽  
Dina Randazzo ◽  
Vidya Chandramohan ◽  
Katherine Peters ◽  
Margaret Johnson ◽  
...  
Keyword(s):  
Dose Level ◽  
Cerebral Edema ◽  
Phase 1 ◽  
Dose Range ◽  
Antibody Fragment ◽  
Genetically Engineered ◽  
Phase 2 ◽  
Who Grade ◽  
Recombinant Immunotoxin ◽  
Grade 3

Abstract BACKGROUND D2C7-IT is a recombinant immunotoxin comprised of a dual-specific antibody fragment targeting EGFRwt and EGFRvIII and a genetically engineered form of the Pseudomonas exotoxin, PE38-KDEL. We report results of a phase 1 trial, with dose expansion at the selected phase 2 dose, evaluating D2C7-IT delivered intratumorally by CED. METHODS Eligible patients are adults with recurrent supratentorial WHO grade III or IV MG; solitary tumor; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS >70%. Two patients per dose level (DL) were to be enrolled in the dose escalation portion (dose range: 40ng/mL to 23,354ng/mL), followed by dose expansion at the selected phase 2 dose (DL13). RESULTS As of 6/07/2019, 51 patients have been treated; 10 patients on the phase 2 dose. Observed dose limiting toxicities include: grade 4 seizure (n=1) on DL3, grade 3 confusion and pyramidal tract syndrome (n=1) on DL13, and grade 4 cerebral edema (n=1) and grade 3 dysphasia (n=1) on DL17. Grade 3 or higher adverse events possibly related to D2C7-IT include: seizure (grade 4, n=2, grade 3, n=3), cerebral edema (grade 4, n=1), hydrocephalus (grade 3, n=5), headache (grade 3, n=4), hemiparesis (grade 3, n=4), dysphasia (grade 3, n=4), lymphopenia (grade 3, n=3), thromboembolic event (grade 3, n=3); and one each of grade 3 elevated ALT, urinary tract infection, fall, wound complication, generalized muscle weakness, confusion, encephalopathy, and somnolence. Fourteen patients are alive. Three patients have partial radiographic response and remain alive without additional therapy more than 46, 27 and 21 months after D2C7-IT infusion. CONCLUSION Dose level 13 was selected as the optimal phase 2 dose and patient accrual is ongoing on the dose expansion arm. Encouraging efficacy results have been observed. A trial of D2C7-IT with checkpoint inhibitor is planned to start in the near future.

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