scholarly journals Pharmacokinetics and Safety Profile of the Human Anti-Pseudomonas aeruginosa Serotype O11 Immunoglobulin M Monoclonal Antibody KBPA-101 in Healthy Volunteers

2009 ◽  
Vol 53 (8) ◽  
pp. 3442-3446 ◽  
Author(s):  
Hedvika Lazar ◽  
Michael P. Horn ◽  
Adrian W. Zuercher ◽  
Martin A. Imboden ◽  
Peter Durrer ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Pseudomonas Aeruginosa ◽  
Body Weight ◽  
Healthy Volunteers ◽  
Human Monoclonal Antibody ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Immunoglobulin M ◽  
Serious Adverse Events ◽  
The Mean

ABSTRACT KBPA-101 is a human monoclonal antibody of the immunoglobulin M isotype, which is directed against the O-polysaccharide moiety of Pseudomonas aeruginosa serotype O11. This double-blind, dose escalation study evaluated the safety and pharmacokinetics of KBPA-101 in 32 healthy volunteers aged 19 to 46 years. Each subject received a single intravenous infusion of KBPA-101 at a dose of 0.1, 0.4, 1.2, or 4 mg/kg of body weight or placebo infused over 2 h. Plasma samples for pharmacokinetic assessments were taken before infusion as well as 0.25, 0.5, 1, 2, 2.5, 4, 6, 8, 12, 24, 36, and 48 h and 4, 7, 10, and 14 days after start of dosing. Plasma concentrations of KBPA-101 were detected with mean maximum concentrations of drug in plasma of 1,877, 7,571, 24,923, and 83,197 ng/ml following doses of 0.1, 0.4, 1.2, and 4.0 mg/kg body weight, respectively. The mean elimination half-life was between 70 and 95 h. The mean volume of distribution was between 4.76 and 5.47 liters. Clearance ranged between 0.039 and 0.120 liters/h. At the highest dose of 4.0 mg/kg, plasma KBPA-101 levels were greater than 5,000 ng/ml for 14 days. KBPA-101 exhibited linear kinetics across all doses. No anti-KBPA-101 antibodies were detected after dosing in any subject. Overall, the human monoclonal antibody KBPA-101 was well tolerated over the entire dose range in healthy volunteers, and no serious adverse events have been reported.

scholarly journals Open-Label, Dose Escalation Study of the Safety and Pharmacokinetic Profile of Tefibazumab in Healthy Volunteers

2005 ◽  
Vol 49 (3) ◽  
pp. 959-962 ◽  
Author(s):  
Sandra Reilley ◽  
Eric Wenzel ◽  
Laurie Reynolds ◽  
Beth Bennett ◽  
Joseph M. Patti ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Dose Escalation ◽  
Maximum Concentration ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Open Label ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Label Dose ◽  
The Mean

ABSTRACT Tefibazumab (Aurexis) is a humanized monoclonal antibody being evaluated as adjunctive therapy for the treatment of Staphylococcus aureus infections. This open-label, dose escalation study evaluated the safety and pharmacokinetics of tefibazumab in 19 healthy volunteers aged 18 to 69 years. Each subject received a single administration of tefibazumab at a dose of 2, 5, 10, or 20 mg/kg of body weight infused over 15 min. Plasma samples for pharmacokinetic assessments were obtained before infusion as well as 1, 6, 12, and 24 h and 3, 4, 7, 21, 28, 42, and 56 days after dosing. Plasma concentrations of tefibazumab were detected 1 h after the end of the infusion, with a mean maximum concentration of drug in serum (C max) of 59, 127, 252, and 492 μg/ml following doses of 2, 5, 10, and 20 mg/kg, respectively. The median time to maximum concentration of drug in serum (T max) was 1.0 h for each dose. The mean elimination half-life (t 1/2) was approximately 22 days. The volume of distribution (V) was 4.7, 6.7, 7.2, and 7.2 liters after doses of 2, 5, 10, and 20 mg/kg, respectively. Clearance (CL) was 6.0, 9.2, 10.2, and 9.9 ml/hr, respectively. At the highest dose, plasma levels of tefibazumab were >100 μg/ml for 21 days. On day 56, the mean plasma concentrations were 6.3, 10.0, 16.4, and 30.5 μg/ml for the 2, 5, 10, and 20 mg/kg doses, respectively. Tefibazumab exhibited linear kinetics across doses of 5, 10, and 20 mg/kg. No anti-tefibazumab antibodies were detected after dosing in any subject. There were no serious adverse events, and tefibazumab was well tolerated over the entire dose range.

scholarly journals Influence ofABCC2andABCC4Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

2015 ◽  
Vol 59 (6) ◽  
pp. 3240-3245 ◽  
Author(s):  
Kanokrat Rungtivasuwan ◽  
Anchalee Avihingsanon ◽  
Narukjaporn Thammajaruk ◽  
Siwaporn Mitruk ◽  
David M. Burger ◽  
...  
Keyword(s):  
Body Weight ◽  
Multivariate Analysis ◽  
Plasma Concentration ◽  
Protease Inhibitors ◽  
Demographic Data ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
The Mean

ABSTRACTTenofovir (TFV) is eliminated by renal excretion, which is mediated through multidrug-resistant protein 2 (MRP2) and MRP4, encoded byABCC2andABCC4, respectively. Genetic polymorphisms of these transporters may affect the plasma concentrations of tenofovir. Therefore, the aim of this study was to investigate the influence of genetic and nongenetic factors on tenofovir plasma concentrations. A cross-sectional study was performed in Thai HIV-infected patients aged ≥18 years who had been receiving tenofovir disoproxil fumarate at 300 mg once daily for at least 6 months. A middose tenofovir plasma concentration was obtained. Multivariate analysis was performed to investigate whether there was an association between tenofovir plasma concentrations and demographic data, including age, sex, body weight, estimated glomerular filtration rate (eGFR), hepatitis B virus coinfection, hepatitis C virus coinfection, duration of tenofovir treatment, concomitant use of ritonavir-boosted protease inhibitors, and polymorphisms ofABCC2andABCC4. A total of 150 Thai HIV-infected patients were included. The mean age of the patients was 43.9 ± 7.2 years. The mean tenofovir plasma concentration was 100.3 ± 52.7 ng/ml. In multivariate analysis, a low body weight, a low eGFR, the concomitant use of ritonavir-boosted protease inhibitors, and theABCC44131T → G variation (genotype TG or GG) were independently associated with higher tenofovir plasma concentrations. After adjusting for weight, eGFR, and the concomitant use of ritonavir-boosted protease inhibitors, a 30% increase in the mean tenofovir plasma concentration was observed in patients having theABCC44131 TG or GG genotype. Both genetic and nongenetic factors affect tenofovir plasma concentrations. These factors should be considered when adjusting tenofovir dosage regimens to ensure the efficacy and safety of a drug. (This study has been registered at ClinicalTrials.gov under registration no. NCT01138241.)

Pharmacokinetics of an IgM Human Monoclonal Antibody against Pseudomonas aeruginosa in Nonseptic Patients

1993 ◽  
Vol 167 (3) ◽  
pp. 784-785 ◽  
Author(s):  
G. Meng ◽  
T. Wong ◽  
L. D. Saravolatz ◽  
J. E. Pennington
Keyword(s):  
Monoclonal Antibody ◽  
Pseudomonas Aeruginosa ◽  
Human Monoclonal Antibody

scholarly journals The early changes in retinol-binding protein and prealbumin concentrations in plasma of protein–energy malnourished children after treatment with retinol and an improved diet

1980 ◽  
Vol 43 (3) ◽  
pp. 393-402 ◽  
Author(s):  
Suzanne Large ◽  
G. Neal ◽  
J. Glover ◽  
O. Thanangkul ◽  
R. E. Olson
Keyword(s):  
Body Weight ◽  
Vitamin A ◽  
Nutritional Status ◽  
Plasma Proteins ◽  
Binding Protein ◽  
Vitamin A Deficiency ◽  
Plasma Concentrations ◽  
Retinol Binding Protein ◽  
Mean Values ◽  
The Mean

1. Changes in total retinol-binding protein (RBP), the holoprotein (holoRBP) and prealbumin (PA) concentrations have been monitored in plasma of thirty protein- and vitamin A-deficient preschool children from within a few hours up to 7 weeks after treatment with retinol and a good-quality protein diet.2. The children were classified into groups according to nutritional status as having either kwashiorkor, marasmus-kwashiorkor or marasmus, and given formula diets whose protein and energy contents increased stepwise from 1 g and 105 kJ/kg body-weight respectively up to 4 g and 733 kJ/kg body-weight after 4 weeks. Retinol was administered in the forms of retinyl palmitate either orally or intramuscularly.3. PA and total RBP were determined by electroimmunoassay procedures and the holoRBP by its fluorescence after separation from other plasma proteins.4. RBP in plasma of the vitamin A-deficient child is largely denatured and incapable of binding administered retinol, which must first be taken up by the liver before native holoRBP is released. An increased pool of native apoprotein accumulates in the liver during vitamin A deficiency which is released into plasma quickly after retinol uptake to form peak concentrations of total and holoRBP approximately 3 h after dosing intramuscularly and 6 h orally.5. The accumulated pool of RBP was highest in livers from the marasmus group and lowest in those from the kwashiorkor group, reflecting their relative capacities to synthesize plasma proteins.6. The mean plasma concentrations of total and holoRBP for the various groups were minimal 24–48 h after dosing with retinol and then improved almost linearly over the following week.7. Mean plasma PA concentrations of the various groups on admission were also in order of the severity of their malnutrition. There was little or no change in this protein concentration over the first 24 h after dosing with retinol, but thereafter the mean values rose almost linearly over 2 weeks. Albumin on the other hand changed little during the first week. The results show that PA is the more sensitive measurement of protein nutritional status.

scholarly journals SUN-377 Efficacy of Low Dose Denosumab in Maintaining Bone Mineral Density in Postmenopausal Women with Osteoporosis: A Real World, Prospective Observational Study

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Aliya Aziz Khan ◽  
Hajar Abu Alrob ◽  
Iman M’Hiri ◽  
Hosay Said ◽  
Sharjil Hussain ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Monoclonal Antibody ◽  
Single Dose ◽  
Lumbar Spine ◽  
Postmenopausal Women ◽  
Low Dose ◽  
Human Monoclonal Antibody ◽  
Mineral Density ◽  
Percent Change ◽  
The Mean

Abstract Introduction: Denosumab, a fully human monoclonal antibody to RANK-ligand, has been shown to increase bone mineral density (BMD) and reduce the risk of hip, vertebral and non-vertebral fractures in postmenopausal women with osteoporosis (1-3). Varying doses of denosumab including 30mg/3months have demonstrated a decrease in bone remodelling in a dose-dependent manner (2,4-6). The primary objective of this study is to evaluate the efficacy of low dose denosumab (30mg/6 months) in postmenopausal women with osteoporosis who are reluctant to consider or continue the full dose of denosumab due to adverse events (AE) or concerns of potential AE. Methods: Following informed consent, postmenopausal women with a T-score of ≤ -2.5 at the lumbar spine (LS) or at the total hip (TH) received denosumab 30mg/6months. Patients with an additional skeletal disorder, prior fragility fracture, or on oral steroids (daily in the past 12 months) were excluded. The primary endpoint was the percent change in BMD at the lumbar spine (LS), total hip (HP), femoral neck (FN) and 1/3 radius (1/3R) at 12 months. Secondary outcomes were 1) percent change in BMD at the LS, TH, FN, and 1/3R at 24 months and 2) AE. Results: We enrolled 183 patients. The mean age was 69 years (SD= 7.07), 80% of patients had a moderate fracture risk (CAROC tool), 3% were current smokers and 9% consumed alcohol daily. 14.4% of patients were on SSRI/SNRI, 9.6% were on PPI, and no patient was on an aromatase inhibitor. At 12 months (n=125), the mean BMD significantly increased by +2.0% (95% CI 2.8%-1.3%) at the LS (p<0.001). There was no significant change in BMD at the FN, TH, AND 1/3R. At 24 months (n=65), the percent change in BMD was +3.4% (95% CI 4.8%-2.0%: p<0.001) at the LS, +1.5% (95% CI 2.9%-0.15%: p=0.031) at the FN, +1.9% (95% CI 3.5%-0.24%: p=0.025) at the 1/3R. There was no significant change in BMD at the TH. Conclusion: Low dose denosumab appears to be effective in maintaining BMD in postmenopausal women with a moderate fracture risk and may be of benefit in individuals who are experiencing side effects or concerns of side effects. This may also be of value following 10 years of therapy in order to maintain BMD. References 1.Bekker, PJ, Holloway DL, Rasmussen AS, Murphy R, Martin SW, Leese PT... Depaoli AM. A Single-Dose Placebo-Controlled Study of AMG 162, a Fully Human Monoclonal Antibody to RANKL, in Postmenopausal Women. JBMR, 2004;19(7), 1059-1066. 2.Kumagai Y, Hasunuma T, Padhi D. A randomized, double-blind, placebo-controlled, single-dose study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of denosumab administered subcutaneously to postmenopausal Japanese women. Bone, 2011;49(5), 1101-1107. 3.Lewiecki EM, Miller PD, Mcclung MR, Cohen SB, Bolognese MA, Liu Y, . . . Fitzpatrick LA. Two-Year Treatment With Denosumab (AMG 162) in a Randomized Phase 2 Study of Postmenopausal Women With Low BMD. JBMR, 2007;22(12), 1832-1841.

scholarly journals Imipenem/Cilastatin/Relebactam Alone and in Combination against Pseudomonas aeruginosa in the In Vitro Pharmacodynamic Model

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Iris H. Chen ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Pharmacodynamic Model ◽  
Resistance Development ◽  
Content Type ◽  
Combination Studies ◽  
The Mean ◽  
Combined Drugs

ABSTRACT Combination therapy may enhance imipenem/cilastatin/relebactam’s (I/R) activity against Pseudomonas aeruginosa and suppress resistance development. Human-simulated unbound plasma concentrations of I/R at 1.25 g every 6 h (h), colistin at 360 mg daily, and amikacin at 25 mg/kg daily were reproduced alone and in combination against six imipenem-nonsusceptible P. aeruginosa isolates in an in vitro pharmacodynamic model over 24 h. For I/R alone, the mean reductions in CFU ± the standard errors by 24 h were −2.52 ± 0.49, −1.49 ± 0.49, −1.15 ± 0.67, and −0.61 ± 0.10 log10 CFU/ml against isolates with MICs of 1/4, 2/4, 4/4, and 8/4 μg/ml, respectively. Amikacin alone also resulted in 24 h CFU reductions consistent with its MIC, while colistin CFU reductions did not differ. Resistant subpopulations were observed after 24 h in 1, 4, and 3 I/R-, colistin-, and amikacin-exposed isolates, respectively. The combination of I/R and colistin resulted in synergistic (n = 1) or additive (n = 2) interactions against three isolates with 24-h CFU reductions ranging from −2.62 to −4.67 log10 CFU/ml. The combination of I/R and amikacin exhibited indifferent interactions against all isolates, with combined drugs achieving −0.51- to −3.33-log10 CFU/ml reductions. No resistant subpopulations were observed during I/R and colistin combination studies, and when added to amikacin, I/R prevented the emergence of amikacin resistance. Against these six multidrug-resistant P. aeruginosa, I/R alone achieved significant CFU reductions against I/R-susceptible isolates. Combinations of I/R plus colistin resulted in additivity or synergy against some P. aeruginosa, whereas the addition of amikacin did not provide further antibacterial efficacy against these isolates.

scholarly journals Modulation of the Lung Inflammatory Response to Serotype 8 Pneumococcal Infection by a Human Immunoglobulin M Monoclonal Antibody to Serotype 8 Capsular Polysaccharide

2005 ◽  
Vol 73 (8) ◽  
pp. 4530-4538 ◽  
Author(s):  
Tamika Burns ◽  
Maria Abadi ◽  
Liise-anne Pirofski
Keyword(s):  
Monoclonal Antibody ◽  
Inflammatory Response ◽  
Capsular Polysaccharide ◽  
Human Monoclonal Antibody ◽  
Pneumococcal Infection ◽  
Immunoglobulin M ◽  
Enzyme Linked Immunosorbent Assay ◽  
Necrosis Factor Alpha ◽  
Monocyte Chemoattractant Protein 1

ABSTRACT The human monoclonal antibody to serotype 8 pneumococcal capsular polysaccharide D11 [immunoglobulin M(κ)] protects wild-type and complement component 4 knockout (C4 KO) mice against lethal intratracheal challenge with serotype 8 pneumococcus, but it does not promote polymorphonuclear leukocyte (PMN)-mediated pneumococcal killing in vitro. In this study, we investigated the effect of D11 on the blood and lung bacterial burdens and the serum and lung expression of inflammatory chemokines and cytokines in an intratracheal challenge model with serotype 8 pneumococcus in C4 KO mice. Pneumococcus was not detected in the blood of D11-treated mice, whereas control mice had high-grade bacteremia with >107 CFU. Control mice had a >5-log increase in lung CFU and D11-treated mice manifested a nearly 3-log increase in lung CFU compared to the original inoculum 24 h after infection. Serum and lung levels of soluble macrophage inflammatory protein 2 (MIP-2) and interleulin-6 (IL-6) as measured by an enzyme-linked immunosorbent assay were lower in D11-treated mice than in control mice 24 h after infection. Real-time PCR was performed to examine lung mRNA chemokine and cytokine expression. The results showed that D11-treated mice had significantly less gamma interferon, MIP-2, IL-12, monocyte chemoattractant protein 1/JE, and tumor necrosis factor alpha expression than control mice 24 h after infection. Histopathology and immunohistochemical staining of lung tissues revealed that D11-treated mice had less inflammation, fewer PMNs, and less myeloperoxidase staining than control mice 24 h after infection. These findings suggest that the efficacy of certain serotype-specific antibodies against pneumococcal pneumonia could be associated with modulation of the lung inflammatory response and a reduction in host damage.

scholarly journals Effect of Thunbergia laurifolia Herbal Tea on Glucose Homeostasis in Healthy Volunteers: A Single-Arm Phase I Study

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Lukana Preechasuk ◽  
Pravit Akarasereenont ◽  
Ranida Boonrak ◽  
Onusa Thamsermsang ◽  
Busadee Pratumvinit ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Healthy Volunteers ◽  
Glucose Homeostasis ◽  
Plasma Glucose ◽  
Fasting Plasma Glucose ◽  
Plasma Concentrations ◽  
Herbal Tea ◽  
Serious Adverse Events ◽  
Fasting Plasma ◽  
Thunbergia Laurifolia

Background. Thunbergia laurifolia (TL) is a commonly used herbal medicine in Thailand and in other Asian countries. TL has been approved as a Thai traditional medicine for detoxifying poisons, and the list of possible adverse effects includes hypoglycemia. TL showed hypoglycemic effect in animals possibly due to antioxidant effect and beta-cell preservation. However, the safety of TL herbal tea and its effects on glucose homeostasis have never been investigated in humans. Methods. Twenty healthy volunteers (10 men and 10 women) drank TL herbal tea 3 times/day for 2 weeks. Ten subjects took TL herbal tea 9 grams daily. After the safety of TL herbal tea was established, 10 more subjects took TL 12 grams daily. Clinical and biochemical tests were assessed at baseline and at 2 weeks. Results. Mean age was 34.9 ± 10.2 years, and mean body mass index was 27.5 ± 5.8 kg/m2. Baseline and posttreatment plasma concentrations were as follows: fasting plasma glucose (89 ± 6 vs. 89 ± 7 mg/dL), fructosamine (213 ± 32 vs. 212 ± 33 μmol/L), fasting insulin (8.8 [IQR: 5.9–18.4] vs. 10.4 [IQR: 7.4–15.2] μU/mL), HOMA-B (101.6 [IQR: 82.3–189.8] vs. 120.4 [IQR: 93.2–153.2]), and HOMA-IR (1.1 [IQR: 0.8–2.3] vs. 1.4 [IQR: 0.9–2.0]), all respectively. There were no significant changes in these parameters, including body weight, blood pressure, lipid profile, and C-reactive protein. No serious adverse events were observed during the study period. Conclusions. TL herbal tea at doses of 9 and 12 grams daily had good tolerability without any significant adverse effects on fasting plasma glucose level or other glucose homeostasis parameters measured.

scholarly journals Opposite Effects of Single-Dose and Multidose Administration of the Ethanol Extract of Danshen on CYP3A in Healthy Volunteers

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Furong Qiu ◽  
Jian Jiang ◽  
Yueming Ma ◽  
Guangji Wang ◽  
Chenglu Gao ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Plasma Concentrations ◽  
In Vitro Study ◽  
Ethanol Extract ◽  
Tanshinone Iia ◽  
Open Label ◽  
The Mean

The aim of this study was to investigate the effect of single- and multidose administration of the ethanol extract of danshen on in vivo CYP3A activity in healthy volunteers. A sequential, open-label, and three-period pharmacokinetic interaction study design was used based on 12 healthy male individuals. The plasma concentrations of midazolam and its metabolite 1-hydroxymidazolam were measured. Treatment with single dose of the extract caused the meanCmaxof midazolam to increase by 87% compared with control. After 10 days of the danshen extract intake, the mean AUC0–12,Cmax, andt1/2of midazolam were decreased by 79.9%, 66.6%, and 43.8%, respectively. The mean clearance of midazolam was increased by 501.6% compared with control. The in vitro study showed that dihydrotanshinone I in the extract could inhibit CYP3A, while tanshinone IIA and cryptotanshinone could induce CYP3A. In conclusion, a single-dose administration of the danshen extract can inhibit intestinal CYP3A, but multidose administration can induce intestinal and hepatic CYP3A.

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