scholarly journals Development of an Innovative Berberine Food-Grade Formulation with an Ameliorated Absorption: In Vitro Evidence Confirmed by Healthy Human Volunteers Pharmacokinetic Study

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Giovanna Petrangolini ◽  
Fabrizio Corti ◽  
Massimo Ronchi ◽  
Lolita Arnoldi ◽  
Pietro Allegrini ◽  
...  
Keyword(s):  
Oral Administration ◽  
Healthy Volunteers ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Healthy Human ◽  
Food Grade ◽  
Dose Linearity ◽  
Human Volunteers ◽  
Intestinal Fluids

Objective. To evaluate in vitro solubility, bioaccessibility, and cytotoxic profile, together with a pharmacokinetic profile by oral administration to healthy volunteers of a novel food-grade berberine formulation (BBR-PP, i.e., berberine Phytosome®). Results. An in vitro increase of solubility in simulated gastric and intestinal fluids and an improved bioaccessibility at intestinal level along with a lower cytotoxicity with respect to berberine were observed with BBR-PP. The pharmacokinetic profile of the oral administration to healthy volunteers confirmed that berberine Phytosome® significantly ameliorated berberine absorption, in comparison to unformulated berberine, without any observed side effects. The berberine plasma concentrations observed with both doses of BBR-PP were significantly higher than those seen after unformulated berberine administration, starting from 45 min (free berberine) and 30 min (total berberine). Furthermore, BBR-PP improved berberine bioavailability (AUC) was significantly higher, around 10 times on molar basis and with observed dose linearity, compared to the unformulated berberine. Conclusion. These findings open new perspectives on the use of this healthy berberine formulation in metabolic discomforts.

Protection of chemo-radiation therapy induced oral mucositis (OM) in pre-clinical and clinical studies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5567-5567
Author(s):  
A. Rehemtulla ◽  
W. Grove ◽  
P. Sunkara ◽  
M. Naidu ◽  
B. D. Ross
Keyword(s):  
Clinical Studies ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Tumor Control ◽  
Healthy Human ◽  
Human Volunteers ◽  
Radiation Induced ◽  
Grade 3 ◽  
Historical Controls

5567 Background: D-methionine, was shown to selectively protect normal but not tumor cells from loss of mitochondrial integrity and viability in response to ionizing radiation. OM is a debilitating complication of radiotherapy (RT) and chemotherapy (CT). MRx-1024, a orally bio-available formulation of this agent was evaluated as a treatment for the protection of OM. Methods: A mouse model of radiation-induced lip erythema was used to evaluate the efficacy of MRx-1024. Pharmacokinetic profile of MRX-1024 in healthy human volunteers as well as evaluation of oral MRX-1024 was accomplished in patients (pts) with head and neck cancer receiving RT or RT+CT. Pts received 1.8–2.0 Gy of RT daily for 5 days each week, to a total of 60 Gy. Selected pts also received cisplatin, 50mg/m2 weekly. MRX-1024 suspension was given 1 hour before and again after each RT fraction. Pts were evaluated weekly using 4 accepted scales for assessing OM. Results: A significant protection of radiation-induced lip erythema was achieved in pre-clinical studies without compromising tumor control. Plasma concentrations of MRx-1024 achieved in normal volunteers after oral administration were similar to those required for efficacy in pre-clinical studies. No major adverse events were attributed to MRx-1024. The incidence of OM from 21 evaluable pts was compared with historical controls from the same institution. MRX-1024 was found to be a safe, easily administered and well-tolerated agent that completely ameliorated the incidence of Grade 4 (21% in historical controls) and reduced the incidence of Grade 3 by 80% over historical controls. In addition, preliminary analysis indicated that MRX-1024 did not compromise antitumor activity. Conclusions: These pre-clinical and clinical studies provide exciting proof of principle evidence for the use of MRx-1024 in the treatment of OM. Follow-up clinical studies are underway to further validate these results. [Table: see text]

Gastroretentive Floating Capsules of Risedronate Sodium: Development, Optimization, in vitro and in vivo Evaluation in Healthy Human Volunteers

2015 ◽  
Vol 8 (2) ◽  
pp. 2835-2842
Author(s):  
Bhikshapathi D. V. R. N. ◽  
Arun Kumar Jarathi ◽  
Suresh Gande ◽  
Viswaja Medipally ◽  
Ramesh Bomma
Keyword(s):  
Drug Release ◽  
Sustained Release ◽  
Zero Order ◽  
Wet Granulation ◽  
Capsule Formulation ◽  
In Vivo Evaluation ◽  
Healthy Human ◽  
X Ray ◽  
Human Volunteers

Background and the purpose of the study: Risedronate sodium inhibits osteoclast bone resorption and modulates bone metabolism. Risedronate has a high affinity for hydroxyapatite crystals in bone and is a potent antiresorptive agent. In the present investigation efforts were made to improve the bioavailability of risedronate sodium by increasing the residence time of the drug through sustained-release matrix capsule formulation via gastroretentive mechanism. Capsules were prepared by wet granulation technique. The influence of gel forming agents, amount of risedronate and total weight of capsules on physical properties, in vitro buoyancy, drug release, FTIR, DSC, X-ray studies were investigated. The release mechanisms were explored and explained by applying zero order, first order, Higuchi and Korsmeyer equations. The selected formulations were subjected to stability study at 40 °C/75% RH, 25 °C/60% RH for the period of three months. For all formulations, kinetics of drug release from capsules followed Higuchi’s square root of time kinetic treatment heralding diffusion as predominant mechanism of drug release. Formulation containing 25 mg HPMC K4M and 75 mg HPMC K100 LV (F-8) showed zero order release profile. There was no significant change in the selected formulation, when subjected to accelerated stability conditions over a period of three months. X-ray imaging in six healthy human volunteers revealed a mean gastric retention period of 5.60 ± 0.77 hrs for the selected formulation. Stable, sustained release effervescent floating capsules of risedronate sodium could be prepared by wet granulation technique.  

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals Pharmacokinetic Profile of μSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats

2015 ◽  
Vol 10 (9) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Rosario Russo ◽  
Angelo Mancinelli ◽  
Michele Ciccone ◽  
Fabio Terruzzi ◽  
Claudio Pisano ◽  
...  
Keyword(s):  
Oral Administration ◽  
Plasma Concentrations ◽  
Compartmental Analysis ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Sprague Dawley ◽  
Time Curve ◽  
Maximum Plasma Drug Concentration

Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (μSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t1/2), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with μSMIN Plus™ compared with animals treated with micronized diosmin. In particular, μSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for μSMIN Plus™, which may represent a new tool for CVI management.

scholarly journals ABT-378, a Highly Potent Inhibitor of the Human Immunodeficiency Virus Protease

1998 ◽  
Vol 42 (12) ◽  
pp. 3218-3224 ◽  
Author(s):  
Hing L. Sham ◽  
Dale J. Kempf ◽  
Akhteruzammen Molla ◽  
Kennan C. Marsh ◽  
Gondi N. Kumar ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Response To Therapy ◽  
Hiv Protease ◽  
Healthy Human ◽  
Human Volunteers ◽  
Immunodeficiency Virus ◽  
Potent Protease Inhibitor

ABSTRACT The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 μM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, ≤0.06 μM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.

scholarly journals Comparative Bioavailabilitv Studv of Two Brands of Terbutaline Sulphate Tablets in Healthy Human Volunteers

2004 ◽  
Vol 72 (3) ◽  
pp. 227-237
Author(s):  
Nahla S. Barakat ◽  
Nawal M. Khalafallah ◽  
Said A. Khalil
Keyword(s):  
Single Dose ◽  
Reference Product ◽  
Hplc Method ◽  
Fasting State ◽  
Unchanged Drug ◽  
Healthy Human ◽  
Terbutaline Sulphate ◽  
Human Volunteers

The purpose of this study was to evaluate the bioavailability of locally produced 2.5 mg terbutaline sulphate tablets (brand A ) relative to a reference product, Bricanyl 2.5 mg tablets (brand 6). The study was a single dose 5 mg randomized crossover one in 15 healthy volunteers in the fasting state. Urine was collected at intervals of 24 h. Total terbutaline excreted in urine as unchanged drug and as conjugates (sulphate and glucuronide) was determined by a developed and validated HPLC method. In-vitro characteristics of both brands were similar. Based on percent of the dose excreted in urine, the oral bioavailability ranged from 33.5% to 75.8% for both brands. Statistics were applied to judge bioequivalence according to USP 24 in-vivo bioequivalence guidance. Results indicated that brand A and B were bioequivalent and hence interchangeable in medical practice.

In vivo generation of human dendritic cell subsets by Flt3 ligand

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 878-884 ◽  
Author(s):  
Eugene Maraskovsky ◽  
Elizabeth Daro ◽  
Eileen Roux ◽  
Mark Teepe ◽  
Charlie R. Maliszewski ◽  
...  
Keyword(s):  
T Cell Immunity ◽  
Human Dendritic Cell ◽  
Flt3 Ligand ◽  
Healthy Human ◽  
Cell Immunity ◽  
Human Volunteers ◽  
Immune Response Regulation ◽  
Dendritic Cell Subsets

Abstract Dendritic cells (DCs) represent a family of ontogenically distinct leukocytes involved in immune response regulation. The ability of DCs to stimulate T-cell immunity has led to their use as vectors for immunotherapy vaccines. However, it is unclear whether and to what degree in vitro–generated DCs are representative of DCs that develop in vivo. Treatment of mice with human Flt3 ligand (FL) dramatically increases the number of DCs. We report here that administration of FL to healthy human volunteers increased the number of circulating CD11c+ IL-3Rlow DC (mean 44-fold) and CD11c− IL-3Rhigh DC precursors (mean 12-fold). Moreover, the CD11c+ DCs were efficient stimulators of T cells in vitro. Thus, FL can expand the number of circulating, functionally competent human DCs in vivo.

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.

scholarly journals Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non–transferrin-bound iron

Blood ◽  
2011 ◽  
Vol 118 (25) ◽  
pp. 6675-6682 ◽  
Author(s):  
Eldad A. Hod ◽  
Gary M. Brittenham ◽  
Genia B. Billote ◽  
Richard O. Francis ◽  
Yelena Z. Ginzburg ◽  
...  
Keyword(s):  
Total Bilirubin ◽  
Transferrin Saturation ◽  
Serum Total Bilirubin ◽  
Healthy Human ◽  
Human Volunteers ◽  
Iron Parameters ◽  
Rapid Clearance ◽  
Fresh Rbcs ◽  
Proliferation In Vitro

Abstract Transfusions of RBCs stored for longer durations are associated with adverse effects in hospitalized patients. We prospectively studied 14 healthy human volunteers who donated standard leuko-reduced, double RBC units. One unit was autologously transfused “fresh” (3-7 days of storage), and the other “older” unit was transfused after 40 to 42 days of storage. Of the routine laboratory parameters measured at defined times surrounding transfusion, significant differences between fresh and older transfusions were only observed in iron parameters and markers of extravascular hemolysis. Compared with fresh RBCs, mean serum total bilirubin increased by 0.55 mg/dL at 4 hours after transfusion of older RBCs (P = .0003), without significant changes in haptoglobin or lactate dehydrogenase. In addition, only after the older transfusion, transferrin saturation increased progressively over 4 hours to a mean of 64%, and non–transferrin-bound iron appeared, reaching a mean of 3.2μM. The increased concentrations of non–transferrin-bound iron correlated with enhanced proliferation in vitro of a pathogenic strain of Escherichia coli (r = 0.94, P = .002). Therefore, circulating non–transferrin-bound iron derived from rapid clearance of transfused, older stored RBCs may enhance transfusion-related complications, such as infection. The trial was registered with www.clinicaltrials.gov as #NCT01319552.

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