Phase I and pharmacokinetic (PK) dose-adjusted study of IV vinflunine (VFL) in cancer patients with liver dysfunction (LD): Pharmacokinetic results

2523 Background: VFL is a novel microtubule inhibitor of the vinca alkaloid class that has shown high antitumour activity in several in vivo tumour models and in clinical trials. VFL is mainly eliminated through metabolism and bile excretion. Therefore this trial was designed to determine if LD could increase exposure and toxicity of VFL and require a dose-adjustment. Methods: This trial had a sequential design with the objective of determining the maximal tolerated dose (MTD) and the recommended dose (RD) in three groups of LD based on clinical and biological criteria: mild (PT > 70% and UNL < serum bilirubin = 1.5xUNL), moderate (Child-Pugh A) and severe (Child-Pugh B). VFL and 4-O-deacetylvinflunine (DVFL), its only active metabolite, were quantified in whole blood during cycle 1. PK parameters (AUCinf, Cltot) were estimated using a non-compartmental analysis and were compared using a one-way ANOVA with group factor either between groups or between groups and a control group of 49 patients without LD enrolled in phase I trials). Results: Three VFL doses were investigated: The inter-individual variability (CV) in AUCinf was approximately 30% for all groups. Even if AUCinf increased between mild and moderate groups, no difference was demonstrated between moderate and severe LD groups. All individual values were within the range of control values. Cltot were also similar between groups and the control group. Statistical analysis did not evidence any significant difference between groups. No difference was observed in blood concentrations of DVFL compared to the control group. No relationship between dose limiting toxicity and blood exposure was evidenced. Conclusions: The results showed that vinflunine and DVFL pharmacokinetic parameters do not appear to be affected by the degree of LD. However, the dose of VFL has to be adjusted to the level of LD for safety reasons. [Table: see text] No significant financial relationships to disclose.

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Optimizing Manufacturing and Osseointegration of Ti6Al4V Implants through Precision Casting and Calcium and Phosphorus Ion Implantation? In Vivo Results of a Large-Scale Animal Trial

Materials ◽

10.3390/ma13071670 ◽

2020 ◽

Vol 13 (7) ◽

pp. 1670 ◽

Cited By ~ 2

Author(s):

Wölfle-Roos JV ◽

Katmer Amet B ◽

Fiedler J ◽

Michels H ◽

Kappelt G ◽

...

Keyword(s):

Ion Implantation ◽

Large Scale ◽

In Vivo Studies ◽

Control Group ◽

Implant Surface ◽

Precision Casting ◽

Pull Out ◽

Significant Difference ◽

Calcium And Phosphorus

Background: Uncemented implants are still associated with several major challenges, especially with regard to their manufacturing and their osseointegration. In this study, a novel manufacturing technique—an optimized form of precision casting—and a novel surface modification to promote osseointegration—calcium and phosphorus ion implantation into the implant surface—were tested in vivo. Methods: Cylindrical Ti6Al4V implants were inserted bilaterally into the tibia of 110 rats. We compared two generations of cast Ti6Al4V implants (CAST 1st GEN, n = 22, and CAST 2nd GEN, n = 22) as well as cast 2nd GEN Ti6Al4V implants with calcium (CAST + CA, n = 22) and phosphorus (CAST + P, n = 22) ion implantation to standard machined Ti6Al4V implants (control, n = 22). After 4 and 12 weeks, maximal pull-out force and bone-to-implant contact rate (BIC) were measured and compared between all five groups. Results: There was no significant difference between all five groups after 4 weeks or 12 weeks with regard to pull-out force (p > 0.05, Kruskal Wallis test). Histomorphometric analysis showed no significant difference of BIC after 4 weeks (p > 0.05, Kruskal–Wallis test), whereas there was a trend towards a higher BIC in the CAST + P group (54.8% ± 15.2%), especially compared to the control group (38.6% ± 12.8%) after 12 weeks (p = 0.053, Kruskal–Wallis test). Conclusion: In this study, we found no indication of inferiority of Ti6Al4V implants cast with the optimized centrifugal precision casting technique of the second generation compared to standard Ti6Al4V implants. As the employed manufacturing process holds considerable economic potential, mainly due to a significantly decreased material demand per implant by casting near net-shape instead of milling away most of the starting ingot, its application in manufacturing uncemented implants seems promising. However, no significant advantages of calcium or phosphorus ion implantation could be observed in this study. Due to the promising results of ion implantation in previous in vitro and in vivo studies, further in vivo studies with different ion implantation conditions should be considered.

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An in Vivo Comparison of Antimicrobial Efficacy of Sodium Hypochlorite and Biopure MTAD™ against Enterococcus Faecalis in Primary Teeth: A qPCR Study

Journal of Clinical Pediatric Dentistry ◽

10.17796/jcpd.39.1.c4q2155r16817219 ◽

2014 ◽

Vol 39 (1) ◽

pp. 30-34 ◽

Cited By ~ 3

Author(s):

SG Tulsani ◽

N Chikkanarasaiah ◽

S Bethur

Keyword(s):

Root Canal ◽

Primary Teeth ◽

Antimicrobial Efficacy ◽

Permanent Teeth ◽

Control Group ◽

Statistical Significant Difference ◽

Anterior Teeth ◽

Significant Difference ◽

Root Canal Irrigant

Objectives: Biopure MTAD™, a new root canal irrigant has shown promising results against the most common resistant microorganism, E. faecalis, in permanent teeth. However, there is lack of studies comparing its antimicrobial effectiveness with NaOCl in primary teeth. The purpose of this study was to compare the in vivo antimicrobial efficacy of NaOCl 2.5% and Biopure MTAD™ against E. faecalis in primary teeth. Study design: Forty non vital single rooted primary maxillary anterior teeth of children aged 4-8 years, were irrigated either with NaOCl 2.5% (n=15), Biopure MTAD™ (n=15) and 0.9% Saline (n=10, control group). Paper point samples were collected at baseline (S1) and after chemomechanical preparation (S2) during the pulpectomy procedure. The presence of E. faecalis in S1 & S2 was evaluated using Real time Polymerase Chain Reaction. Results: Statistical significant difference was found in the antimicrobial efficacy of NaOCl 2.5 % and BioPure MTAD™ when compared to saline (p>0.05). However, no statistical significant difference was found between the efficacies of both the irrigants. Conclusions: NaOCl 2.5% and BioPure MTAD™, both irrigants are equally efficient against E. faecalis in necrotic primary anterior teeth. MTAD is a promising irrigant, however clinical studies are required to establish it as ideal root canal irrigant in clinical practice.

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Effect of insulin-induced hypoglycaemia on antral, pyloric and duodenal motility in fasting subjects

Clinical Science ◽

10.1042/cs0810281 ◽

1991 ◽

Vol 81 (2) ◽

pp. 281-285 ◽

Cited By ~ 4

Author(s):

R. Fraser ◽

J. Fuller ◽

M. Horowitz ◽

J. Dent

Keyword(s):

Blood Glucose ◽

Gastric Emptying ◽

Phase I ◽

Blood Glucose Concentration ◽

Migrating Motor Complex ◽

Control Group ◽

Motor Complex ◽

Significant Difference ◽

Interdigestive Migrating Motor Complex ◽

Pyloric Motility

1. Hyperglycaemia alters gastric motility and delays gastric emptying. By contrast, there is little information regarding the effect of sub-normal blood glucose concentrations on gastric and, in particular, pyloric motility, although limited data suggest that hypoglycaemia is associated with accelerated gastric emptying despite an apparently increased basal pyloric pressure. 2. To determine the effects of hypoglycaemia on pyloric motility, we compared the effects of an intravenous injection of insulin (0.15 units/kg) with those of a placebo injection of saline in eight healthy human volunteers during phase I of the interdigestive migrating motor complex. 3. All subjects developed profound hypoglycaemia (mean blood glucose concentration 1.6 mmol/l compared with 4.0 mmol/l in the control group). 4. There was no significant difference in the number of antral (9 versus 7, P = 0.34), pyloric (3 versus 0, P = 0.31) or duodenal (21 versus 13, P = 0.42) pressure waves or in the basal pyloric pressure (0.3 mmHg versus 0.1 mmHg, P = 0.37) in the 45 min after insulin injection (hypoglycaemia) when compared with the 45 min after saline injection (euglycaemia). In both the euglycaemic and hypoglycaemic studies there was a time-dependent increase in the numbers of antral and duodenal waves consistent with the expected changes in the interdigestive migrating motor complex. 5. These results indicate that insulin-induced hypoglycaemia has no significant effect on pyloric motility during phase I of the interdigestive migrating motor complex.

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Capacity of Human Nisin- and Pediocin-Producing Lactic Acid Bacteria To Reduce Intestinal Colonization by Vancomycin-Resistant Enterococci

Applied and Environmental Microbiology ◽

10.1128/aem.02150-07 ◽

2008 ◽

Vol 74 (7) ◽

pp. 1997-2003 ◽

Cited By ~ 85

Author(s):

Mathieu Millette ◽

Gilbert Cornut ◽

Claude Dupont ◽

François Shareck ◽

Denis Archambault ◽

...

Keyword(s):

Lactic Acid ◽

Lactic Acid Bacteria ◽

In Vivo Study ◽

Control Group ◽

Intestinal Colonization ◽

Strong Activity ◽

Vancomycin Resistant Enterococci ◽

Significant Difference ◽

Vancomycin Resistant

ABSTRACT This study demonstrated the capacity of bacteriocin-producing lactic acid bacteria (LAB) to reduce intestinal colonization by vancomycin-resistant enterococci (VRE) in a mouse model. Lactococcus lactis MM19 and Pediococcus acidilactici MM33 are bacteriocin producers isolated from human feces. The bacteriocin secreted by P. acidilactici is identical to pediocin PA-1/AcH, while PCR analysis demonstrated that L. lactis harbors the nisin Z gene. LAB were acid and bile tolerant when assayed under simulated gastrointestinal conditions. A well diffusion assay using supernatants from LAB demonstrated strong activity against a clinical isolate of VRE. A first in vivo study was done using C57BL/6 mice that received daily intragastric doses of L. lactis MM19, P. acidilactici MM33, P. acidilactici MM33A (a pediocin mutant that had lost its ability to produce pediocin), or phosphate-buffered saline (PBS) for 18 days. This study showed that L. lactis and P. acidilactici MM33A increased the concentrations of total LAB and anaerobes while P. acidilactici MM33 decreased the Enterobacteriaceae populations. A second in vivo study was done using VRE-colonized mice that received the same inocula as those in the previous study for 16 days. In L. lactis-fed mice, fecal VRE levels 1.73 and 2.50 log10 CFU/g lower than those in the PBS group were observed at 1 and 3 days postinfection. In the P. acidilactici MM33-fed mice, no reduction was observed at 1 day postinfection but a reduction of 1.85 log10 CFU/g was measured at 3 days postinfection. Levels of VRE in both groups of mice treated with bacteriocin-producing LAB were undetectable at 6 days postinfection. No significant difference in mice fed the pediocin-negative strain compared to the control group was observed. This is the first demonstration that human L. lactis and P. acidilactici nisin- and pediocin-producing strains can reduce VRE intestinal colonization.

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PENGARUH EKSTRAK DAGING LIDAH BUAYA (Aloe Vera) TERHADAP PENYEMBUHAN ULSERASI MUKOSA MULUT PADA MALE WISTAR RATS

ODONTO Dental Journal ◽

10.30659/odj.1.1.25-28 ◽

2015 ◽

Vol 1 (1) ◽

pp. 25

Author(s):

Laila Fitrotuz Zahroh ◽

Rahmawati Sri Praptiningsih ◽

Moh. Baehaqi

Keyword(s):

Oral Mucosa ◽

Wistar Rats ◽

Healing Process ◽

Research Result ◽

Aloe Vera ◽

Control Group ◽

Control Group Design ◽

Significant Difference ◽

Male Wistar Rats

Background: Oral mucosa ulceration which often occurs usually in the form of white-yellowish spot with concave surface, reddish edge and pain. Based on previous research, Aloe vera process anti-inflammation substance that could help quickening ulceration healing process. This research aims to know the effect of Aloe vera flesh extract on Male wistar rats oral mucosa ulceration in-vivo. Method: this research was quasi experimental research with the post-test only control group design using Male wistar rats as the testing animal. In the research, there were three treatment groups: The first groups which was given aquadest treatment, second groups with Aloe vera flesh extract, and third groups which was given chlorhexidine gluconate 0,2% treatment. The data collecting was based on histopathology observation concerning the increase of fibroblast quantity. Result: The research result based on comparison test among the three groups with One Way Anova showed that on Day 3th, the average quantity of fibroblast didn't have significant difference between the treatment group and control group positive that was p>0,05, meanwhile on Day 7th every group showed significant difference p<0,05. Conclusion: It concluded that Aloe vera flesh extract has influence on the healing of Male wistar rats oral mucosa ulceration as shown by fibroblast increasing quantity.

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Comparison of Biocompatibility of Experimental Tricalcium Phosphate Cement versus Biodentin and Mineral Trioxide Aggregate used for Furcation Perforation Repair (in vivo study)

The Open Dentistry Journal ◽

10.2174/1874210602115010532 ◽

2021 ◽

Vol 15 (1) ◽

pp. 532-538

Author(s):

Mostafa M. El-Bialy ◽

Magdy M. Ali ◽

Engy M. Kataia ◽

Reham S. El Nemr ◽

Reham Hassan

Keyword(s):

Tricalcium Phosphate ◽

Mineral Trioxide Aggregate ◽

Positive Control ◽

Control Group ◽

Tooth Survival ◽

Significant Difference ◽

Operative Evaluation ◽

Root Canal System ◽

Bone Deposition

Background: The interaction between the root canal system and the oral cavity caused by iatrogenic perforations significantly affects the treatment outcome and tooth survival. Objectives: This study was directed to compare the biocompatibility of an experimental tricalcium phosphate cement versus biodentine and mineral Trioxide aggregate used for furcation perforation repair in dogs. Methods: Perforations were done in 60 teeth (premolars and molars) of six adult dogs. Animals were divided randomly into 3 equal groups of 2 animals each according to the post-operative evaluation period of 1 week, 1 month, and 3-months. Each group was further subdivided into 4 subgroups according to either being repaired with the experimental tricalcium phosphate cement (n=6), or Biodentine (n=6), Mineral Trioxide Aggregate (MTA) (n=6), and positive control(n=2). After evaluation periods, tissue blocks were harvested and histologically examined. Results: No statistically significant difference was found regarding bone deposition scores and inflammatory reaction in the three groups after 1 week, 1 month, or 3 months. All three groups showed a statistically significant difference between all three time periods. Regardless of the repair material used, inflammation scores at 1-week showed the highest scores, decreasing over time except for the control group. Conclusion: The experimental material could be considered as a successful treatment option for repairing furcation perforation.

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Effect of Titanium Implants Coated with Radiation-Crosslinked Collagen on Stability and Osseointegration in Rat Tibia

Materials ◽

10.3390/ma11122520 ◽

2018 ◽

Vol 11 (12) ◽

pp. 2520 ◽

Cited By ~ 4

Author(s):

Eun-Bin Bae ◽

Ji-Hyun Yoo ◽

Sung-In Jeong ◽

Min-Su Kim ◽

Youn-Mook Lim ◽

...

Keyword(s):

Gamma Radiation ◽

Human Mesenchymal Stem Cells ◽

Region Of Interest ◽

Bone Volume ◽

Titanium Implants ◽

Control Group ◽

Gene Expressions ◽

Significant Difference

This study aimed to evaluate the titanium (Ti) implants coated with collagen type Ⅰ crosslinked using gamma-irrigation or glutaraldehyde (GA). The in vitro surface observations, quantification assay, and cell studies using human mesenchymal stem cells (hMSCs) were conducted. For in vivo experiments, the implants were divided into three groups and inserted into the rat tibias: control group (non-treated Ti implant), GA group (Ti implants coated with GA-crosslinked collagen) and 25 kGy group (Ti implants coated with gamma-radiation-crosslinked collagen at dose of 25 kGy). The animals were sacrificed at 4 weeks after implantation and the tissue sections were obtained. New bone volume (mm3) and bone-to-implant contact (BIC, %) within the region of interest (ROI) was measured. The in vitro results showed the highest osteogenic differentiation and levels of osteogenesis-related gene expressions in the 25 kGy group without cytotoxicity. The new bone volume of GA group was significantly higher than the control (p < 0.05). In the result of the BIC, the 25 kGy group was significantly higher than the control (p < 0.05). However, there was no significant difference between the experimental groups. Within the limitations of this study, Ti implant coated with gamma-radiation-crosslinked collagen has potential utility without side effects from chemical agents.

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Decrease in Platelet Aggregability after Total Oophorectomy

10.1055/s-0039-1680560 ◽

1977 ◽

Author(s):

H. Yamazaki ◽

T. Motomiya ◽

M. Sonoda ◽

N. Miyagawa

Keyword(s):

Platelet Count ◽

Clinical Evidence ◽

Coulter Counter ◽

Control Group ◽

Bilateral Oophorectomy ◽

Platelet Volume ◽

Platelet Aggregability ◽

Significant Difference ◽

Before And After

Substantial clinical evidence indicates that large doses of estrogen frequenly result in thromboembolic disorders. Effects of estrogen on platelet aggregability were examined in women with uterine myoma before and after oophorectomy. Bilateral oophorectomy on 15 cases (48.7+0.12 yrs, mean+SE) and unilateral or no oophorectomy on 18 cases (control group : 42.2+0.18 yrs) were performed with myomectomy of the uterus. On one day before and one day, one week and one month after the operation performed, their platelet count by Coulter counter, platelet volume by Coulter channelyzer and platelet aggregability by Sienco aggregometer were measured. 24 hrs total estrogen in urine was also determined. In the control group, platelet counts were 85.1+ 4.9 % of the preoperated value one day after, 127.9+9.0 % one week after and 98.1+7.6 % one month after the operation. In the bilateral oophorectomy group, these were 82.4+5.2 % one day after, 124.0+4.7 % one week after and 96.1+4.8 % one month after. Both the groups showed the same change. Platelet aggregability by 3 μM ADP were 76.9+14.3 % one day after, 203.0+57.1 % one week after and 193.4+59.0 % one month after in the control, while 55.0+13.6 % one day after, 102.5+12.9 % one week after and 60.6+14.7 % one month after the operation in the total oophorectomy group. There was a statistically significant difference in the values obtained one month after the operation between the groups (p<0.05). Characteristic changes in platelet volumes were also observed. A significant correlation was observed between the platelet aggre-gabilities and the daily urinary estrogen excretion levels. The above results suggest that estrogen may enhance platelet aggregability in vivo.

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Acmella oleracea (L) R. K. Jansen Reproductive Toxicity in Zebrafish: An In Vivo and In Silico Assessment

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/1237301 ◽

2019 ◽

Vol 2019 ◽

pp. 1-19 ◽

Cited By ~ 9

Author(s):

Gisele Custodio de Souza ◽

Arlindo César Matias Pereira ◽

Muller Duarte Viana ◽

Adriana Maciel Ferreira ◽

Ianna Dias Ribeiro da Silva ◽

...

Keyword(s):

Embryonic Development ◽

In Silico ◽

Reproductive Toxicity ◽

Control Group ◽

The North ◽

Significant Difference ◽

Hydroethanolic Extract ◽

Primary Compound ◽

F1 Generation

The plant species Acmella oleracea L. is used in the north of Brazil for the treatment of a range of illnesses, such as tuberculosis, flu, cough, and rheumatism and as an anti-inflammatory agent; besides, hydroethanolic formulations with this species are popularly used as a female aphrodisiac agent. However, currently, there are no studies performed evaluating its effect on embryonic development. Hence, this research aimed to evaluate the effects of the hydroethanolic extract of A. oleracea (EHFAo) on the reproductive performance (parental) and embryonic development (F1 generation) of zebrafish, at concentrations of 50, 100, and 200 μg/L. Histopathology of parental gonads after 21 days of exposure to EHFAo reveals few alterations in the ovaries and testes, not impairing the reproduction; an increase of eggs deposition was observed in animals treated with EHFAo at the highest concentrations. Nevertheless, concerning the embryonic development of F1, teratogenic effects were observed including tail deformation, cardiac and yolk edema, scoliosis, and growth retardation; these alterations were more prominent in the groups born from progenitors exposed to the highest concentrations (100 and 200 μg/L.); but only the occurrence of yolk and cardiac edema had a statistically significant difference when compared to the control group. The chromatographic analysis shows that spilanthol (affinin) was the primary compound found in the EHFAo. Hence, in silico assessment was performed to evaluate the pharmacokinetic and toxicological properties of this molecule and 37 metabolites derived from it. Overall, our data show that the treatment caused no detrimental changes in progenitors regarding their gonads or fertility but caused some potentially teratogenic activity in embryos, which may be due to the action of spilanthol’s metabolites M3, M6, M7, M8, M16, M28, and M31.

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Phenolhexyl Isothiocyanate, a New Histone Deacetylase Inhibitor, Can Prevent Tumor Formation and Inhibit Leukemia Cell Growth In Vivo.

Blood ◽

10.1182/blood.v106.11.4625.4625 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4625-4625

Author(s):

Lulu Lu ◽

Xudong Ma ◽

A. Becklemisheva ◽

J.W. Chaio ◽

Delong Liu

Keyword(s):

Cell Growth ◽

Apoptotic Cell ◽

Leukemia Cell ◽

Chemotherapeutic Agents ◽

Tumor Formation ◽

Control Group ◽

Immunodeficient Mice ◽

Standard Design ◽

Significant Difference

Abstract We have demonstrated that phenolhexyl isothiocyanate (PHI) induces growth arrest and apoptosis in leukemia cells HL-60 through inhibition of the activity of histone deacetylases (HDAC), the enhancement of histone acetylation and activation of p21. In this study, we examined the effects of PHI on the growth of HL-60 leukemic xenograft in immunodeficient mice. The PHI was given to the mice by gavage. The maximum tolerated dose by the mice was determined following standard design. To determine the in vivo effect of PHI on leukemia growth, a sub-MTD dose was given to the control and the treatment groups with 17 mice in each group after injection of 1.0 x 10e6 HL-60 cells per mouse. There was a significant reduction in the incidence of tumor formation (94.1% control group vs 58.5% PHI group, p=0.004). In addition, there was also a significant difference in the tumor size between the two groups. Determined at autopsy, the mean weight of control tumors was 0.8 g vs. the tumors of the experimental group 0.35g, revealing a significant reduction of 44.4% (P<0.03). There were no detectable toxicity as evaluated by body and organ weight, and necropsy examination. The histology of the tumor showed increased apoptotic cell death. Apoptosis in the tumors was further confirmed by the cleavage of poly ADP-ribose polymerase (PARP), the target of proteolysis of caspases that execute apoptosis with Western blot analyses. The results suggest that PHI can prevent tumor formation and inhibit leukemia cell growth in vivo without significant toxicity that is routinely associated with conventional chemotherapeutic agents.

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