scholarly journals Docetaxel Skin Exposure and Micronucleation Contributes to Skin Toxicity Caused by CPC634

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3741
Author(s):  
Florence Atrafi ◽  
Ruben A. G. van Eerden ◽  
Stijn L. W. Koolen ◽  
Peter de Bruijn ◽  
Cristianne J. F. Rijcken ◽  
...  
Keyword(s):  
Histopathological Examination ◽  
Plasma Concentrations ◽  
Skin Toxicity ◽  
Treatment Result ◽  
Pharmacokinetic Analysis ◽  
Histopathological Changes ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Ki 67 ◽  
Skin Exposure ◽  
Skin Biopsies

Docetaxel entrapped nanoparticle CPC634 is associated with dose-related skin toxicity that resembles conventional docetaxel (Cd)-related skin toxicity. This study compared the cutaneous pharmacokinetics and pharmacodynamics of docetaxel and CPC634. In this randomised cross-over study, patients with solid tumours received one cycle of CPC634 and Cd (both at 75 mg/m2). Skin biopsies were taken at baseline and at day 8 of both cycles. Released and total docetaxel (released docetaxel plus entrapped docetaxel) concentrations and histopathological changes in the skin biopsies were evaluated. Twenty patients underwent paired skin biopsies for pharmacokinetic analysis and 10 patients had biopsies available for histopathological assessment. The total skin docetaxel concentration was 369% (95%CI: 229% to 569%, p < 0.001) higher after CPC634 administration compared to Cd while the released docetaxel concentrations were not statistically different (95%CI: −9% to 63%, p = 0.169). The CPC634 released docetaxel concentration in the skin was positively correlated with plasma concentrations (Pearson’s correlation 0.48, p = 0.03). Histopathological examination revealed increased apoptosis, mitotic cells with nuclear atypia, and micronucleation with an enhanced Ki-67 index for both compounds. In conclusion, both CPC634 and Cd treatment result in docetaxel exposure in the skin causing cutaneous anti-mitotic effects such as micronucleation, which could induce an inflammatory reaction leading to skin toxicity.

Phase 1 study with BIBW 2992, an irreversible dual tyrosine kinase inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) in a 2 week on 2 week off schedule

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3025-3025 ◽  
Author(s):  
C. H. Mom ◽  
F. A. Eskens ◽  
J. A. Gietema ◽  
K. Nooter ◽  
M. J. De Jonge ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Peak Plasma ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Ki 67 ◽  
Bibw 2992 ◽  
Skin Biopsies ◽  
Grade 3

3025 Background: BIBW 2992 is a highly selective, potent, irreversible tyrosine inhibitor of EGFR and HER2. A phase 1 study of orally administered BIBW 2992 was performed to determine its safety, PK and PD. Methods: Patients (pts) with advanced solid malignancies received BIBW 2992 once daily (OD) for 2 weeks, in 4 week cycles. Adverse events were evaluated according to CTCv3.0 and tumor response according to RECIST. In cycle 1 and 2, BIBW 2992 plasma PK analysis was performed. Before and after cycle 1, biomarkers involved in EGFR activation were assessed in skin biopsies. Results: 38 pts received 10 mg (n=3), 20 mg (n=3), 30 mg (n=3), 45 mg (n=3), 70 mg (n=18), 100 mg (n=2) and 85 mg (n=6) OD. At 100 mg dose-limiting toxicities (DLTs) consisted of grade 3 skin rash (n=1) and grade 3 diarrhea despite loperamide (n=1). At the dose level of 85 mg, DLTs were seen in 2 pts (diarrhea in both). An additional 12 pts were subsequently enrolled at 70 mg. A total of 3 DLTs was seen in the 18 pts treated at 70 mg (all 3 diarrhea, in one case with additional grade 3 nausea and ALT increase). In other pts, diarrhea was controllable with loperamide, whereas skin events could be ameliorated with minocycline. The dose of 70 mg BIBW 2992 OD was therefore set as the recommended phase 2 dose. Exposure (AUC0-∞ and AUCτ,ss range 82–2080 ng·h/mL) and peak plasma concentrations (Cmax and Cmax,ss range 7–150 ng/mL) increased with increasing doses. High interpatient variability in all PK parameters was found, but was within the range expected for an orally administered drug. The volume of distribution (Vz/F) ranged from 800–2900 L, indicating high tissue distribution. Median tmax values ranged between 1–4 h. The gMean terminal t1/2 ranged between 13–32 h. Accumulation ratio based on AUC was between 2–2.9. Steady state was reached around day 8. After cycle 1, a >20% reduction in Ki-67 (range 20–83%), reflecting inhibition of keratinocyte proliferation, was seen in paired skin biopsies of 31 pts. Ki-67 positive cells (mean ± SD) decreased from 14 ± 4.5% pre-treatment to 7.9 ± 4.5% on day 13 (p<0.0001). SD lasting ≥4 cycles occurred in 8 pts. Conclusions: 70 mg BIBW 2992 OD can be safely administered in a 2 week on, 2 week off schedule. Further evaluation in phase 2 trials in warranted. [Table: see text]

TO FIND OUT ELECTRO-CARDIOGRAPHIC CHANGES & ECHO CHANGES IN ALUMINIUM PHOSPHIDE AND ETHYLENE DIBROMIDE POISONING

2020 ◽  
Vol 4 (10) ◽  
Author(s):  
Hemant Nargawe ◽  
Sumeet Sisodiya
Keyword(s):  
Biochemical Analysis ◽  
Histopathological Examination ◽  
Common Finding ◽  
Histopathological Changes ◽  
Ethylene Dibromide ◽  
Medical College ◽  
Aluminium Phosphide ◽  
Urine Examination ◽  
Cardiovascular Involvement ◽  
Careful Clinical Examination

Background & Method: The study was conducted in the Department of Medicine Shyam Shah Medical College and Associated Sanjay Gandhi Memorial Hospital, Rewa (M.P). History was followed by a careful clinical examination i.e. cardiovascular, respiratory and gastrointestinal and nervous system. Investigations had done included routine haematological examination, Biochemical analysis, urine examination, ECG, 2 D. Echo & Histopathological examination was done. Result: ST-T changes were most common finding in Aluminium phosphide poisoning in relation to mortality. However hyperkalemia was the most ominous finding associated with 100% mortality, ECG finding in EDB was normal ECG. The most ominous finding was arrhythmia which was associated with 100% mortality. Survivors of ethylene dibromide poisoning echocardiography was normal in 11 (84.61%) followed by pericardial effusion in 2 (15.38%) patients. Conclusion: Noteworthy finding was absence of correlation between cardiovascular involvement, histopathological changes and ECG findings. It was seen that even if ECG showed normal pattern there were significant histopathological changes in heart. Keywords: electro-cardiographic, Aluminium phosphide, ethylene dibromide & poisoning.

scholarly journals Histopathological specialized staining of oral lichen planus-induced fibrotic changes and surgical treatment of associated restricted mouth opening: a case report

2021 ◽  
Vol 45 (1) ◽  
Author(s):  
Atsushi Shudo
Keyword(s):  
Surgical Treatment ◽  
Lichen Planus ◽  
Oral Lichen Planus ◽  
Histopathological Examination ◽  
Mouth Opening ◽  
Ki 67 ◽  
Collagen Formation ◽  
Immune Mediated ◽  
Cytokeratin 13 ◽  
Oral Lichen

Abstract Background Oral lichen planus is a chronic inflammatory and immune-mediated disease that affects the oral mucosa. Recent findings have suggested that oral lichen planus is often associated with submucosal fibrotic changes. Fibrotic changes in the buccal submucosa may cause restricted mouth opening. This report discusses the histopathological examination (including specialized staining) and surgical treatment for oral lichen planus-induced fibrotic changes. Case presentation Here, we describe a 63-year-old woman who had oral lichen planus with fibrotic changes. Her maximum mouth opening distance was approximately 30 mm due to submucosal fibrotic changes, and she exhibited gradual fibrosis progression. Histological examinations were performed to assess the oral lichen planus-induced fibrotic changes. Then, double Z-plasty were performed as treatment for restricted mouth opening. The immunohistochemical staining results were negative for cytokeratin 13 and positive in some layers for cytokeratin 17 and Ki-67/MIB-1. Masson's trichrome staining showed enhanced collagen formation. Postoperative mouth opening training enabled the patient to achieve a mouth opening distance of > 50 mm. Conclusion Our findings suggest that histopathological examination with specialized staining can aid in the evaluation of oral lichen planus-induced fibrotic changes, and that Z-plasty is effective for the treatment of restricted mouth opening due to oral lichen planus.

Potentiation of Mivacurium Blockade by Low Dose of Pancuronium

2003 ◽  
Vol 98 (5) ◽  
pp. 1057-1062 ◽  
Author(s):  
Cyrus Motamed ◽  
Riad Menad ◽  
Robert Farinotti ◽  
Krassen Kirov ◽  
Xavier Combes ◽  
...  
Keyword(s):  
Acetylcholine Receptors ◽  
Low Dose ◽  
Cholinesterase Activity ◽  
Plasma Concentrations ◽  
Orotracheal Intubation ◽  
Plasma Cholinesterase ◽  
Neuromuscular Blocking ◽  
Pharmacokinetic Analysis ◽  
Plasma Cholinesterase Activity ◽  
Before And After

Background Mivacurium is potentiated by pancuronium to a much greater extent than other relaxants. In a previous investigation we suggested that this potentiation could be due to the ability of pancuronium to inhibit plasma cholinesterase activity, but we did not measure plasma concentrations of mivacurium. In the current study we performed a pharmacokinetic analysis by measuring the plasma concentration of mivacurium when preceded by administration of a low dose of pancuronium. Methods After induction of general anesthesia with propofol and fentanyl and orotracheal intubation, 10 patients (pancuronium-mivacurium group) received 15 microg/kg pancuronium followed 3 min later by 0.1 mg/kg mivacurium, whereas 10 other patients (mivacurium group) received saline followed by 0.13 mg/kg mivacurium 3 min later. Plasma cholinesterase activity was measured before and 3 and 30 min after pancuronium dosing in the pancuronium-mivacurium group and was measured before and after administration of saline in the mivacurium group. Arterial plasma concentrations of mivacurium and its metabolites were measured at 0.5, 1, 1.5, 2, 4, 10, 20, and 30 min after injection. Neuromuscular blockade was assessed by mechanomyography. Results Plasma cholinesterase activity decreased by 26% in the pancuronium-mivacurium group 3 min after injection of pancuronium (P &lt; 0.01) and returned to baseline values 30 min later; however, no significant variation was observed in the mivacurium group. The clearances of the two most active isomers (Cis-Trans and Trans-Trans) were lower in the pancuronium-mivacurium group (17.6 +/- 5.1, 14.7 +/- 5.3 ml. min-1. kg-1, respectively) than in the mivacurium group (32.4 +/- 20.2, 24.8 +/- 13.5 ml. min-1. kg-1; P &lt; 0.05). Conclusions A subparalyzing dose of pancuronium decreased plasma cholinesterase activity and the clearance of the two most active isomers of mivacurium. Pancuronium potentiates mivacurium more than other neuromuscular blocking agents because, in addition to its occupancy of postsynaptic acetylcholine receptors, it slows down the hydrolysis of mivacurium.

Recovery ability of common carp (Cyprinus carpio) after a short-term exposure to terbuthylazine

2013 ◽  
Vol 16 (1) ◽  
pp. 17-23 ◽  
Author(s):  
I. Mikulikova ◽  
H. Modra ◽  
J. Blahova ◽  
K. Kruzikova´ ◽  
P. Marsalek ◽  
...  
Keyword(s):  
Cyprinus Carpio ◽  
Histopathological Examination ◽  
Recovery Period ◽  
Plasma Concentrations ◽  
Hepatosomatic Index ◽  
Short Term ◽  
Plasma Albumin ◽  
Short Term Exposure ◽  
High Regeneration ◽  
Biomarkers Of Oxidative Stress

Abstract Effects of a high terbuthylazine concentration (3.3 mg/l) on Cyprinus carpio were studied using a commercial herbicide formulation Click 500 SC (terbuthylazine 500 g/l). The fish were exposed to the pesticide for 24 h and allowed to recover for 6 days. Biometric parameters, plasma biochemical parameters and biomarkers of oxidative stress as well as histopathological changes in selected tissues were assessed on day 1 and 7. After a 24-h exposure, there were significant alterations found in the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as well as in the plasma concentrations of glucose, natrium, chlorides, calcium and phosphorus. Hepatosomatic index, plasma albumin and lactate reflected the treatment with a delay. Ion levels and ALT were found to be restored after a 6-day recovery period, which was too short for AST activity and glucose to diminish to the control levels. The histopathological examination revealed disorders in the gills of the exposed fish, however, the changes were not detected after a 6-day recovery period. The study shows high regeneration potential of the fish.

scholarly journals In vitro and in vivo evaluation of hypothermia on pharmacokinetics and pharmacodynamics of nimodipine in rabbits

2017 ◽  
Vol 46 (1) ◽  
pp. 335-347 ◽  
Author(s):  
Yu-xing Fei ◽  
Tian-hong Zhang ◽  
Jing Zhao ◽  
He Ren ◽  
Ya-nan Du ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Protein Binding ◽  
Plasma Concentrations ◽  
Liver Microsomes ◽  
Intrinsic Clearance ◽  
Pharmacokinetics And Pharmacodynamics ◽  
In Vivo Evaluation

Objective To investigate the effect of hypothermia on the pharmacokinetics and pharmacodynamics of nimodipine in rabbits using in vivo and in vitro methods. Methods Five healthy New Zealand rabbits received a single dose of nimodipine (0.5 mg/kg) intravenously under normothermic and hypothermic conditions. Doppler ultrasound was used to monitor cerebral blood flow, vascular resistance, and heart rate. In vitro evaluations of protein binding, hepatocyte uptake and intrinsic clearance of liver microsomes at different temperatures were also conducted. Results Plasma concentrations of nimodipine were significantly higher in hypothermia than in normothermia. Nimodipine improved cerebral blood flow under both conditions, but had a longer effective duration during the hypothermic period. Low temperature decreased the intrinsic clearance of liver microsomes, with no change in protein binding or hepatocyte uptake of nimodipine. Conclusion Nimodipine is eliminated at a slower rate during hypothermia than during normothermia, mainly due to the decreased activity of cytochrome P450 enzymes. This results in elevated system exposure with little enhancement in pharmacological effect.

scholarly journals Effects of electrochemotherapy with cisplatin and peritumoral IL-12 gene electrotransfer on canine mast cell tumors: a histopathologic and immunohistochemical study

2017 ◽  
Vol 51 (3) ◽  
pp. 286-294 ◽  
Author(s):  
Claudia Salvadori ◽  
Tanja Svara ◽  
Guido Rocchigiani ◽  
Francesca Millanta ◽  
Darja Pavlin ◽  
...  
Keyword(s):  
Mast Cell ◽  
T Lymphocytes ◽  
Mhc Class Ii ◽  
Cellular Response ◽  
Histopathological Examination ◽  
Combined Treatment ◽  
Gene Electrotransfer ◽  
Neoplastic Cells ◽  
Ki 67 ◽  
Mast Cell Tumors

AbstractBackgroundThe study was aimed to characterize tumor response after combined treatment employing electrochemotherapy with IL-12 gene electrotransfer in dogs with spontaneous mast cell tumors (MCT).Materials and methodsEleven dogs with eleven MCTswere included in the study. Histological changes were investigated in biopsy specimens collected before the treatment (T0), and 4 (T1) and 8 weeks (T2) later. Cellular infiltrates were characterized immunohistochemically by using anti CD3, CD20, Foxp3 (Treg), CD68 and anti MHC-class II antibodies. Proliferation and anti-apoptotic activity of neoplastic cells were assessed using anti Ki-67 and Bcl-2 antibodies. Angiogenetic processes were investigated immunohistochemically by using anti Factor VIII and anti CD31 antibodies and micro vessel density quantification.ResultsHistopathological examination of samples at T0confirmed the diagnosis and the presence of scanty infiltrates consisted mainly of T-lymphocytes and macrophages. At T1and T2neoplastic cells were drastically reduced in 7/11 cases, small clusters of neoplastic cells were detected in 3/11 cases and 1/11 cases neoplastic cells were still evident. Proliferation activity of neoplastic cells was significantly reduced at T1and T2and expression of anti-apoptotic protein at T1. Microvessel density was drastically reduced in all samples after treatment. The number of T-lymphocytes increased at T1, although not significant, while Treg were significant higher at T1and macrophages at T2.ConclusionsThe combined electrochemotherapy and IL-12 gene electrotransfer effectively induced a cellular response against neoplastic cells characterized mainly by the recruitment of T-lymphocytes and macrophages and a fibrotic proliferation with reduction of microvessels.

scholarly journals Nodular fasciitis on the zygomatic region: a rare presentation

2013 ◽  
Vol 88 (6 suppl 1) ◽  
pp. 89-92 ◽  
Author(s):  
Ilner de Souza e Souza ◽  
Mayra Carriijo Rochael ◽  
Rogério Estevam Farias ◽  
Roberto Bezerra Vieira ◽  
Janaina Silva Tirapelle Vieira ◽  
...  
Keyword(s):  
Benign Tumor ◽  
Histopathological Examination ◽  
Excisional Biopsy ◽  
Nodular Fasciitis ◽  
Rare Presentation ◽  
Ki 67 ◽  
Immunohistochemical Markers ◽  
The Face ◽  
Rare Location ◽  
High Cellularity

Nodular fasciitis is a benign tumor, resulting from reactive proliferation composed of fibroblastic/myofibroblastic cells. Due to its rapid growth and high cellularity it may be mistaken for sarcoma. Despite the possibility of spontaneous regression, excision is the treatment of choice. A 24-year-old female patient presented with a nodule on the zygomatic region with 3 months of evolution. Excisional biopsy was performed. Histopathological examination associated with immunohistochemical markers HHF35, AML and Ki-67 allowed diagnostic confirmation. The main relevance of the case presented is its rare location, suggesting its inclusion among the differential diagnoses of tumor lesions on the face.

scholarly journals Poisoning of Dogs in the Republic of Macedonia- Pathomorphological Changes and the Impact on Animal Welfare

2018 ◽  
Vol 41 (2) ◽  
pp. 203-207
Author(s):  
Ivica Gjurovski ◽  
Monika Dovenska ◽  
Aleksandar Janevski ◽  
Trpe Ristoski
Keyword(s):  
Gastrointestinal Tract ◽  
Histopathological Examination ◽  
Unknown Origin ◽  
Wild Animals ◽  
Histopathological Changes ◽  
Animal Suffering ◽  
Republic Of Macedonia ◽  
The Republic ◽  
Comparison Of The Results ◽  
The Impact

Abstract The illegal poisoning of dogs and other domestic and wild animals presents a worldwide problem causing animal suffering and R. Macedonia is not an exeption. The goal of this study is to make a comparison of the results from the histopathological examination conducted among poisoned dogs in the Republic of Macedonia. Morphological and histopathological changes in poisoned dogs were investigated for a period of 10 years. The examination was performed on 31 dogs, 13 of which were home kept, 7 were street dogs and 11 of unknown origin. The most significant necropsy findings concerned the inflammatory and necrotic processes of the gastrointestinal tract. The histopathological changes were mainly located in the kidneys, stomach, intestines and the lungs.

scholarly journals Influence of CYP3A Metabolizer Status on the Pharmacokinetics and Pharmacodynamics of Amiodarone

2000 ◽  
Vol 43 (3) ◽  
pp. 95-101
Author(s):  
Stanislav Mičuda ◽  
Martin Hodač ◽  
Petr Pařízek ◽  
Miloslav Pleskot ◽  
Luděk Šišpera ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Inverse Correlation ◽  
Urinary Free Cortisol ◽  
Information Value ◽  
Therapeutic Drug ◽  
Amiodarone Therapy ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Electrophysiologic Study ◽  
Free Cortisol ◽  
Trough Plasma

The present work was designed to determine whether the individual differences in pharmacokinetics and pharmacodynamics of amiodarone and its N-desethyl metabolite are related to cytochrome CYP3A metabolizer status. Methods: 12 cardiac patients with inducible ventricular tachyarrhythmias during the baseline electrophysiologic study were enrolled in this study. Urinary 24-hour excretion of 6β-hydroxycortisol (6β-OHC and the ratio of 6β-hydroxycortisol to urinary free cortisol (6β-OHC/UFC) were measured before the first amiodarone administration. Trough plasma concentrations of amiodarone and N-desethylamiodarone (N-DEA) were measured after 79 ± 11 days (2nd period) and after 182 ± 25 days (3rd period). Electrophysiologic effects of amiodarone therapy were established with serial electrophysiologic studies in 9 of these patients at the baseline and after 79 ± 11 days (during the second period). Results: Both the 6β-OHC excretion and 6β-OHC/UFC ratio varied approximately 6-fold between the patients. We found significant inverse correlation between the 6β-OHC excretion and the trough plasma concentrations of amiodarone at the time of the 3rd period (rs = -0.58, p < 0.05). Similarly, there was correlation between the 24-hour urinary 6β-OHC excretion and trough plasma concentrations of amiodarone during the 3rd period (rs = -0.64, p < 0.025). We were unable to detect any association between CYP3A activity and amiodarone pharmacodynamics. Conclusion: This study points toward important information value of CYP3A metabolizer status in the context of therapeutic drug monitoring of amiodarone.

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