Ototoxicity of Carboplatin Delivered Locally in a Monkey Brainstem

2005 ◽  
Vol 24 (6) ◽  
pp. 443-449 ◽  
Author(s):  
J. P. Carey ◽  
T. Cooper ◽  
G. I. Jallo ◽  
B. S. Carson ◽  
M. Guarnieri
Keyword(s):  
Hair Cells ◽  
Cell Damage ◽  
Maximum Tolerated Dose ◽  
Nonparametric Tests ◽  
Common Side Effect ◽  
Vestibular Hair Cells ◽  
Cell Counts ◽  
Platinum Based Chemotherapy ◽  
Csf Levels ◽  
Vestibular Sensory Epithelia

Ototoxicity is a common side effect of platinum-based chemotherapy. Intratumoral drug delivery theoretically could reduce the ototoxic effects of systemic drug infusions. However, local delivery to central nervous system (CNS) tumors might promote ototoxicity through drug release into cerebrospinal fluid (CSF). This report describes an examination of the cytoarchitecture of vestibular cells of cynomolgus monkeys that had chronic brainstem infusions with the maximum tolerated dose (MTD) of carboplatin. The brainstems of adult monkeys were infused for 30 days at 0.42 μl/h with 0.025 to 0.25 mg/kg (MTD) of carboplatin. The vestibular sensory epithelia of eight drug-treated animals were isolated for microscopic examination of vestibular hair cells and support cells. Local infusions produced chronic elevated CSF levels of platinum, neurological symptoms, and radiographic evidence of pontine injury. Histology revealed significant cell damage at the infusion sites. Microscopic examinations of vestibular support cells and hair cells demonstrate a small reduction in cell counts in the drug-treated monkeys compared to a noninfused control animal. Parametric and nonparametric tests show no effect of dose in predicting the vestibular cell counts. In this single study of eight monkeys, a dose-dependent reduction of vestibular hair cells or support cells was not observed in animals infused with brainstem infusions of 0.025 to 0.25 mg/kg of carboplatin.

scholarly journals Progress in protecting vestibular hair cells

2021 ◽  
Author(s):  
Luoying Jiang ◽  
Zhiwei Zheng ◽  
Yingzi He
Keyword(s):  
Hair Cells ◽  
Genetic Factors ◽  
Cell Damage ◽  
Sensory Epithelium ◽  
Therapeutic Strategies ◽  
Vestibular Dysfunction ◽  
Vestibular Hair Cells ◽  
Hair Cell Damage ◽  
Ototoxic Drugs ◽  
Mechanosensory Receptors

AbstractVestibular hair cells are mechanosensory receptors that are capable of detecting changes in head position and thereby allow animals to maintain their posture and coordinate their movement. Vestibular hair cells are susceptible to ototoxic drugs, aging, and genetic factors that can lead to permanent vestibular dysfunction. Vestibular dysfunction mainly results from the injury of hair cells, which are located in the vestibular sensory epithelium. This review summarizes the mechanisms of different factors causing vestibular hair cell damage and therapeutic strategies to protect vestibular hair cells.

High Levels of Serum Uric Acid, Cystain C and Lipids Concentration and their Clinical Significance in Primary Gouty Arthritis Patients

2019 ◽  
Vol 15 (2) ◽  
pp. 141-145 ◽  
Author(s):  
Quan-Bo Zhang ◽  
Dan Zhu ◽  
Zhong Wen ◽  
Ting Yi ◽  
Qing Li ◽  
...  
Keyword(s):  
Uric Acid ◽  
Blood Cell ◽  
Serum Uric Acid ◽  
Clinical Significance ◽  
Cell Damage ◽  
Density Lipoprotein ◽  
Neutrophil Granulocyte ◽  
Renal Disorder ◽  
Cell Counts ◽  
Positive Correlations

Objective: To investigate the changes of serum Uric Acid (sUA), lipids and Cystatin C (CysC) in primary gout patients, and to explore the clinical significance in gout patients. Methods: : sUA, CysC, high-sensitivity C-reactive Protein (hsCRP) and other biochemical parameters were measured in 326 gout patient and 210 healthy control subjects, blood cell counts were also detected. Clinical data were collected from gout patients. Results: sUA, CysC, hsCRP, Body Mass Index (BMI), White Blood Cell (WBC) counts, neutrophil Granulocyte (GR), Monocyte (Mo), Triglycerides (TG), plasma Total Cholesterol (TC), Very Low Density Lipoprotein (VLDL), apolipoprotein B100 (apoB100), Blood Glucose (GLU), serum Creatinine (sCr) and Urea Nitrogen (BUN) were significantly increased in gout patients compared with HC subjects (P<0.01, respectively), while lymphocyte counts and High Density Lipoprotein- Cholesterol (HDL-C) were significantly decreased in gout patients compared with HC subjects (P<0.01, respectively). Positive correlations were observed between concentration of sUA and age, TG, VLDL, sCr and CysC (P<0.05, respectively). While negative correlations were observed between the concentration of sUA and HDL-C(P<0.01). Besides, Positive correlations were observed between concentration of CysC and WBC, GR, Mo, apoA1, GLU, sCr, BUN, sUA, hsCRP (P<0.05, respectively). While negative correlations were observed between the concentration of CysC and TC, LDL-C(P<0.01, respectively). Conclusions: Blood lipid profile changes in gout patients. Gout patients who suffer from lipid metabolism disorder and vascular diseases might be associated with hyperuricemia, which leads to endothelial cell damage and vascular smooth muscle cell proliferation. CysC might be a marker for renal function damage and inflammation. Hyperuricemia is the risk factor of renal disorder in gout patients.

Signaling pathway for apoptosis of vestibular hair cells of Mice due to aminoglycosides

2004 ◽  
Vol 124 (sup551) ◽  
pp. 69-74 ◽  
Author(s):  
Ji Eun Lee ◽  
Takayuki Nakagawa ◽  
Tae Soo Kim ◽  
Fukuichiro Iguchi ◽  
Tsuyoshi Endo ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Hair Cells ◽  
Vestibular Hair Cells

Insulin-like growth factor 1 protects vestibular hair cells from aminoglycosides

Neuroreport ◽  
2011 ◽  
Vol 22 (1) ◽  
pp. 38-43 ◽  
Author(s):  
Nakarin Angunsri ◽  
Akiko Taura ◽  
Takayuki Nakagawa ◽  
Yushi Hayashi ◽  
Shin-ichiro Kitajiri ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hair Cells ◽  
Insulin Like Growth Factor ◽  
Vestibular Hair Cells

scholarly journals Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2–transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048)

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 3211-3219 ◽  
Author(s):  
Shinichi Kitada ◽  
Christina L. Kress ◽  
Maryla Krajewska ◽  
Lee Jia ◽  
Maurizio Pellecchia ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
Parent Compound ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Low Grade ◽  
Altered Expression ◽  
Cell Counts

Abstract Altered expression of Bcl-2 family proteins plays central roles in apoptosis dysregulation in cancer and leukemia, promoting malignant cell expansion and contributing to chemoresistance. In this study, we compared the toxicity and efficacy in mice of natural product gossypol and its semisynthetic derivative apo-gossypol, compounds that bind and inhibit antiapoptotic Bcl-2 family proteins. Daily oral dosing studies showed that mice tolerate doses of apogossypol 2- to 4-times higher than gossypol. Hepatotoxicity and gastrointestinal toxicity represented the major adverse activities of gossypol, with apogossypol far less toxic. Efficacy was tested in transgenic mice in which Bcl-2 is overexpressed in B cells, resembling low-grade follicular lymphoma in humans. In vitro, Bcl-2–expressing B cells from transgenic mice were more sensitive to cytotoxicity induced by apogossypol than gossypol, with LD50 values of 3 to 5 μM and 7.5 to 10 μM, respectively. In vivo, using the maximum tolerated dose of gossypol for sequential daily dosing, apogossypol displayed superior activity to gossypol in terms of reducing splenomegaly and reducing B-cell counts in spleens of Bcl-2–transgenic mice. Taken together, these studies indicate that apogossypol is superior to parent compound gossypol with respect to toxicology and efficacy, suggesting that further development of this compound for cancer therapy is warranted.

Ionic Currents and Electromotility in Inner Ear Hair Cells From Humans

1998 ◽  
Vol 79 (4) ◽  
pp. 2235-2239 ◽  
Author(s):  
John S. Oghalai ◽  
Jeffrey R. Holt ◽  
Takashi Nakagawa ◽  
Thomas M. Jung ◽  
Newton J. Coker ◽  
...  
Keyword(s):  
Inner Ear ◽  
Hair Cells ◽  
Ionic Currents ◽  
Sensory Epithelium ◽  
Outer Hair Cells ◽  
Sensory Receptor ◽  
Surgical Removal ◽  
Type I ◽  
Vestibular Hair Cells ◽  
Sensory Receptor Cells

Oghalai, John S., Jeffrey R. Holt, Takashi Nakagawa, Thomas M. Jung, Newton J. Coker, Herman A. Jenkins, Ruth Anne Eatock, and William E. Brownell. Ionic currents and electromotility in inner ear hair cells from humans. J. Neurophysiol. 79: 2235–2239, 1998. The upright posture and rich vocalizations of primates place demands on their senses of balance and hearing that differ from those of other animals. There is a wealth of behavioral, psychophysical, and CNS measures characterizing these senses in primates, but no prior recordings from their inner ear sensory receptor cells. We harvested human hair cells from patients undergoing surgical removal of life-threatening brain stem tumors and measured their ionic currents and electromotile responses. The hair cells were either isolated or left in situ in their sensory epithelium and investigated using the tight-seal, whole cell technique. We recorded from both type I and type II vestibular hair cells under voltage clamp and found four voltage-dependent currents, each of which has been reported in hair cells of other animals. Cochlear outer hair cells demonstrated electromotility in response to voltage steps like that seen in rodent animal models. Our results reveal many qualitative similarities to hair cells obtained from other animals and justify continued investigations to explore quantitative differences that may be associated with normal or pathological human sensation.

Molecular characterization of an inward rectifier channel (IKir) found in avian vestibular hair cells: cloning and expression of pKir2.1

2004 ◽  
Vol 19 (2) ◽  
pp. 155-169 ◽  
Author(s):  
Manning J. Correia ◽  
Thomas G. Wood ◽  
Deborah Prusak ◽  
Tianxiang Weng ◽  
Katherine J. Rennie ◽  
...  
Keyword(s):  
Hair Cells ◽  
Cho Cells ◽  
Dwell Time ◽  
Single Channel ◽  
Cloning And Expression ◽  
Single Type ◽  
Type I ◽  
Type Ii ◽  
Vestibular Hair Cells ◽  
Inwardly Rectifying

A fast inwardly rectifying current has been observed in some of the sensory cells (hair cells) of the inner ear of several species. While the current was presumed to be an IKir current, contradictory evidence existed as to whether the cloned channel actually belonged to the Kir2.0 subfamily of potassium inward rectifiers. In this paper, we report for the first time converging evidence from electrophysiological, biochemical, immunohistochemical, and genetic studies that show that the Kir2.1 channel carries the fast inwardly rectifying currents found in pigeon vestibular hair cells. Following cytoplasm extraction from single type II and multiple pigeon vestibular hair cells, mRNA was reverse transcribed, amplified, and sequenced. The open reading frame (ORF), consisting of a 1,284-bp nucleotide sequence, showed 94, 85, and 83% identity with Kir2.1 subunit sequences from chick lens, Kir2 sequences from human heart, and a mouse macrophage cell line, respectively. Phylogenetic analyses revealed that pKir2.1 formed an immediate node with hKir2.1 but not with hKir2.2–2.4. Hair cells (type I and type II) and supporting cells in the sensory epithelium reacted positively with a Kir2.1 antibody. The whole cell current recorded in oocytes and CHO cells, transfected with pigeon hair cell Kir2.1 (pKir2.1), demonstrated blockage by Ba2+ and sensitivity to changing K+ concentration. The mean single-channel linear slope conductance in transfected CHO cells was 29 pS. The open dwell time was long (∼300 ms at −100 mV), and the closed dwell time was short (∼34 ms at −100 mV). Multistates ranging from 3–6 were noted in some single-channel responses. All of the above features have been described for other Kir2.1 channels. Current clamp studies of native pigeon vestibular hair cells illustrated possible physiological roles of the channel and showed that blockage of the channel by Ba2+ depolarized the resting membrane potential by ∼30 mV. Negative currents hyperpolarized the membrane ∼20 mV before block but ∼60 mV following block. RT-PCR studies revealed that the pKir2.1 channels found in pigeon vestibular hair cells were also present in pigeon vestibular nerve, vestibular ganglion, lens, neck muscle, brain (brain stem, cerebellum and optic tectum), liver, and heart.

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