Assessment of diabetes mellitus (DM) as a risk factor for development of cisplatin-induced nephrotoxicity (CIN)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13537-e13537
Author(s):  
J. Weese ◽  
P. D. Sandhu ◽  
A. Mody ◽  
H. Ozer ◽  
M. Jafari ◽  
...  
Keyword(s):  
Risk Factor ◽  
Organic Cation Transporter ◽  
Serum Glucose ◽  
In Vivo Studies ◽  
Continuous Variables ◽  
Glucose Levels ◽  
Organic Cation Transporter 2 ◽  
Diabetic Treatment ◽  
Student’S T

e13537 Background: DM is the most common cause of kidney disease in the US, and it may increase the risk of CIN. In vivo studies however suggest that DM not only is not a risk factor for CIN, it may even be protective. This may be explained by dysfunction of organic cation transporter-2, the critical transporter for cisplatin uptake in proximal tubules, in diabetic kidneys. We conducted a case-control study to assess the relationship between DM and CIN. Methods: Records of all patients (pts) who received cisplatin between 1/1/00 and 12/31/06 at Oklahoma City VA Hospital were reviewed. DM was diagnosed if pt had (1) been taking anti-diabetic treatment, or (2) Hgb A1C ≥6.5%, or (3) ≥2 fasting outpatient serum glucose levels 126–199 mg/dl, or (4) ≥1 serum glucose level ≥200 mg/dl at any time, prior to receiving cisplatin. CIN was defined as increase in serum creatinine (SCr) by ≥50% above baseline and higher than upper limit of normal, after exclusion of other causes of elevated SCr, during or within 8 weeks of completion of treatment. Continuous variables are reported by means and ranges, and compared using 2-tailed student's t test. Odds ratio (OR) was calculated to compare risk of CIN between diabetics and non-diabetics. Results: Two hundred pts (2 females, 198 males) received cisplatin in the study period, 50 (25%) were diabetic. Distribution of age (years, diabetics: 62 [46–77]; non-diabetics: 60 [26–79], p = 0.18) and baseline SCr (mg/dl, diabetics: 1.0 [0.4–1.5]; non-diabetics: 1.0 [0.5–1.6], p = 0.86) were similar between the two groups. Overall 15% of pts (30 of 200) developed CIN. Risk of CIN was not different between diabetics (8 of 50 pts, 16%) and non-diabetics (22 of 150 pts, 14.7%); OR = 1.11 (95% CI = 0.46 to 2.67) (Table). Conclusions: DM was not shown to be a risk factor for development of CIN. This finding is consistent with in vivo data obtained through animal diabetic models. [Table: see text] No significant financial relationships to disclose.

Promising Anti-stroke Signature of Voglibose: Investigation through In- Silico Molecular Docking and Virtual Screening in In-Vivo Animal Studies

2020 ◽  
Vol 20 (3) ◽  
pp. 223-235
Author(s):  
Pooja Shah ◽  
Vishal Chavda ◽  
Snehal Patel ◽  
Shraddha Bhadada ◽  
Ghulam Md. Ashraf
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
In Silico ◽  
Reductase Activity ◽  
Infarct Volume ◽  
Docking Studies ◽  
Serum Glucose ◽  
In Vivo Studies ◽  
In Silico Molecular Docking

Background: Postprandial hyperglycemia considered to be a major risk factor for cerebrovascular complications. Objective: The current study was designed to elucidate the beneficial role of voglibose via in-silico in vitro to in-vivo studies in improving the postprandial glycaemic state by protection against strokeprone type 2 diabetes. Material and Methods: In-Silico molecular docking and virtual screening were carried out with the help of iGEMDOCK+ Pymol+docking software and Protein Drug Bank database (PDB). Based on the results of docking studies, in-vivo investigation was carried out for possible neuroprotective action. T2DM was induced by a single injection of streptozotocin (90mg/kg, i.v.) to neonates. Six weeks after induction, voglibose was administered at the dose of 10mg/kg p.o. for two weeks. After eight weeks, diabetic rats were subjected to middle cerebral artery occlusion, and after 72 hours of surgery, neurological deficits were determined. The blood was collected for the determination of serum glucose, CK-MB, LDH and lipid levels. Brains were excised for determination of brain infarct volume, brain hemisphere weight difference, Na+-K+ ATPase activity, ROS parameters, NO levels, and aldose reductase activity. Results: In-silico docking studies showed good docking binding score for stroke associated proteins, which possibly hypotheses neuroprotective action of voglibose in stroke. In the present in-vivo study, pre-treatment with voglibose showed a significant decrease (p<0.05) in serum glucose and lipid levels. Voglibose has shown significant (p<0.05) reduction in neurological score, brain infarct volume, the difference in brain hemisphere weight. On biochemical evaluation, treatment with voglibose produced significant (p<0.05) decrease in CK-MB, LDH, and NO levels in blood and reduction in Na+-K+ ATPase, oxidative stress, and aldose reductase activity in brain homogenate. Conclusion: In-silico molecular docking and virtual screening studies and in-vivo studies in MCAo induced stroke, animal model outcomes support the strong anti-stroke signature for possible neuroprotective therapeutics.

scholarly journals Welding Fumes, a Risk Factor for Lung Diseases

2020 ◽  
Vol 17 (7) ◽  
pp. 2552 ◽  
Author(s):  
Maria Grazia Riccelli ◽  
Matteo Goldoni ◽  
Diana Poli ◽  
Paola Mozzoni ◽  
Delia Cavallo ◽  
...  
Keyword(s):  
Risk Factor ◽  
Ultrafine Particles ◽  
Lung Diseases ◽  
Occupational Safety ◽  
Meta Analysis ◽  
Technical Information ◽  
In Vivo Studies ◽  
Welding Fumes

(1) Background: Welding fumes (WFs) are composed of fine and ultrafine particles, which may reach the distal airways and represent a risk factor for respiratory diseases. (2) Methods: In vitro and in vivo studies to understand WFs pathogenesis were selected. Epidemiological studies, original articles, review, and meta-analysis to examine solely respiratory disease in welders were included. A systematic literature search, using PubMed, National Institute for Occupational Safety and Health Technical Information Center (NIOSHTIC), and Web of Science databases, was performed. (3) Results: Dose, time of exposure, and composition of WFs affect lung injury. Inflammation, lung defense suppression, oxidative stress, DNA damage, and genotoxic effects were observed after exposure both to mild and stainless steel WFs. (4) Conclusions: The detection of lung diseases associated with specific occupational exposure is crucial as complete avoidance or reduction of the exposure is difficult to achieve. Further studies in the area of particle research may aid the understanding of mechanisms involved in welding-related lung disease and to expand knowledge in welding-related cardiovascular diseases.

scholarly journals Mucin-Grafted Polyethylene Glycol Microparticles Enable Oral Insulin Delivery for Improving Diabetic Treatment

2020 ◽  
Vol 10 (8) ◽  
pp. 2649 ◽  
Author(s):  
Momoh A. Mumuni ◽  
Ugwu E. Calister ◽  
Nafiu Aminu ◽  
Kenechukwu C. Franklin ◽  
Adedokun Musiliu Oluseun ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Oral Delivery ◽  
Subcutaneous Administration ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Insulin Solution ◽  
Diabetic Treatment ◽  
Short Time

In this study, different ratios of mucin-grafted polyethylene-glycol-based microparticles were prepared and evaluated both in vitro and in vivo as carriers for the oral delivery of insulin. Characterization measurements showed that the insulin-loaded microparticles display irregular porosity and shape. The encapsulation efficiency and loading capacity of insulin were >82% and 18%, respectively. The release of insulin varied between 68% and 92% depending on the microparticle formulation. In particular, orally administered insulin-loaded microparticles resulted in a significant fall of blood glucose levels, as compared to insulin solution. Subcutaneous administration showed a faster, albeit not sustained, glucose fall within a short time as compared to the polymeric microparticle-based formulations. These results indicate the possible oral delivery of insulin using this combination of polymers.

Differentiated pharmacokinetic and pharmacodynamic properties of a highly selective MET kinase inhibitor, OMO-1: Implications for efficacy and safety.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14674-e14674
Author(s):  
Timothy Pietro Suren Perera ◽  
Marion Libouban ◽  
Ellen Jansen ◽  
Marc Tjwa ◽  
Eric Ciamporcero ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Kinase Inhibitor ◽  
Nsclc Patient ◽  
Organic Cation Transporter ◽  
Therapy Resistance ◽  
Clinical Activity ◽  
In Vivo Models ◽  
Organic Cation Transporter 2

e14674 Background: The MET kinase is an established therapeutic target in a range of cancer indications, being a primary oncogenic and therapy resistance driver. Methods: OMO-1 is a highly potent, selective oral inhibitor of MET kinase and Organic Cation Transporter 2 (OCT2) that is currently being explored in a Phase I/II study (NCT03138083). Results: Pre-clinical data for OMO-1 indicates that anti-tumor efficacy against MET driven tumor models does not require 24/7 exposure in the plasma. PK/PD assessments indicate that OMO-1 efficacy is AUC driven. Exposures above a trough concentration of ~600ng/ml for a period of 6-8hr and an AUC of 3000ng.h/ml result in complete target inhibition sufficient to induce regression or stasis of MET driven in-vivo models. Dosing of OMO-1 at 12.5mg/kg BD 4hr apart, or split over 4 doses 2hr apart, with a dosing-free period of 18-20hr was sufficient to obtain the effects preclinically. The ongoing Phase I/II study in patients with solid tumours utilised learnings from the pre-clinical and FIH study (NCT01964872) where ascending single doses and multiple doses were evaluated. The selected starting dose for the patient study (100mg BD, 4 hr apart) achieved exposures above the predicted MBAD. Paired tumor biopsies were obtained from a higher dose level (200mg BD). A MET exon 14 skipping mutation NSCLC patient at this dosed demonstrated near-complete inhibition of phospho MET accompanied by signs of clinical benefit and lesion shrinkage, thereby matching the preclinical data. Certain ‘class effect’ adverse events, such as edema, were not observed. Conclusions: OMO-1 is an oral, potent MET TKI with a novel dosing regime, identified during preclinical optimization (BD 4hr apart), that demonstrates encouraging signs of clinical activity without certain ‘class-specific’ adverse events. Further evaluation of this differentiated and efficacious agent is warranted and ongoing.

Pharmacodynamic profile of a novel inhibitor of the hepatic glucose-6-phosphatase system

1998 ◽  
Vol 274 (6) ◽  
pp. G1087-G1093 ◽  
Author(s):  
Andreas W. Herling ◽  
Hans-Joerg Burger ◽  
Dietmar Schwab ◽  
Horst Hemmerle ◽  
Peter Below ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Intravenous Infusion ◽  
In Vivo Studies ◽  
Isolated Perfused Rat Liver ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Pharmacodynamic Profile ◽  
Hepatic Glucose ◽  
Glucose Output

The glucose-6-phosphatase (G-6- Pase) system catalyzes the terminal enzymatic step of gluconeogenesis and glycogenolysis. Inhibition of the G-6- Pase system in the liver is expected to result in a reduction of hepatic glucose production irrespective of the relative contribution of gluconeogenesis or glycogenolysis to hepatic glucose output. In isolated perfused rat liver, S-3483, a derivative of chlorogenic acid, produced concentration-dependent inhibition of gluconeogenesis and glycogenolysis in a similar concentration range. In fed rats, glucagon-induced glycogenolysis resulted in hyperglycemia for nearly 2 h. Intravenous infusion of 50 mg ⋅ kg−1 ⋅ h−1S-3483 prevented the hyperglycemic peak and subsequently caused a further lowering of blood glucose. In 24-h starved rats, in which normoglycemia is maintained predominantly by gluconeogenesis, intravenous infusion of S-3483 resulted in a constant reduction of blood glucose levels. Intrahepatic concentrations of glucose-6-phosphate (G-6- P) and glycogen were significantly increased at the end of both in vivo studies. In contrast, lowering of blood glucose in starved rats by 3-mercaptopicolinic acid was accompanied by a reduction of G-6- P and glycogen. Our results demonstrate for the first time in vivo a pharmacologically induced suppression of hepatic G-6- P activity with subsequent changes in blood glucose levels.

scholarly journals Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor Regression In Vivo

2017 ◽  
Vol 10 (3) ◽  
pp. 198-207 ◽  
Author(s):  
L. Allyson Checkley ◽  
Michael C. Rudolph ◽  
Elizabeth A. Wellberg ◽  
Erin D. Giles ◽  
Reema S. Wahdan-Alaswad ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mammary Tumor ◽  
Organic Cation ◽  
Tumor Regression ◽  
Organic Cation Transporter ◽  
Organic Cation Transporter 2

scholarly journals Noncontact Optical Measurement of Aqueous Humor Glucose Levels and Correlation with Serum Glucose Levels in Rabbit

Biosensors ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 387
Author(s):  
Yih-Shiou Hwang ◽  
Eugene Yu-Chuan Kang ◽  
Chia-Rui Shen ◽  
Wei-Hsin Hong ◽  
Wei-Chi Wu
Keyword(s):  
Aqueous Humor ◽  
Optical System ◽  
Near Infrared ◽  
Optical Measurement ◽  
Serum Glucose ◽  
Mean Difference ◽  
Optical Measurements ◽  
Glucose Levels

The noninvasive measurement of serum glucose levels has been investigated for the monitoring of blood sugar control in diabetes. In our study, we aimed to develop a novel noncontact glucometer (NCGM) utilizing an optical approach to measure the intraocular aqueous humor glucose levels in the anterior chamber of rabbit eyes. The NCGM consists of a hybrid optical system that simultaneously measures near-infrared absorption and the polarized rotatory distribution of glucose molecules in the aqueous humor. In vitro optical measurements demonstrated that NCGM measurements had high precision and repeatability for different glucose levels, including 50 mg/dL (14.36%), 100 mg/dL (−4.05%), 200 mg/dL (−5.99%), 300 mg/dL (4.86%), 400 mg/dL (−2.84%), 500 mg/dL (−0.11%), and 600 mg/dL (4.48%). In the rabbit experiments, we found a high correlation between aqueous glucose levels and serum glucose levels, with a mean difference of 8 mg/dL. According to the testing results, the in vivo NCGM measurement of aqueous humor glucose levels also displayed a high correlation with serum glucose levels, with a mean difference of 29.2 mg/dL. In conclusion, aqueous humor glucose levels were accurately measured using the NCGM, and the results correlated with serum glucose levels.

Modulation of GLUT4 expression by oral administration of Mg2+ to control sugar levels in STZ-induced diabetic rats

2014 ◽  
Vol 92 (6) ◽  
pp. 438-444 ◽  
Author(s):  
Haniah Solaimani ◽  
Nepton Soltani ◽  
Kianoosh MaleKzadeh ◽  
Shahla Sohrabipour ◽  
Nina Zhang ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Magnesium Sulfate ◽  
Mrna Expression ◽  
Insulin Level ◽  
Diabetic Rats ◽  
In Vivo Studies ◽  
Glucose Levels ◽  
Blood Glucose Levels

It has been previously shown that oral magnesium administration decreases the levels of glucose in the plasma. However, the mechanisms are not fully understood. The aim of this study was to determine the potential role of GLUT4 on plasma glucose levels by orally administering magnesium sulfate to diabetic rats. Animals were distributed among 4 groups (n = 10 rats per group): one group served as the non-diabetic control, while the other groups had diabetes induced by streptozotocin (intraperitoneal (i.p.) injection). The diabetic rats were either given insulin by i.p. injection (2.5 U·(kg body mass)–1·day–1), or magnesium sulfate in their drinking water (10 g·L–1). After 8 weeks of treatment, we conducted an i.p. glucose tolerance test (IPGTT), measured blood glucose and plasma magnesium levels, and performed in-vitro and in-vivo insulin level measurements by radioimmunoassay. Gastrocnemius (leg) muscles were isolated for the measurement of GLU4 mRNA expression using real-time PCR. Administration of magnesium sulfate improved IPGTT and lowered blood glucose levels almost to the normal range. However, the insulin levels were not changed in either of the in-vitro or in-vivo studies. The expression of GLU4 mRNA increased 23% and 10% in diabetic magnesium-treated and insulin-treated groups, respectively. Our findings suggest that magnesium lowers blood glucose levels via increased GLU4 mRNA expression, independent to insulin secretion.

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