Respiratory, endocrine, cardiac, and renal topics
Evelyne Jacqz-Aigrain, Imti Choonara in Paediatric Clinical Pharmacology, 2021
Cyclophosphamide is used for the treatment of numerous malignant diseases, such as neuroblastoma and acute lymphoblastic leukaemias. It is used before allogenic haematopoietic stem cell transplantation in numerous malignant or non-malignant diseases. Cyclophosphamide is administered either at conventional doses of 100 to 300 mg/m2, or at high doses (1.2 g/m2 or 200 mg/kg) in combination with other cytotoxic agents. During the administration of doses over 1 g/m2, prophylactic measures must be taken to avoid haemorrhagic cystitis. Acrolein is toxic to the bladder mucosa. The occurrence of bladder toxicity depends on the concentration of acrolein present in urine and the duration of the contact between acrolein and the mucosa. This toxicity is aggravated by urine stagnation and previous bladder irradiation. Hyperhydration, resulting in significant diuresis, along with the administration of mesna, which inactivates acrolein by conjugation, minimises toxicity.
Effect of Neutrophils on Airway Smooth Muscle Responsiveness
Devendra K. Agrawal, Robert G. Townley in Inflammatory Cells and Mediators in Bronchial Asthma, 2020
In the guinea pig and rat, there is evidence that neutrophils are not necessary for ozone-induced increase in airway reactivity. Murlas and Roum38 found that the neutrophil influx into guinea pig airways after ozone lagged behind the increase in airway reactivity and that neutrophils persisted longer than did the increased airway responsiveness. Neutrophil depletion did not affect ozone-induced increases in airway reactivity.39 Likewise, ozone did not alter the small numbers of neutrophils in rat airways, although reactivity measured in isolated perfused lungs increased.40 Acrolein, an unsaturated aldehyde found in cigarette smoke, is a potent respiratory irritant that causes increased airway responsiveness, neutrophil influx, and increased concentrations of TXB2 and PGF2α in BAL fluid from guinea pigs.41 The increased airway reactivity, like that found after ozone in guinea pigs, occurred before neutrophils appeared in BAL fluid in greater number. It may be that, in rodents, airway reactivity is not modulated by neutrophils.42,80
The Toxic Environment and Its Medical Implications with Special Emphasis on Smoke Inhalation
Jacob Loke in Pathophysiology and Treatment of Inhalation Injuries, 2020
Acrolein is present in cigarette smoke, photochemical smog, and fires involving polyethylene, polypropylene, and vinylon materials (Terrill et al., 1978). Because of the irritant effects of acrolein, the Occupational Safety and Health Administration (OSHA) sets the threshold limit value for an 8 hr exposure period at 0.1 ppm. The lungs of animals (rats) exposed for 62 days to an acrolein concentration of 4.0 ppm showed decreased flow-volume curves, a leftward shift of pressure volume curves, and an increase in lung volumes, suggesting airway obstruction of both small and large airways (Costa et al., 1986).
Diallyl sulfide alleviates cyclophosphamide-induced nephropathic encephalopathy in rats
Published in Toxicology Mechanisms and Methods, 2020
Shereen M. Galal, Heba H. Mansour, Abeer A. Elkhoely
Cyclophosphamide (CP) is an alkylating agent, clinically used in the management of definite tumors and autoimmune diseases (Moraes et al. 2013; Ghareeb et al. 2015). However, its potentially serious side effects such as myelosuppression, hemorrhagic cystitis, and an increased risk of malignancy limit its use (Shin et al. 2018). CP is a prodrug activated by hepatic microsomal cytochrome P450 variegated function oxidase. Upon activation, CP produces active alkylating metabolites such as acrolein, 4-hydroxycyclophosphamide, and aldophosphamide mustard, which hamper cellular DNA and ultimately lead to cell death (Ahmed 2018). Acrolein, a toxic metabolite of CP, chemically alkylates DNA, protein, producing cross-links and thus stimulating cytotoxicity (Bhattacharjee et al. 2015). The mechanism of acrolein toxicity is complicated and includes gene activation and diminution of cellular thiols (Dobrek and Thor 2012).
Bidirectional role of reactive oxygen species during inflammasome activation in acrolein-induced human EAhy926 cells pyroptosis
Published in Toxicology Mechanisms and Methods, 2021
Liping Jiang, Songsong Luo, Tianming Qiu, Qiannan Li, Chunteng Jiang, Xiance Sun, Guang Yang, Cong Zhang, Xiaofang Liu, Lijie Jiang
The human endothelial-like cell line (EAhy926 cells) was obtained from Peking Union Medical College. EAhy926 cells were cultured in Dulbecco's modified Eagle’s medium (DMEM) medium (Gibco) supplemented with 10% fetal bovine serum (Biological Industries, Israel) and antibiotics (1% penicillin/streptomycin). EAhy926 cells were grown at 37 °C in a humidified incubator of 5% CO2. Acrolein was purchased from Kelong Chemical Reagent Factory (Chengdu, China, 107-02-8, ≥99%). The stock solution concentration of acrolein is 40 mM. EAhy926 cells were pretreated with lipopolysaccharide (LPS, 1 μg/mL) for 3 h before acrolein treatment. In inhibition experiments, the autophagy inhibitor 3MA (1 mM), ROS scavenger N-acetyl-L-cysteine (NAC, 5 mM), or the pyroptosis inhibitor glycine (5 mM) for 2 h were used before treated with acrolein.
Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-β signaling molecules
Published in Drug Delivery, 2023
Ashif Iqubal, Abul Kalam Najmi, Shadab Md, Huda Mohammed Alkreathy, Javed Ali, Mansoor Ali Syed, Syed Ehtaishamul Haque
Cyclophosphamide CP) is among the most extensively and explicitly used anticancer drugs in various types of solid tumors and hematological malignancies. Apart from being a commonly used anticancer drug, it is also an immunosuppressive agent and uses in nephrotic syndrome (Hu et al., 2022). Pharmacokinetically, it is a prodrug and hence undergoes hepatic metabolism. In the liver, CP is acted upon by CYP34A and converted into phosphoramide mustard and acrolein. Phosphoramide mustard acts as an active metabolite and exhibits a potent anticancer effect via binding to N-7 of the guanine residue and altering DNA replication (Barnett et al., 2021). Acrolein, another active metabolite of CP, a small-length carbon chain and is hydrophobic in nature. Acrolein and other metabolites, such as hydroxyphosphamide, are reported to exhibit deleterious effects on various organs. Thus. When CP is administered for therapeutic purposes, it also exhibits significant toxicity, apart from its anticancer effect (Mills & Roberts, 1979). This often limit its widespread use and negatively affect patients’ quality of life. Among the various toxic manifestations of CP, nephrotoxicity is commonly observed at the therapeutic dose (Ayza et al., 2022). The kidney is an essential vital organ that regulates intracellular and extracellular physiological functions. In other words, the kidney maintains the ionic gradient, pH, fluidity, and overall body homeostasis. Thus, any alteration in kidney function directly affects the body’s overall function (Ayza et al., 2022).
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