scholarly journals Inhaled Sphingosine Has no Adverse Side Effects in Isolated Ventilated and Perfused Pig Lungs

2021 ◽  
Author(s):  
Henning Carstens ◽  
Katharina Kalka ◽  
Rabea Verhaegh ◽  
Fabian Schumacher ◽  
Matthias Soddemann ◽  
...  
Keyword(s):  
Side Effects ◽  
Lung Transplantation ◽  
Performance Test ◽  
Ex Vivo ◽  
High Dose ◽  
Tissue Samples ◽  
Bronchial Epithelial ◽  
Luminal Membrane ◽  
High Doses ◽  
New Treatment

Abstract Background: Ex-vivo lung perfusion (EVLP) systems like XVIVOâ are more and more common in the setting of lung transplantation, since marginal donor-lungs can easily be subjected to a performance test or be treated with corticosteroids or antibiotics in high dose regimes. Donor lungs are frequently positive in bronchoalveolar lavage (BAL) bacterial cultures (46-89%) which leads to a donor-to-recipient transmission and subsequent to a higher risk of lung infection with reduced posttransplant outcome. We have previously shown that sphingosine very efficiently kills a variety of pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus and epidermidis, Escherichia coli or Haemophilus influenzae. Thus, sphingosine could be a new treatment option with broadspectrum antiinfective potential, which may improve outcome after lung transplantation when administered prior to lung re-implantation. Here, we tested whether sphingosine has any adverse effects in the respiratory tract when applied into the isolated ventilated and perfused lungs. Methods: A 4-hour EVLP run using minipig lungs was performed. Functional parameters as well as perfusate measurements where obtained. Biopsies were obtained 30 min and 150 min after inhalation of sphingosine. Tissue samples were fixed in paraformaldehyde, embedded in paraffin and sectioned. Hemalaun, TUNEL as well as Cy3-coupled anti-sphingosine/ceramide antibodies stainings were implemented. Results: We demonstrate that tube-inhalation of sphingosine into ex-vivo perfused and ventilated minipig lungs results in increased levels of sphingosine in the luminal membrane of bronchi and the trachea without morphological side effects up to very high doses of sphingosine. Sphingosine also did not affect functional lung performance.Conclusion: In summary, the inhalation of sphingosine results in an increase of sphingosine concentrations in the luminal plasma membrane of tracheal and bronchial epithelial cells. The inhalation has no local side effects in ex-vivo perfused and ventilated minipig lungs.

scholarly journals Inhaled sphingosine has no adverse side effects in isolated ventilated and perfused pig lungs

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Henning Carstens ◽  
Katharina Kalka ◽  
Rabea Verhaegh ◽  
Fabian Schumacher ◽  
Matthias Soddemann ◽  
...  
Keyword(s):  
Side Effects ◽  
Lung Transplantation ◽  
Performance Test ◽  
Ex Vivo ◽  
High Dose ◽  
Tissue Samples ◽  
Bronchial Epithelial ◽  
Luminal Membrane ◽  
High Doses ◽  
New Treatment

AbstractEx-vivo lung perfusion (EVLP) systems like XVIVO are more and more common in the setting of lung transplantation, since marginal donor-lungs can easily be subjected to a performance test or be treated with corticosteroids or antibiotics in high dose regimes. Donor lungs are frequently positive in bronchoalveolar lavage (BAL) bacterial cultures (46–89%) which leads to a donor-to-recipient transmission and after a higher risk of lung infection with reduced posttransplant outcome. We have previously shown that sphingosine very efficiently kills a variety of pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus and epidermidis, Escherichia coli or Haemophilus influenzae. Thus, sphingosine could be a new treatment option with broadspectrum antiinfective potential, which may improve outcome after lung transplantation when administered prior to lung re-implantation. Here, we tested whether sphingosine has any adverse effects in the respiratory tract when applied into isolated ventilated and perfused lungs. A 4-h EVLP run using minipig lungs was performed. Functional parameters as well as perfusate measurements where obtained. Biopsies were obtained 30 min and 150 min after inhalation of sphingosine. Tissue samples were fixed in paraformaldehyde, embedded in paraffin and sectioned. Hemalaun, TUNEL as well as stainings with Cy3-coupled anti-sphingosine or anti-ceramide antibodies were implemented. We demonstrate that tube-inhalation of sphingosine into ex-vivo perfused and ventilated minipig lungs results in increased levels of sphingosine in the luminal membrane of bronchi and the trachea without morphological side effects up to very high doses of sphingosine. Sphingosine also did not affect functional lung performance. In summary, the inhalation of sphingosine results in an increase of sphingosine concentrations in the luminal plasma membrane of tracheal and bronchial epithelial cells. The inhalation has no local side effects in ex-vivo perfused and ventilated minipig lungs.

Role of High-Dose Intravenous Frusemide Therapy in the Management of Chronic Renal Failure

1975 ◽  
Vol 3 (4) ◽  
pp. 245-250
Author(s):  
Mam Chandra ◽  
M K Mitra ◽  
N N Gupta
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Side Effects ◽  
Treated Group ◽  
Fixed Dose ◽  
High Dose ◽  
Dose Regime ◽  
Diuretic Response ◽  
High Doses

The results of using high doses of intravenous frusemide in the management of 28 patients suffering from chronic renal failure are presented. The results are compared with those obtained from 14 patients also suffering from chronic renal failure, who received identical ‘conservative management’ but were not treated with diuretics. Large doses of intravenous frusemide produced a satisfactory diuretic response in a higher percentage of treated patients (71%) compared with controls (36%). It was also observed that in the treated group of patients a significant diuretic response could be obtained in patients with a creatinine clearance below 4 ml per minute. The study also demonstrated that in the group of patients receiving frusemide the response was better in those who were given a progressive-dose regime; 88% of patients improved with this regime compared with 68% of patients who were treated with a fixed dose of frusemide. Transient deafness with tinnitus and vertigo were the only side-effects observed. However these effects were only seen in patients who received 1000 mg or more frusemide in one day, administered over a period of one to two hours. It is concluded that all patients suffering from chronic renal failure should be given a trial of large doses of intravenous frusemide therapy, along with other conventional measures, particularly where facilities for dialysis are not immediately available.

scholarly journals The ex vivo perfused human lung is resistant to injury by high-dose S. pneumoniae bacteremia

2020 ◽  
Vol 319 (2) ◽  
pp. L218-L227 ◽  
Author(s):  
James T. Ross ◽  
Nicolas Nesseler ◽  
Aleksandra Leligdowicz ◽  
Rachel L. Zemans ◽  
Rahul Y. Mahida ◽  
...  
Keyword(s):  
Human Lung ◽  
Ex Vivo ◽  
Alveolar Epithelium ◽  
Lung Model ◽  
High Dose ◽  
Alveolar Epithelial ◽  
Low Protein ◽  
Alveolar Epithelial Injury ◽  
High Doses ◽  
Protein Permeability

Few patients with bacteremia from a nonpulmonary source develop acute respiratory distress syndrome (ARDS). However, the mechanisms that protect the lung from injury in bacteremia have not been identified. We simulated bacteremia by adding Streptococcus pneumoniae to the perfusate of the ex vivo perfused human lung model. In contrast to a pneumonia model in which bacteria were instilled into the distal air spaces of one lobe, injection of high doses of S. pneumoniae into the perfusate was not associated with alveolar epithelial injury as demonstrated by low protein permeability of the alveolar epithelium, intact alveolar fluid clearance, and the absence of alveolar edema. Unexpectedly, the ex vivo human lung rapidly cleared large quantities of S. pneumoniae even though the perfusate had very few intravascular phagocytes and lacked immunoglobulins or complement. The bacteria were cleared in part by the small number of neutrophils in the perfusate, alveolar macrophages in the airspaces, and probably by interstitial pathways. Together, these findings identify one mechanism by which the lung and the alveolar epithelium are protected from injury in bacteremia.

Investigation of Effects of Silymarin in 5-Fluorouracil Hepatotoxicity and Nephrotoxicity in Mice

2021 ◽  
Author(s):  
Emin Sengul ◽  
Volkan Gelen ◽  
Serkan Yildirim ◽  
Esra Senturk ◽  
Yusuf Dag ◽  
...  
Keyword(s):  
Dna Damage ◽  
Side Effects ◽  
Total Bilirubin ◽  
Control Group ◽  
High Dose ◽  
Liver And Kidney ◽  
Group 5 ◽  
High Doses ◽  
Kidney Functions ◽  
Liver And Kidney Damage

Abstract Hepatotoxicity and nephrotoxicity are common side effects of 5-Fluorouracil (5-FU). The present study aimed to investigate the effects of Silymarin (SLY) on 5-FU induced hepatotoxicity and nephrotoxicity in mice. In our study, 10 mice in each group were randomly divided into four groups as the control group, 5-FU, SLY50+5-FU, and SLY100+5-FU group. SLY50+5-FU and SLY100+5-FU groups were administered at a dose of 50 and 100 mg/kg for seven days, respectively. 5-FU was administered at a dose of 400 mg/kg intraperitoneally on the fourth day. After the applications, the mice were decapitated under anesthesia. The liver and kidney functions which urea, creatinine, AST, ALT, and total bilirubin levels were analyzed in serum. In liver and renal tissues, MDA and GSH levels, SOD, CAT, and GR activity were determined. Also, histopathological and immunohistochemical changes were examined in liver and kidney sections. Urea, creatinine, ALT, AST, and total bilirubin levels increased 5-FU group according to control and prevented to this increases the especially high dose of SLY. 5-FU also causes histopathological and immunohistochemical changes such as degeneration, necrosis, hyperemia, DNA damage, and IL-6 increase in kidney and liver tissue. High doses of SLY prevented these changes caused by 5-FU. As a result of this study, it was determined that SLY has hepatoprotective and nephroprotective effects on 5-FU-induced liver and kidney damage in mice.

Proteoglycan and Collagen Biochemical Variations during Fluoroquinolone-Induced Chondrotoxicity in Mice

1999 ◽  
Vol 43 (12) ◽  
pp. 2915-2921 ◽  
Author(s):  
Marie-Agnès Simonin ◽  
Pascale Gegout-Pottie ◽  
Alain Minn ◽  
Pierre Gillet ◽  
Patrick Netter ◽  
...  
Keyword(s):  
Side Effects ◽  
Ex Vivo ◽  
Extracellular Proteins ◽  
Proteoglycan Synthesis ◽  
High Dose ◽  
Carbonyl Derivatives ◽  
Low Incidence ◽  
First Time ◽  
Serum Sulfate

ABSTRACT Although fluoroquinolone antibacterials have a broad therapeutic use, with a relatively low incidence of severe side effects, they have been reported to induce lesions in the cartilage of growing animals by a mechanism that remains unclear. This study was undertaken to determine the potentially deleterious effect of a high dose of pefloxacin (400 mg/kg of body weight) on two main constituents of cartilage in mice, i.e., proteoglycans and collagen. Variations in levels of proteoglycan anabolism measured by in vivo [35S]sulfate incorporation into cartilage and oxidative modifications of collagen assessed by detection of carbonyl derivatives were monitored after administration of pefloxacin. Treatment of mice with 1 day of pefloxacin treatment significantly decreased the rate of biosynthesis of proteoglycan for the first 24 h. However, no difference was observed after 48 h. The decrease in proteoglycan synthesis was accompanied by a marked drop in serum sulfate concentration and a concomitant increase in urinary sulfate excretion. The decrease in proteoglycan synthesis, also observed ex vivo, may suggest a direct effect of pefloxacin on this process, rather than it being a consequence of a low concentration of sulfate. On the other hand, treatment with pefloxacin for 10 days induced oxidative damage to collagen. In conclusion, this study demonstrates, for the first time, that pefloxacin administration to mice leads to modifications in the metabolism and integrity of extracellular proteins, such as collagen and proteoglycans, which may account for the side effects observed. These results offer new insights to explain quinolone-induced disorders in growing articular cartilage.

Dialysis therapy for lactic acidosis caused by metformin intoxication: presentation of two cases

2011 ◽  
Vol 30 (12) ◽  
pp. 1995-1997 ◽  
Author(s):  
Yasemin Usul Soyoral ◽  
Huseyin Begenik ◽  
Habib Emre ◽  
Enver Aytemiz ◽  
Mustafa Ozturk ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Side Effects ◽  
Lactic Acidosis ◽  
Type Ii Diabetes ◽  
Type Ii Diabetes Mellitus ◽  
High Dose ◽  
Type Ii ◽  
Dialysis Therapy ◽  
Oral Antidiabetic ◽  
High Doses

Metformin is an oral antidiabetic, which is frequently used in the treatment of type II diabetes mellitus. Serious side effects may be seen during the administration of high doses of metformin. Two cases of lactic acidosis due to ingestion of high dose metformin for suicidal purposes have been presented here; in both cases, clinical improvement was seen with bicarbonate hemodialysis.

scholarly journals Systemic Minoxidil Accidental Exposure in a Paediatric Population: A Case Series Study of Cutaneous and Systemic Side Effects

2021 ◽  
Vol 10 (18) ◽  
pp. 4257
Author(s):  
Manuel Sánchez-Díaz ◽  
David López-Delgado ◽  
Trinidad Montero-Vílchez ◽  
Luis Salvador-Rodríguez ◽  
Alejandro Molina-Leyva ◽  
...  
Keyword(s):  
Side Effects ◽  
Treatment Time ◽  
Case Series ◽  
Paediatric Population ◽  
High Dose ◽  
Retrospective Case ◽  
Case Series Study ◽  
High Doses ◽  
Initial Zone ◽  
Series Study

Oral minoxidil is an approved treatment for high blood pressure which is also used as an off-label drug for alopecia. Knowledge about the effects of systemic minoxidil in the paediatric population is limited. A retrospective case series study of paediatric patients with history of systemic minoxidil intake due to contaminated sets of omeprazole was performed to describe side effects of high dose oral minoxidil intake in children. Twenty patients aged between 2 months and 13 years joined the study. They had received high doses of oral minoxidil (mean dose 0.90 mg/kg/day) during a mean time of 38.3 days. Hypertrichosis appeared in 65%, with a mean latency time of 24.31 days. Treatment time was associated with the appearance of hypertrichosis (p < 0.05). Most common initial zone of hypertrichosis was the face. Systemic effects developed in 15%, with no cases of severe disorders. The present study shows a novel insight into the side effects of high doses of oral minoxidil in children.

scholarly journals Effects of rhBMP-2 Loaded Hydroxyapatite Granules/beta-Tricalcium Phosphate Hydrogel (HA/β-TCP hydrogel) Composite on a Rat Model of Coccygeal Intervertebral Fusion.

2021 ◽  
Author(s):  
Shinichi Nakagawa ◽  
Rintaro Okada ◽  
Junichi Kushioka ◽  
Joe Kodama ◽  
Hiroyuki Tsukazaki ◽  
...  
Keyword(s):  
Side Effects ◽  
Tricalcium Phosphate ◽  
Posterior Lumbar Interbody Fusion ◽  
High Dose ◽  
Fusion Model ◽  
Intervertebral Fusion ◽  
Beta Tricalcium Phosphate ◽  
Morphogenetic Protein ◽  
Ectopic Bone ◽  
High Doses

Abstract The effects and inflammation-related side effects of bone morphogenetic protein (BMP)-2 on posterior lumbar interbody fusion are controversial. One of the potential causes for the inconsistent results is the uncontrolled release of BMP-2 from the collagen carrier. Therefore, BMP delivery systems which support effective bone regeneration while attenuating side effects are strongly sought for. We developed NOVOSIS putty (NP), a novel composite material of hydroxyapatite (HA), beta-tricalcium phosphate (β-TCP)-hydrogel, and BMP-2, which can sustainably release BMP-2 over two weeks. This study investigated the effects and side effects of NP compared with those of collagen sponge (CS) containing BMP-2 using a rat coccygeal intervertebral fusion model. The fusion rates of NP with low and high doses of BMP-2 were significantly higher than those of an iliac bone (IB) graft, but those of CS with low and high doses of BMP-2 were not different from those of the IB graft. Furthermore, the incidences of ectopic bone formation and soft tissue swelling were significantly lower in the NP group than in the CS group. The HA/β-TCP hydrogel carrier enabled superior bone induction with low-dose BMP-2 and decreased the incidence of side effects caused by high-dose BMP-2 compared with that of the collagen carrier.

scholarly journals Radiosurgery for ventricular tachycardia: preclinical and clinical evidence and study design for a German multi-center multi-platform feasibility trial (RAVENTA)

2020 ◽  
Vol 109 (11) ◽  
pp. 1319-1332 ◽  
Author(s):  
Oliver Blanck ◽  
Daniel Buergy ◽  
Maren Vens ◽  
Lina Eidinger ◽  
Adrian Zaman ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Side Effects ◽  
Safety Profile ◽  
Feasibility Trial ◽  
First Year ◽  
High Dose ◽  
Single Session ◽  
High Definition ◽  
Registration Number ◽  
New Treatment

Abstract Background Single-session high-dose stereotactic radiotherapy (radiosurgery) is a new treatment option for otherwise untreatable patients suffering from refractory ventricular tachycardia (VT). In the initial single-center case studies and feasibility trials, cardiac radiosurgery has led to significant reductions of VT burden with limited toxicities. However, the full safety profile remains largely unknown. Methods/design In this multi-center, multi-platform clinical feasibility trial which we plan is to assess the initial safety profile of radiosurgery for ventricular tachycardia (RAVENTA). High-precision image-guided single-session radiosurgery with 25 Gy will be delivered to the VT substrate determined by high-definition endocardial electrophysiological mapping. The primary endpoint is safety in terms of successful dose delivery without severe treatment-related side effects in the first 30 days after radiosurgery. Secondary endpoints are the assessment of VT burden, reduction of implantable cardioverter defibrillator (ICD) interventions [shock, anti-tachycardia pacing (ATP)], mid-term side effects and quality-of-life (QoL) in the first year after radiosurgery. The planned sample size is 20 patients with the goal of demonstrating safety and feasibility of cardiac radiosurgery in ≥ 70% of the patients. Quality assurance is provided by initial contouring and planning benchmark studies, joint multi-center treatment decisions, sequential patient safety evaluations, interim analyses, independent monitoring, and a dedicated data and safety monitoring board. Discussion RAVENTA will be the first study to provide the initial robust multi-center multi-platform prospective data on the therapeutic value of cardiac radiosurgery for ventricular tachycardia. Trial registration number NCT03867747 (clinicaltrials.gov). Registered March 8, 2019. The study was initiated on November 18th, 2019, and is currently recruiting patients. Graphic abstract

Acute cerebellar toxicity induced by high dose of cytarabine (HiDAC): A case report

2020 ◽  
Vol 26 (6) ◽  
pp. 1492-1494 ◽  
Author(s):  
Hamid Rahmani ◽  
Mojan Radmehr ◽  
Molouk Hadjibabaie ◽  
Mohammad Solduzian
Keyword(s):  
Acute Myeloid Leukemia ◽  
Case Report ◽  
Side Effects ◽  
Myeloid Leukemia ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Pyrimidine Analogue ◽  
High Doses ◽  
Different Doses ◽  
Acute Myeloid

Cytarabine is a pyrimidine analogue that is used for the treatment of acute myeloid leukemia at different doses. Standard doses of cytarabine are used for induction therapy, while high doses are used for post-remission (consolidation) and relapsed/refractory treatment. One of the major side effects of its high doses is acute cerebellar toxicity occurring in 10 to 25% of patients. We report a case that developed this side effect after receiving two doses of high-dose cytarabine. The patient’s symptoms improved after withholding the drug. Thereafter, the patient tolerated treatment continuation with lower doses.

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