scholarly journals Cyclophosphamide treatment evoked side effects on skeletal muscle monitored by DSC

2020 ◽  
Vol 142 (5) ◽  
pp. 1897-1901
Author(s):  
Dénes Lőrinczy
Keyword(s):  
Skeletal Muscle ◽  
Locomotor Activity ◽  
Side Effects ◽  
Side Effect ◽  
Muscle Protein ◽  
Scanning Calorimetry ◽  
Drug Induced ◽  
Severe Problem ◽  
Cyclophosphamide Treatment

AbstractPolyneuropathy is defined as a simultaneous malfunction of several peripheral nerves, which could be a side effect of cancer therapy as well. Many kinds of drugs, supposedly cyclophosphamide, also can induce a disease classified as toxic polyneuropathy. It is well known that a severe problem in the locomotor activity can join to it. Recently, we have no enough information about the attacked points in the structure of muscle proteins, as well as about the change in the interaction of myosin actin. In the present study, we analyse this side effect on skeletal muscle (m. gastrocnemius) by differential scanning calorimetry (DSC), as an established thermal analysis method, to follow the possible consequence of drug treatment in the most important muscle protein. We used cyclophosphamide-treated in vitro animal model (guinea pig) with a comparable dosage and time handling of human protocol to show evidences of this drug-induced effects. According to our results, we could show a dose-dependent difference between thermal parameters (denaturation temperature and calorimetric enthalpy) of untreated and treated samples assigned to their contractile proteins (actin and myosin), which can be detected by DSC. It proved that we can create new possibilities in the detection and prognosis of expected and unwanted side effects of cyclophosphamide, such as change of locomotor activity joined to polyneuropathy.

scholarly journals Cyclophosphamide treatment evoked side effect on skeletal muscle actin, monitored by DSC

2021 ◽  
Author(s):  
Péter Farkas ◽  
Dávid Szatmári ◽  
Franciska Könczöl ◽  
Dénes Lőrinczy
Keyword(s):  
Skeletal Muscle ◽  
Side Effect ◽  
Main Peak ◽  
Muscle Actin ◽  
Scanning Calorimetry ◽  
Drug Induced ◽  
Cyclophosphamide Treatment ◽  
Intact Muscle ◽  
Binding Cleft

AbstractSeveral kind of drugs—used in cancer treatments—such as cyclophosphamide (CP) can also trigger a disease classified as toxic polyneuropathy. Polyneuropathy is a simultaneous malfunction of several peripheral nerves, typical side effect of a cancer therapy. In our previous study, we used CP treated in vitro animal model (Guinea pig) with a comparable dosage and time handling of human protocol to show evidences of this drug-induced effects. We could show a dose-dependent difference between in Tm and ΔHcal of untreated and treated samples assigned to their intact muscle and nerve, blood plasma and red blood cells. In our current study we analyze this side effect on skeletal muscle actin (prepared from m. psoas of rabbit) by DSC (differential scanning calorimetry), to follow the possible consequence of drug treatment on the “activator” of muscle contraction. We have demonstrated that run of DSC curves, Tms together with the ΔHcal exhibit clear CP effect. In case of Ca2+ G actin it is manifested in a well separated second high denaturing temperature as a consequence of CP binding into the cleft. This way the nucleotide binding cleft with subdomains 1 and 3 becomes less flexible, indicating clear sensitivity to CP treatment. In F-actin samples, the main peak represents the thermal denaturation of subdomains 1 and 3, and the increased calorimetric enthalpy administrating Ca2+ as well as CP refers to a more rigid structure. These alterations can be the molecular background in the malfunction of muscle in case of polyneuropathy after CP treatment.

Mannose Conjugated Starch Nanoparticles for Preferential Targeting of Liver Cancer

2020 ◽  
Vol 17 ◽  
Author(s):  
Akhlesh Kumar Jain ◽  
Hitesh Sahu ◽  
Keerti Mishra ◽  
Suresh Thareja
Keyword(s):  
Side Effects ◽  
Liver Cancer ◽  
Entrapment Efficiency ◽  
Xrd Analysis ◽  
In Vitro Cytotoxicity ◽  
Physical Interaction ◽  
Scanning Calorimetry ◽  
Starch Nanoparticles

Aim: To design D-Mannose conjugated 5-Fluorouracil (5-FU) loaded Jackfruit seed starch nanoparticles (JFSSNPs) for site specific delivery. Background: Liver cancer is the third leading cause of death in world and fifth most often diagnosed cancer is the major global threat to public health. Treatment of liver cancer with conventional method bears several side effects, thus to undertake these side effects as a formulation challenge, it is necessary to develop novel target specific drug delivery system for the effective and better localization of drug into the proximity of target with restricting the movement of drug in normal tissues. Objective: To optimize and characterize the developed D-Mannose conjugated 5-Fluorouracil (5-FU) loaded Jackfruit seed starch nanoparticles (JFSSNPs) for effective treatment of liver cancer. Materials and methods: 5-FU loaded JFSSNPs were prepared and optimized formulation had higher encapsulation efficiency were conjugated with D-Mannose. These formulations were characterized for size, morphology, zeta potential, X-Ray Diffraction, and Differential Scanning Calorimetry. Potential of NPs were studied using in vitro cytotoxicity assay, in vivo kinetic studies and bio-distribution studies. Result and discussion: 5-Fluorouracil loaded NPs had particle size between 336 to 802nm with drug entrapment efficiency was between 64.2 to 82.3%. In XRD analysis, 5-FU peak was diminished in the diffractogram, which could be attributed to the successful incorporation of drug in amorphous form. DSC study suggests there was no physical interaction between 5- FU and Polymer. NPs showed sustained in vitro 5-FU release up to 2 hours. In vivo, mannose conjugated NPs prolonged the plasma level of 5-FU and assist selective accumulation of 5-FU in the liver (vs other organs spleen, kidney, lungs and heart) compared to unconjugated one and plain drug. Conclusion: In vivo, bio-distribution and plasma profile studies resulted in significantly higher concentration of 5- Fluorouracil liver suggesting that these carriers are efficient, viable, and targeted carrier of 5-FU treatment of liver cancer.

scholarly journals Optimization of an in vitro bioassay to monitor growth and formation of myotubes in real time

2016 ◽  
Vol 36 (3) ◽  
Author(s):  
Sylvia M. Murphy ◽  
Maeve Kiely ◽  
Philip M. Jakeman ◽  
Patrick A. Kiely ◽  
Brian P. Carson
Keyword(s):  
Skeletal Muscle ◽  
Real Time ◽  
Muscle Protein ◽  
In Vitro Bioassay ◽  
Protein Balance ◽  
Proliferation And Differentiation

In the present paper we have developed, described and validated an in vitro bioassay to monitor skeletal muscle proliferation and differentiation. We have also demonstrated the use of this assay to evaluate factors which may affect muscle protein balance.

Quinidine hypersensitivity: a side effect of a forgotten antiarrhythmic

2020 ◽  
Vol 13 (8) ◽  
pp. e235528 ◽  
Author(s):  
Layan El-khatib ◽  
Hussayn Alrayes ◽  
Omar Sallam ◽  
Ahmed Elbanna
Keyword(s):  
Differential Diagnosis ◽  
Ventricular Tachycardia ◽  
Side Effects ◽  
Side Effect ◽  
Liver Toxicity ◽  
Drug Induced ◽  
Multiple Factors

Quinidine is one of the oldest antiarrhythmics known. Over the years, its use has decreased along with its side effects. Our case describes a 69-year-old woman with recurrent resistant ventricular tachycardia on Quinidine and Amiodarone who presented with acute liver toxicity. Drug-induced liver toxicity was at the top of our differential diagnosis list. Taking multiple factors into consideration, a decision was made to discontinue Quinidine, the patient’s symptoms and lab abnormalities resolved within 1 week, yielding the diagnosis of Quinidine hypersensitivity.

scholarly journals GSK3787-Loaded Poly(Ester Amide) Particles for Intra-Articular Drug Delivery

Polymers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 736 ◽  
Author(s):  
Ian J. Villamagna ◽  
Danielle M. McRae ◽  
Aneta Borecki ◽  
Xueli Mei ◽  
François Lagugné-Labarthet ◽  
...  
Keyword(s):  
Side Effects ◽  
Ex Vivo ◽  
Joint Space ◽  
Peroxisome Proliferator ◽  
Scanning Calorimetry ◽  
Peroxisome Proliferator Activated Receptor ◽  
Force Microscopy ◽  
Young’S Moduli ◽  
Joint Disorder

Osteoarthritis (OA) is a debilitating joint disorder affecting more than 240 million people. There is no disease modifying therapeutic, and drugs that are used to alleviate OA symptoms result in side effects. Recent research indicates that inhibition of peroxisome proliferator-activated receptor δ (PPARδ) in cartilage may attenuate the development or progression of OA. PPARδ antagonists such as GSK3787 exist, but would benefit from delivery to joints to avoid side effects. Described here is the loading of GSK3787 into poly(ester amide) (PEA) particles. The particles contained 8 wt.% drug and had mean diameters of about 600 nm. Differential scanning calorimetry indicated the drug was in crystalline domains in the particles. Atomic force microscopy was used to measure the Young’s moduli of individual particles as 2.8 MPa. In vitro drug release studies showed 11% GSK3787 was released over 30 days. Studies in immature murine articular cartilage (IMAC) cells indicated low toxicity from the drug, empty particles, and drug-loaded particles and that the particles were not taken up by the cells. Ex vivo studies on murine joints showed that the particles could be injected into the joint space and resided there for at least 7 days. Overall, these results indicate that GSK3787-loaded PEA particles warrant further investigation as a delivery system for potential OA therapy.

scholarly journals Tissue-Engineered Human Myobundle System as a Platform for Evaluation of Skeletal Muscle Injury Biomarkers

2020 ◽  
Vol 176 (1) ◽  
pp. 124-136
Author(s):  
Alastair Khodabukus ◽  
Amulya Kaza ◽  
Jason Wang ◽  
Neel Prabhu ◽  
Richard Goldstein ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Injury ◽  
Culture Media ◽  
Contractile Function ◽  
Significant Loss ◽  
Drug Induced ◽  
Skeletal Muscle Injury ◽  
Specificity And Sensitivity ◽  
Novel Biomarkers

Abstract Traditional serum biomarkers used to assess skeletal muscle damage, such as activity of creatine kinase (CK), lack tissue specificity and sensitivity, hindering early detection of drug-induced myopathies. Recently, a novel four-factor skeletal muscle injury panel (MIP) of biomarkers consisting of skeletal troponin I (sTnI), CK mass (CKm), fatty-acid-binding protein 3 (Fabp3), and myosin light chain 3, has been shown to have increased tissue specificity and sensitivity in rodent models of skeletal muscle injury. Here, we evaluated if a previously established model of tissue-engineered functional human skeletal muscle (myobundle) can allow detection of the MIP biomarkers after injury or drug-induced myotoxicity in vitro. We found that concentrations of three MIP biomarkers (sTnI, CKm, and Fabp3) in myobundle culture media significantly increased in response to injury by a known snake venom (notexin). Cerivastatin, a known myotoxic statin, but not pravastatin, induced significant loss of myobundle contractile function, myotube atrophy, and increased release of both traditional and novel biomarkers. In contrast, dexamethasone induced significant loss of myobundle contractile function and myotube atrophy, but decreased the release of both traditional and novel biomarkers. Dexamethasone also increased levels of matrix metalloproteinase-2 and -3 in the culture media which correlated with increased remodeling of myobundle extracellular matrix. In conclusion, this proof-of-concept study demonstrates that tissue-engineered human myobundles can provide an in vitro platform to probe patient-specific drug-induced myotoxicity and performance assessment of novel injury biomarkers to guide preclinical and clinical drug development studies.

scholarly journals Effects of potassium deficiency on growth and protein synthesis in skeletal muscle and the heart of rats

1989 ◽  
Vol 62 (2) ◽  
pp. 269-284 ◽  
Author(s):  
Inge Dôrup ◽  
Torben Clausen
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Control Level ◽  
Inhibitory Effect ◽  
Potassium Deficiency ◽  
Skeletal Muscle Protein ◽  
K Deficiency

The effects of potassium deficiency on growth, K content and protein synthesis have been compared in 4–13-week-old rats. When maintained on K-deficient fodder (1 mmol/kg) rats ceased to grow within a few days, and the incorporation of [3H]leucine into skeletal muscle protein in vivo was reduced by 28–38%. Pair-feeding experiments showed that this inhibition was not due to reduced energy intake. Following 14 d on K-deficient fodder, there was a further reduction (39–56 %) in the incorporation of [3H]leucine into skeletal muscle protein, whereas the incorporation into plasma, heart and liver proteins was not affected. The accumulation of the non-metabolized amino acid α-aminoisobutyric acid in the heart and skeletal muscles was not reduced. The inhibitory effect of K deficiency on 3H-labelling of muscle protein was seen following intraperitoneal (10–240 min) as well as intravenous (10 min) injection of [3H]leucine. In addition, the incorporation of [3H]phenylalanine into skeletal muscle protein was reduced in K-depleted animals. Following acute K repletion in vivo leading to complete normalization of muscle K content, the incorporation of [3H]leucine into muscle protein showed no increase within 2 h, but reached 76 and 104% of the control level within 24 and 72 h respectively. This was associated with a rapid initial weight gain, but normal body-weight was not reached until after 7 weeks of K repletion. Following 7 d on K-deficient fodder the inhibition of growth and protein synthesis was closely correlated with the K content of the fodder (1–40 mmol/kg) and significant already at modest reductions in muscle K content. In vitro experiments with soleus muscle showed a linear relationship between the incorporation of [3H]leucine into muscle protein and K content, but the sensitivity to cellular K deficiency induced in vitro was much less pronounced than that induced in vivo. Thus, in soleus and extensor digitorum longus (EDL) muscles prepared from K-deficient rats, the incorporation of [3H]leucine was reduced by 30 and 47 % respectively. This defect was completely restored by 24 h K repletion in vivo. It is concluded that in the intact organism protein synthesis and growth are very sensitive to dietary K deficiency and that this can only partly be accounted for by the reduction in cellular K content per se. The observations emphasize the need for adequate K supplies to ensure optimum utilization of food elements for protein synthesis and growth.

Tumor necrosis factor induces skeletal muscle protein breakdown in rats

1991 ◽  
Vol 260 (5) ◽  
pp. E727-E730 ◽  
Author(s):  
M. N. Goodman
Keyword(s):  
Skeletal Muscle ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Muscle Protein ◽  
Nitrogen Excretion ◽  
Protein Breakdown ◽  
Skeletal Muscle Protein ◽  
Muscle Protein Breakdown ◽  
Necrosis Factor

The metabolic response to infection includes loss of lean tissue and increased nitrogen excretion. The loss of muscle tissue during infection results in large part from accelerated skeletal muscle protein breakdown. Recent studies suggest that macrophage-derived products secreted during infection may signal increased muscle proteolysis. To test this, in the present report the ability of interleukin (IL-1) and tumor necrosis factor (TNF) to enhance muscle proteolysis was examined. Young rats were injected intravenously with either recombinant human IL-1 or TNF. For comparison some rats were injected with bacterial endotoxin. Eight hours after each treatment, the extensor digitorum longus muscles were isolated and incubated in vitro to assess muscle proteolysis by measuring tyrosine and 3-methyl-L-histidine release by the incubated muscles. Treatment of rats with either IL-1, TNF, or endotoxin all induced fever, increased serum lactate, and reduced serum zinc levels. Despite similar metabolic changes, muscle proteolysis responded differently. As expected, endotoxin treatment enhanced muscle protein breakdown, whereas IL-1 treatment was without effect. On the other hand, TNF was effective in accelerating muscle protein breakdown. TNF addition in vitro failed to enhance muscle proteolysis by incubated muscles, suggesting that its effects may be mediated in an indirect manner; however, a direct mode of action cannot yet be ruled out. Overall, the data indicate that the acute administration of TNF can signal increased muscle proteolysis similar to that observed during infection.

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