scholarly journals Repeated Administration of Clinically Relevant Doses of the Prescription Opioids Tramadol and Tapentadol Causes Lung, Cardiac, and Brain Toxicity in Wistar Rats

2021 ◽  
Vol 14 (2) ◽  
pp. 97
Author(s):  
Joana Barbosa ◽  
Juliana Faria ◽  
Fernanda Garcez ◽  
Sandra Leal ◽  
Luís Pedro Afonso ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Wistar Rats ◽  
Brain Cortex ◽  
Dose Range ◽  
Fibrous Tissue ◽  
Lactate Concentration ◽  
Repeated Administration ◽  
Serum Lactate Dehydrogenase ◽  
Prescription Opioids ◽  
Therapeutic Doses

Tramadol and tapentadol, two structurally related synthetic opioid analgesics, are widely prescribed due to the enhanced therapeutic profiles resulting from the synergistic combination between μ-opioid receptor (MOR) activation and monoamine reuptake inhibition. However, the number of adverse reactions has been growing along with their increasing use and misuse. The potential toxicological mechanisms for these drugs are not completely understood, especially for tapentadol, owing to its shorter market history. Therefore, in the present study, we aimed to comparatively assess the putative lung, cardiac, and brain cortex toxicological damage elicited by the repeated exposure to therapeutic doses of both prescription opioids. To this purpose, male Wistar rats were intraperitoneally injected with single daily doses of 10, 25, and 50 mg/kg tramadol or tapentadol, corresponding to a standard analgesic dose, an intermediate dose, and the maximum recommended daily dose, respectively, for 14 consecutive days. Such treatment was found to lead mainly to lipid peroxidation and inflammation in lung and brain cortex tissues, as shown through augmented thiobarbituric acid reactive substances (TBARS), as well as to increased serum inflammation biomarkers, such as C reactive protein (CRP) and tumor necrosis factor-α (TNF-α). Cardiomyocyte integrity was also shown to be affected, since both opioids incremented serum lactate dehydrogenase (LDH) and α-hydroxybutyrate dehydrogenase (α-HBDH) activities, while tapentadol was associated with increased serum creatine kinase muscle brain (CK-MB) isoform activity. In turn, the analysis of metabolic parameters in brain cortex tissue revealed increased lactate concentration upon exposure to both drugs, as well as augmented LDH and creatine kinase (CK) activities following tapentadol treatment. In addition, pneumo- and cardiotoxicity biomarkers were quantified at the gene level, while neurotoxicity biomarkers were quantified both at the gene and protein levels; changes in their expression correlate with the oxidative stress, inflammatory, metabolic, and histopathological changes that were detected. Hematoxylin and eosin (H & E) staining revealed several histopathological alterations, including alveolar collapse and destruction in lung sections, inflammatory infiltrates, altered cardiomyocytes and loss of striation in heart sections, degenerated neurons, and accumulation of glial and microglial cells in brain cortex sections. In turn, Masson’s trichrome staining confirmed fibrous tissue deposition in cardiac tissue. Taken as a whole, these results show that the repeated administration of both prescription opioids extends the dose range for which toxicological injury is observed to lower therapeutic doses. They also reinforce previous assumptions that tramadol and tapentadol are not devoid of toxicological risk even at clinical doses.

scholarly journals Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

2020 ◽  
Vol 13 (7) ◽  
pp. 149
Author(s):  
Joana Barbosa ◽  
Juliana Faria ◽  
Fernanda Garcez ◽  
Sandra Leal ◽  
Luís Pedro Afonso ◽  
...  
Keyword(s):  
Lipid Profile ◽  
Iron Metabolism ◽  
Wistar Rats ◽  
Elevated Serum ◽  
Repeated Administration ◽  
Complement C3 ◽  
Heme Oxygenase 1 ◽  
In Vivo Animal Model ◽  
Liver And Kidney ◽  
Therapeutic Doses

Tramadol and tapentadol are fully synthetic and extensively used analgesic opioids, presenting enhanced therapeutic and safety profiles as compared with their peers. However, reports of adverse reactions, intoxications and fatalities have been increasing. Information regarding the molecular, biochemical, and histological alterations underlying their toxicological potential is missing, particularly for tapentadol, owing to its more recent market authorization. Considering the paramount importance of liver and kidney for the metabolism and excretion of both opioids, these organs are especially susceptible to toxicological damage. In the present study, we aimed to characterize the putative hepatic and renal deleterious effects of repeated exposure to therapeutic doses of tramadol and tapentadol, using an in vivo animal model. Male Wistar rats were randomly divided into six experimental groups, composed of six animals each, which received daily single intraperitoneal injections of 10, 25 or 50 mg/kg tramadol or tapentadol (a low, standard analgesic dose, an intermediate dose and the maximum recommended daily dose, respectively). An additional control group was injected with normal saline. Following 14 consecutive days of administration, serum, urine and liver and kidney tissue samples were processed for biochemical, metabolic and histological analysis. Repeated administration of therapeutic doses of both opioids led to: (i) increased lipid and protein oxidation in liver and kidney, as well as to decreased total liver antioxidant capacity; (ii) decreased serum albumin, urea, butyrylcholinesterase and complement C3 and C4 levels, denoting liver synthesis impairment; (iii) elevated serum activity of liver enzymes, such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and γ-glutamyl transpeptidase, as well as lipid profile alterations, also reflecting hepatobiliary commitment; (iv) derangement of iron metabolism, as shown through increases in serum iron, ferritin, haptoglobin and heme oxygenase-1 levels. In turn, elevated serum cystatin C, decreased urine creatinine output and increased urine microalbumin levels were detected upon exposure to tapentadol only, while increased serum amylase and urine N-acetyl-β-D-glucosaminidase activities were observed for both opioids. Collectively, these results are compatible with kidney injury. Changes were also found in the expression levels of liver- and kidney-specific toxicity biomarker genes, upon exposure to tramadol and tapentadol, correlating well with alterations in lipid profile, iron metabolism and glomerular and tubular function. Histopathological analysis evidenced sinusoidal dilatation, microsteatosis, mononuclear cell infiltrates, glomerular and tubular disorganization, and increased Bowman’s spaces. Although some findings are more pronounced upon tapentadol exposure, our study shows that, when compared with acute exposure, prolonged administration of both opioids smooths the differences between their toxicological effects, and that these occur at lower doses within the therapeutic range.

Genotoxic and mutagenic effects of vigabatrin, a γ-aminobutyric acid transaminase inhibitor, in Wistar rats submitted to rotarod task

2016 ◽  
Vol 35 (9) ◽  
pp. 958-965 ◽  
Author(s):  
VR Coelho ◽  
K Sousa ◽  
TR Pires ◽  
DKM Papke ◽  
CG Vieira ◽  
...  
Keyword(s):  
Acute Treatment ◽  
Wistar Rats ◽  
Micronucleus Test ◽  
Repeated Administration ◽  
Saline Group ◽  
Aminobutyric Acid ◽  
Subchronic Treatment ◽  
Motor Activities ◽  
Male Wistar Rats ◽  
Mutagenic Effects

Vigabatrin (VGB) is an antiepileptic drug thatincreases brain γ-aminobutyric acid (GABA) levels through irreversible inhibition of GABA transaminase. The aim of this study was to evaluate neurotoxicological effects of VGB measuring motor activity and genotoxic and mutagenic effects after a single and repeated administration. Male Wistar rats received saline, VGB 50, 100, or 250 mg/kg by gavage for acute and subchronic (14 days) treatments and evaluated in the rotarod task. Genotoxicity was evaluated using the alkaline version of the comet assay in samples of blood, liver, hippocampus, and brain cortex after both treatments. Mutagenicity was evaluated using the micronucleus test in bone marrow of the same animals that received subchronic treatment. The groups treated with VGB showed similar performance in rotarod compared with the saline group. Regarding the acute treatment, it was observed that only higher VGB doses induced DNA damage in blood and hippocampus. After the subchronic treatment, VGB did not show genotoxic or mutagenic effects. In brief, VGB did not impair motor activities in rats after acute and subchronic treatments. It showed a repairable genotoxic potential in the central nervous system since genotoxicity was observed in the acute treatment group.

scholarly journals Lipid Profile and Oxidative Stress Markers in Wistar Rats following Oral and Repeated Exposure to Fijk Herbal Mixture

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Oluyomi Stephen Adeyemi ◽  
Bukola Temitope Orekoya
Keyword(s):  
Oxidative Stress ◽  
Wistar Rats ◽  
Herbal Remedy ◽  
Repeated Administration ◽  
Rat Plasma ◽  
Repeated Exposure ◽  
Atherogenic Index ◽  
Oral Exposure ◽  
Ether Anesthesia ◽  
Herbal Mixture

This study determined the effect of the oral and repeated administration of Fijk herbal mixture on rat biochemical and morphological parameters. Twenty-four Wistar rats were distributed into four groups of 6. Group A served as control and received oral administration of distilled water daily. The experimental groups B, C, and D were daily and orally exposed to Fijk herbal mixture at 15, 30, and 45 mg/kg, respectively. Treatments lasted for 21 days. The rats were sacrificed under mild diethyl ether anesthesia 24 hr after cessation of treatment. The blood and liver samples were collected and used for the biochemical and morphological analyses. Oral exposure to Fijk caused elevated levels of rat plasma ALT, AST, triglycerides, LDL, and MDA. In contrast, rat plasma HDL, GSH, and ALP levels were lowered by Fijk oral exposure. Also, the herbal remedy caused a dose-dependent elevation in the plasma atherogenic index. The histopathology examinations of rat liver sections revealed inimical cellular alterations caused by repeated exposure to Fijk. Study provides evidence that oral and repeated exposure to Fijk in rats raised the atherogenic index and potentiated oxidative stress as well as hepatic injury.

Cathodal bands in electrophoretograms of creatine kinase isoenzymes in serum collected after cardiac surgery: a poor prognostic sign.

1983 ◽  
Vol 29 (10) ◽  
pp. 1727-1730 ◽  
Author(s):  
A A Keshgegian ◽  
B L Marchant
Keyword(s):  
Creatine Kinase ◽  
Cardiac Surgery ◽  
Adenylate Kinase ◽  
Poor Prognosis ◽  
Postoperative Mortality ◽  
Serum Lactate ◽  
Serum Lactate Dehydrogenase ◽  
Diadenosine Pentaphosphate ◽  
Postoperative Serum ◽  
Very High

Abstract Of 708 patients who had undergone cardiac surgery, the serum of 23 showed one or two enzyme bands cathodal to CK-MM in creatine kinase (CK) isoenzyme electrophoretograms. Postoperative mortality rate during hospitalization was: no bands, 8.8%; one band, 13%, two bands, 63% (p less than 0.001). Patients whose sera showed cathodal bands were slightly older than those without, and their postoperative serum lactate dehydrogenase (LD) activity was greater, with very high proportions of LD 5. The two cathodal bands in patients who died differed in cathodal electrophoretic mobility from the two bands in survivors, implying that different enzyme forms were involved. All cathodal bands were inhibited by reagent containing diadenosine pentaphosphate, as was adenylate kinase from erythrocytes and liver cytoplasm. Mitochondrial CK from liver and presumed mitochondrial CK in serum from a patient with malignancy were not inhibited. We conclude that the appearance of two enzyme bands cathodal to CK-MM, probably representing adenylate kinase and possibly originating from various tissues, is associated with a poor prognosis in patients after cardiac surgery.

scholarly journals Histological studies on the retina and cerebellum of Wistar rats treated with Arteether™

2014 ◽  
Vol 31 (01) ◽  
pp. 028-032
Author(s):  
A. Okunlola ◽  
C. Okunlola ◽  
C. Okani ◽  
O. Adewole ◽  
D. Ofusori ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Study Group ◽  
Group A ◽  
Cervical Dislocation ◽  
Nissl Stain ◽  
Group B ◽  
Haematoxylin And Eosin Stain ◽  
Therapeutic Doses ◽  
Cellular Components ◽  
Group D

Abstract Introduction: Arteether™, a derivative of artemisinin, is among the recent drugs that have given renewed hope for combating malarial menace. The present study investigated the effects of arteether™ on the histology of the retina and cerebellum of Wistar rats. Materials and Methods: Twenty adult albino Wistar rats weighing 150-200 g, were randomly divided into four groups (A, B, C and D) of five animals each and used for this study. Group A rats were given intramuscular (i.m.) arteether™ (3 mg/kg b.w.) daily for 3 days. Group B rats were given i.m. arteether™ (6 mg/kg b.w.) daily for 3 days. Group C rats were also given i. m. of arteether™ (3 mg/kg b. w.) daily for 3 days, and the same dose was repeated at two-weekly intervals for 4 further weeks; while Group D rats which received normal saline (0.9 % w/v, 3 ml/kg b.w.), served as controls. At the end of the experiment, the rats were sacrificed by cervical dislocation. The retina and cerebellum were excised and processed routinely for histopathology changes, using haematoxylin and eosin stain (H & E), as well as Nissl stain. Results: Results obtained showed normal cellular components of the retina and cerebellum in all groups, and no cyto-pathological changes were observed. Conclusion: Thus, this study showed that under light microscopic examination, therapeutic doses of arteether™ caused no significant cyto-pathologic changes in the retina and cerebellum of Wistar rats.

Increased serum lactate dehydrogenase isoenzyme 1 and "flipped" LD-1/LD-2 ratio in myopathy associated with partial carnitine palmitoyltransferase deficiency.

1987 ◽  
Vol 33 (11) ◽  
pp. 2111-2113 ◽  
Author(s):  
G C Moses ◽  
A R Henderson
Keyword(s):  
Creatine Kinase ◽  
Lactate Dehydrogenase ◽  
Serum Lactate ◽  
Creatine Kinase Activity ◽  
Carnitine Palmitoyltransferase ◽  
Serum Lactate Dehydrogenase ◽  
Physiological Basis ◽  
Carnitine Palmitoyltransferase Deficiency ◽  
Total Creatine Kinase Activity ◽  
Partial Deficiency

Abstract We describe a case of a limb-girdle myopathy presenting with myoglobinuria. A partial deficiency of muscle carnitine palmitoyltransferase (EC 2.3.1.21) may also have been present. All "muscle-type" serum enzymes were markedly increased (to between 30- and 400-fold their respective upper reference limits) and creatine kinase (EC 2.7.3.2) isoenzyme 2 (CK-MB) was increased 130-fold but was still less than 2% of the total creatine kinase activity. The isoenzyme pattern of lactate dehydrogenase (EC 1.1.1.27) in serum was "anodic," with isoenzyme 1 greater than isoenzyme 2--an unusual pattern for myopathies. The possible physiological basis for such a finding is discussed.

scholarly journals A High Creatine Kinase Concentration Might Be a Sign of McArdle Disease in Patient With Type 1 Diabetes

2019 ◽  
Vol 12 ◽  
pp. 117862641986140 ◽  
Author(s):  
Kader Ugur ◽  
Yakup Aydogan ◽  
Abdurrahman Akgun ◽  
Suleyman Aydin
Keyword(s):  
Type 1 Diabetes ◽  
Creatine Kinase ◽  
Early Diagnosis ◽  
Lactate Concentration ◽  
Juvenile Diabetes ◽  
Patient Comfort ◽  
Mcardle Disease ◽  
Disease Case ◽  
Insulin Dependent

Type 1 diabetes (the pancreas producing little or no insulin) is usually diagnosed in children and young adults and was previously known as juvenile diabetes. McArdle disease is a common metabolic defect caused by an inherited deficit of myophosphorylase. These 2 diseases might have some clinical heterogeneity. Here, we discuss a McArdle disease case where insulin-dependent diabetes overshadows its early diagnosis. In this case, an insulin-dependent 22-year-old female patient with diabetes mellitus had been on diabetes treatment for 15 years. Although her blood glucose was regulated, her anamnesis showed that muscle weakness, fatigue, cramps or myalgia never healed. Based on her anamnesis, the patient was asked to take a nonischemic forearm exercise test, which revealed significant elevation in levels of creatine kinase (5968-7906 U/L), but no increase was found in lactate concentration, but a slight increase in ammonia concentration (not statistically significant) at the end of the test made us consider McArdle disease. A genetic test was done to confirm this possibility. A homozygous c.2128_2130delTTC/p.Phe710del mutation was detected in the examination of exons of the PYGM gene, which confirmed the diagnosis of McArdle disease in our patient. According to the data, this is a rare case of McArdle disease with type 1 diabetes. During treatment for diabetes, if the above-mentioned symptoms are present in a patient, and especially if the patient’s creatine kinase concentration is high, muscle diseases should be suspected. Therefore, we suggest that this case report will provide new insight to clinicians on metabolic defects in this disease and increase the patient comfort. In such cases, an early diagnosis should reduce health costs.

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