N-Acetyl cysteine does not prevent liver toxicity from chronic low-dose plus subacute high-dose paracetamol exposure in young or old mice

Abstract Normal karyotype AML patients with FLT3 ITD have a higher risk of relapse than those lacking this mutation (Estey EH, Am J Hematol. 2013). Our comparative genomic hybridization study (77 patients) showed that AML cases with as compared to those without FLT3 ITD had significantly lower number of amplifications or deletions (number of total CNV aberrations: 18±4 vs 51±8, p=0.003). The latter observation in concert with that of others (Thiede, Blood 2002) suggest that FLT3 ITD mutation if present in normal karyotype patients is a key player in the pathogenesis of leukaemia and targeting this mutation may be used successfully in FLT3 ITD positive patients relapsing post HSCT. This was also the case in the two patients presented in this study. Patient UPN 952, male, 53 years old, AML M4 (FAB), normal karyotype, received alloHSCT in 2 CR after completion of two lines of remission induction therapies (first: DA3+7 (Daunorubicin, Ara-C), HAM, high dose Ara-C; second: ICE (IDA, Ara-C, VP-16)) and then promptly transplanted. He relapsed 56 days after transplantation. Patient UPN 938, female, 50 years old, AML, normal karyotype, received as an induction DA 3+7, and for consolidation HAM and high dose Ara-C and completed only one course of the maintenance therapy and transplanted in CR. Both cases were transplanted from unrelated donors (10/10 HLA A, B, C, DR and DQ alleles matched), they received myeloablative conditioning (i.v. Busulfan and Cyclophosphamide) and Cyclosporin A as GvHD prophylaxis. At relapse they received salvage chemotherapy tailored to their biological performance (UPN 938 having Age Adjusted Charlson Comorbidity Index 3 received FLAG and UPN 952 with the index 9, ECOG 3, DA2+5). Both cases received in addition Sorafenib (two times 400 mg per day). The response was prompt and the marrow was free from blasts beginning from 11 day post chemotherapy. UPN 952 received as a maintenance only one course of 6-TG with low dose of Ara-C. Due to the substantial comorbidity and liver toxicity WHO3 further chemotherapy treatment was terminated. The patient was left only on Sorafenib (2 times 200 mg per day). UPN 938 was receiving the maintenance therapy (AML protocol) in 6 – 8 weeks intervals based on low dose Ara-C with 6TG or DNR and also Sorafenib (2 times 200 mg per day). In both cases FLT3 signalling pathway (FLT3 Pathway Mutation PCR Array, SABiosciences, Qiagen) revealed a lack of any additional mutation at the check points in FLT3, KRAS, HRAS, NRAS, MEK1, PIK3CA, BRAF and PTEN genes. UPN 938 had in addition to FLT3 ITD mutation c.1807_1808insATGAATATGATCTCAAAT (p.K602_W603insYEYDLK) insertion which relevance was not so far describe. Sorafenib resistance mutations were not found. The patients were on Sorafenib for 8 (UPN 938) and 9 months (UPN 952). The course of UPN938 was uncomplicated. The second case showed mild aGvHD symptoms evolving into cGvHD (skin lesions and dry eye) slowed down with rapamicine. Up to now the patients are in CR and free from FLT3 ITD. The main observation points: - Sorafenib with chemotherapy tailored to the biologic performance of patients contributes to the efficient salvage in patients with relapsing FLT3 ITD positive AML post HSCT and is also effective given alone as a maintenance. - Side effects were seen in one out of two patients likely associated with the blocking of VEGFR signalling transmission (hand foot skin rash, von Willebrandt factor activity – 388%). Conclusion: The use of multikinase inhibitor (Sorafenib) contributes effectively to salvage therapy in FLT3+ AML patients relapsing post alloHSCTSorafenib given alone is able to maintain long-lasting remissionSide effects are individually dependent Supported by NBiR CellsTherpy grant and Byer Health Care Disclosures No relevant conflicts of interest to declare.

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Influence of BCG dose and age of inoculated mice on immunoprotection against tuberculosis and expression of IFN-γ/IL-4

Chinese Journal of Agricultural Biotechnology ◽

10.1017/s147923620999026x ◽

2009 ◽

Vol 6 (2) ◽

pp. 171-176

Author(s):

Guo Hui-Jun ◽

Li Bao-Quan ◽

Chai Jia-Qian ◽

Chang Wei-Shan ◽

Wang Chun-Yang ◽

...

Keyword(s):

Low Dose ◽

Interferon Γ ◽

Interleukin 4 ◽

High Dose ◽

Bacille Calmette Guerin ◽

Il Interleukin ◽

Cell Immunity ◽

Ifn Γ ◽

Old Mice

AbstractBalB/C neonate mice and adult BalB/C mice were vaccinated using BCG (Bacille Calmette–Guerin). The pathogenic growth characteristics of BCG in in vitro culture on spleen cells (SPC) were observed and changes in induced expression of IFN (interferon)-γ and IL (interleukin)-4 in SPC were detected using the ELISPOT assay. The results showed that a low dose of BCG (2×103 cfu) exerted 100% immunoprotection on 7-day-old neonate mice and a high dose of BCG (4×104 cfu) exerted 75% immunoprotection. A low dose of BCG (2×103 cfu) exerted 67% immunoprotection on 35-day-old mice. It is also shown that Th1-type cell immunity dominated by IFN-γ was enhanced significantly in the neonate mice injected with a low dose of BCG (2×103 cfu), and Th2-type cell immunity dominated by IL-4 was depressed at the same time. IFN-γ and IL-4 induced by a high dosage of BCG (4×104 cfu) in neonate mice were both increased. IFN-γ and IL-4 induced by a low dose of BCG (2×103 cfu) in 35-day-old mice were also increased. The results indicate that there exists a marked correlation between immunoprotection by BCG in mice and both the immunizing dose and age of the immune animals, which might be relevant to the changes induced by BCG on Th1- and Th2-type cell immunity.

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Demonstration of the protective effect of ghrelin in the livers of rats with cisplatin toxicity

Human & Experimental Toxicology ◽

10.1177/09603271211026722 ◽

2021 ◽

pp. 096032712110267

Author(s):

R Bademci ◽

MA Erdoğan ◽

E Eroğlu ◽

A Meral ◽

A Erdoğan ◽

...

Keyword(s):

Toxic Effect ◽

Low Dose ◽

Liver Toxicity ◽

Histopathological Examination ◽

Normal Liver ◽

Chemotherapeutic Agents ◽

Control Group ◽

High Dose ◽

Sprague Dawley ◽

Group 2

Despite the various and newly developed chemotherapeutic agents in recent years, cisplatin is still used very frequently as a chemotherapeutic agent, even though cisplatin has toxic effects on many organs. The aim of our study is to show whether ghrelin reduces the liver toxicity of cisplatin in the rat model. Twenty-eight male Sprague Dawley albino mature rats were chosen to be utilized in the study. Group 1 rats (n = 7) were taken as the control group, and no medication was given to them. Group 2 rats (n = 7) received 5 mg/kg/day cisplatin and 1 ml/kg/day of 0.9% NaCl, Group 3 rats (n = 7) received 5 mg/kg/day cisplatin and 10 ng/kg/day ghrelin, Group 4 rats (n = 7) received 5 mg/kg/day cisplatin and 20 ng/kg/day ghrelin for 3 days. Glutathione, malondialdehyde (MDA), superoxide dismutase (SOD), plasma alanine aminotransferase (ALT) levels, and liver biopsy results were measured in rats. It was determined that, especially in the high-dose group, the MDA, plasma ALT, and SOD levels increased less in the ghrelin group as compared to the cisplatin group, and the glutathione level decreased slightly with a low dose of ghrelin, while it increased with a higher dose. In histopathological examination, it was determined that the toxic effect of cisplatin on the liver was reduced with a low dose of ghrelin, and its histopathological appearance was similar to normal liver tissue when given a high dose of ghrelin. These findings show that ghrelin, especially in high doses, can be used to reduce the toxic effect of cisplatin.

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Effectiveness and Toxicity of Methotrexate in Juvenile Idiopathic Arthritis: Comparison of 2 Initial Dosing Regimens

The Journal of Rheumatology ◽

10.3899/jrheum.090826 ◽

2010 ◽

Vol 37 (4) ◽

pp. 870-875 ◽

Cited By ~ 27

Author(s):

MARA L. BECKER ◽

CARLOS D. ROSÉ ◽

RANDY Q. CRON ◽

DAVID D. SHERRY ◽

WARREN B. BILKER ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Clinical Response ◽

Dose Group ◽

Low Dose ◽

Liver Toxicity ◽

High Dose Group ◽

High Dose ◽

Active Joint ◽

Significant Difference ◽

Dosing Regimens

Objective.To compare the incidence of liver toxicity and clinical response between 2 initial dosing regimens of methotrexate (MTX) for treatment of juvenile idiopathic arthritis (JIA).Methods.Clinical and laboratory data were abstracted from the medical records of 220 children newly prescribed MTX from the same geographic region. One cohort received initial doses of MTX > 0.5 mg/kg/week (“high-dose”) and one cohort received initial doses of MTX ≤ 0.5 mg/kg/week (“low-dose”). Toxicity was defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) above the normal range, and positive clinical response was defined as a reduction in active joint count during the first 6 months of MTX therapy.Results.One hundred twenty-six children were in the high-dose MTX group, 94 in the low-dose MTX group. At 6 months, the high-dose group was more likely to have an elevated AST or ALT (adjusted OR 3.89, 95% CI 1.82–8.29, p < 0.0001). Subjects receiving both MTX and nonsteroidal antiinflammatory drugs (NSAID) had no significant difference between groups in change of active joint count, while subjects in the high-dose group but not taking NSAID had more active joints (p = 0.036) at 6 months compared to the low-dose group.Conclusion.Initial high-dose MTX was associated with an increased risk of at least one liver enzyme abnormality with no significant improvement in active joint count. This suggests that there is no apparent benefit, while the potential for liver toxicity is increased, when using higher doses of MTX at treatment inception in patients with JIA.

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Hepatoprotective Effect of Captopril on Liver Toxicity Induced by High and Low Dose of Paracetamol in Rats:Histological Study

Asian Journal of Pharmaceutical Research and Health Care ◽

10.18311/ajprhc/2016/4412 ◽

2016 ◽

Vol 8 (3) ◽

pp. 92

Author(s):

Turki M. Al-Shaikh ◽

Mahmoud M. E. Mudawi ◽

Abdelhadi Y. A. Yassin ◽

Rami S. Habeballa ◽

Vijay R. Chidrawar

Keyword(s):

Normal Saline ◽

Low Dose ◽

Liver Toxicity ◽

Hepatoprotective Effect ◽

High Dose ◽

Over The Counter ◽

Single Oral Administration ◽

High Single Dose ◽

Two Phases ◽

Histopathological Studies

Many patients may administered medications like captopril (ACE inhibitor) for treatment of chronic diseases and may also take Paracetamol as an Over The Counter (OTC) drug which may interact with captopril. Therefore, the aim of this study is to evaluate of the hepatoprotective effect of captopril on liver toxicity induced by low and high dose of paracetamol in rats. This study was conducted in two phases: first study for low dose of paracetamol (300 mg/kg); animals were divided into 4 groups of 6 rats each (n = 6); all groups were treated orally either 0.9 % Normal Saline (NS), captopril 20 mg/kg, paracetamol 300 mg/kg or captopril 20 mg/kg plus paracetamol 300 mg/kg for 10 consecutive days. Second study for single high dose of paracetamol (3000 mg/kg); animals were divided into 4 groups of 6 rats each (n = 6); all groups were pretreated orally either 0.9 % Normal Saline (NS) or captopril 20 mg/kg for 7 consecutive days followed by single oral administration of Paracetamol 3000 mg/kg or normal saline. The administration of Paracetamol or normal saline was performed 24 hours after the last administration of captopril. After 48 hours of hepatic injury induction, the animals were then sacrificed and the liver was removed for histopathological studies. Low dose (300 mg/kg) for 10 days and high single dose (3000 mg/kg) of paracetamol produced hepatotoxic effects. While captopril 20 mg/kg showed marked protection against changes induced by low and high dose of paracetamol on the liver.

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Acetaminophen: Neonatal hepatotoxicity due to late pregnancy exposure

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100127906 ◽

1987 ◽

Vol 45 ◽

pp. 718-719

Author(s):

G.A. Miranda ◽

M.A. Arroyo ◽

C.A. Lucio ◽

M. Mongeotti ◽

S.S. Poolsawat

Keyword(s):

Low Dose ◽

Fetal Liver ◽

Late Pregnancy ◽

Toxic Chemicals ◽

Control Group ◽

High Dose ◽

Over The Counter ◽

Liver And Kidney ◽

Neonatal Liver ◽

Childbearing Women

Exposure to drugs and toxic chemicals, during late pregnancy, is a common occurrence in childbearing women. Some studies have reported that more than 90% of pregnant women use at least 1 prescription; of this, 60% used more than one. Another study indicated that 80% of the consumed drugs were not prescribed, and of this figure, 95% were “over-the-counter” drugs. Acetaminophen, the safest of all over-the-counter drugs, has been reported to induce fetal liver necrosis in man and animals and to have abortifacient and embryocidal action in mice. This study examines the degree to which acetaminophen affects the neonatal liver and kidney, when a fatty diet is simultaneously fed to the mother during late pregnancy.Timed Swiss Webster female mice were gavaged during late pregnancy (days 16-19) with fat suspended acetaminophen at a high dose, HD = 84.50 mg/kg, and a low dose, LD = 42.25 mg/kg; a control group received fat alone.

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Evaluation of hippocampus in rhesus monkeys after chronic (1-year) inhalation exposure to marijuana: I. Electron microscopy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100159539 ◽

1990 ◽

Vol 48 (3) ◽

pp. 398-399

Author(s):

A.M. Andrews ◽

S.W. Wilson ◽

A.C. Scallet ◽

S.F. Ali ◽

J. Bailey ◽

...

Keyword(s):

Synaptic Vesicles ◽

Rhesus Monkeys ◽

Low Dose ◽

Inhalation Exposure ◽

Synaptic Cleft ◽

High Dose ◽

Withdrawal Time ◽

Treatment Groups ◽

Ultrastructural Evidence ◽

Male Rhesus

Exposure of rhesus monkeys (Macaca mulatta) to marijuana via inhalation or to intravenous delta-9-tetrahydrocannabinol (THC), reportedly caused ultrastructural evidence of increased synaptic width. Chronic marijuana smoke in a single rhesus monkey examined after a six month withdrawal time caused ultrastructure changes in the septal, hippocampal and amygdala regions; the synaptic cleft was widened, electron opaque material was found in the cleft and in the pre- and postsynaptic regions, with some clumping of the synaptic vesicles. The objective of our study was to assess neuropathological alterations produced by chronic inhalation of marijuana smoke.Nineteen male rhesus monkeys, 3-5 years of age and weighing 3-8 kg, were divided into four treatment groups: a) sham control, b) placebo smoke (7 days/ week) c) low dose marijuana (2 times/week with 5 days/week sham) and d) high dose marijuana (7 times/week). A smoke exposure consisted of smoke from one cigarette (2.6% THC) burned down to 10 mm butt length. Smoke was administered via smoke generator (ADL II, Arthur D. Little, Inc. Cambridge, MA) and nose-mouth only masks (local production) equipped with one-way valves.

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Benefit/Risk Profile of Combined Antiplatelet Therapy with Ticlopidine and Aspirin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648180 ◽

1991 ◽

Vol 65 (05) ◽

pp. 504-510 ◽

Cited By ~ 20

Author(s):

Raffaele De Caterina ◽

Rosa Sicari ◽

Walter Bernini ◽

Guido Lazzerini ◽

Giuliana Buti Strata ◽

...

Keyword(s):

Platelet Function ◽

Low Dose ◽

Bleeding Time ◽

Ex Vivo ◽

Stable Coronary Artery Disease ◽

High Dose ◽

Single Drug ◽

Before And After ◽

Serum Thromboxane ◽

Artery Disease

SummaryTiclopidine (T) and aspirin (ASA) are two antiplatelet drugs both capable of prolonging bleeding time (BT), with a different mechanism of action. A synergism in BT prolongation has been reported and is currently considered an argument for not recommending their combination. However, a profound suppression of platelet function might be a desirable counterpart of a marked prolongation of BT, with a possible use in selected clinical situations. We therefore studied ex vivo platelet function (aggregation by ADP 0.5-1-2.5 μM; adrenaline 0.75-2.5 μM; collagen 1.5-150 μg/ml; arachidonic acid 1 mM; PAF 1 μM; adrenaline 0.17 μM + ADP 0.62 μM; serum thromboxane ([TX]B2 generation) and BT (Mielke) in 6 patients with stable coronary artery disease receiving such combination. Patients underwent sequential laboratory evaluations at baseline, after 7 days of T 250 mg b.i.d., before and after the intravenous administration of ASA 500 mg, respectively, and, finally, after a minimum of 7 days of sole ASA oral administration (50 mg/day). The experimental design, therefore, allowed a comparison of T and ASA effects (2nd and 4th evaluation), and an assessment of the combination effect (3rd evaluation). Platelet aggregation in response to all doses of ADP was depressed more by T than by ASA. Conversely, responses to adrenaline, and arachidonate were affected more by ASA than by T. For all other agents, differences were not significant. T + ASA combination was more effective (p <0.05) than either treatment alone in depressing responses to high-dose collagen (% over control, mean ± SEM: T: 95 ± 3; ASA: 96 ± 5; T + ASA: 89 ± 4). Serum TXB2 (basal, ng/ml: 380 ± 54) did not change with T (372 ± 36), dropped to <1 ng/ml on ASA injection and slightly re-increased to 9.1 ± 3.1 ng/ml on oral low-dose ASA. BT (basal 7.4 ± 0.6 min) was affected similarly by T (9.2 ± 0.8) or ASA (9.7 ± 0.9) alone, but increased to 15.0 ± 0.7 min on combination treatment (106% increase over control). Thus, the strong synergism in BT prolongation by ASA-T combination has a counterpart in the inhibition of platelet function in response to strong stimuli such as high-dose collagen, not otherwise affected significantly by single-drug treatment. This effect is a possible rationale for the clinical evaluation of T + ASA combination.

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Intensive Initial Oral Anticoagulation and Shorter Heparin Treatment in Deep Vein Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661195 ◽

1984 ◽

Vol 52 (03) ◽

pp. 276-280 ◽

Cited By ~ 17

Author(s):

Sam Schulman ◽

Dieter Lockner ◽

Kurt Bergström ◽

Margareta Blombäck

Keyword(s):

Deep Vein Thrombosis ◽

Oral Anticoagulation ◽

Dose Group ◽

Low Dose ◽

Clinical Signs ◽

Coagulation Factor ◽

High Dose ◽

Vein Thrombosis ◽

Heparin Treatment ◽

Deep Vein

SummaryIn order to investigate whether a more intensive initial oral anticoagulation still would be safe and effective, we performed a prospective randomized study in patients with deep vein thrombosis. They received either the conventional regimen of oral anticoagulation (“low-dose”) and heparin or a more intense oral anticoagulation (“high-dose”) with a shorter period of heparin treatment.In the first part of the study 129 patients were randomized. The “low-dose” group reached a stable therapeutic prothrombin complex (PT)-level after 4.3 and the “high-dose” group after 3.3 days. Heparin was discontinued after 6.0 and 5.0 days respectively. There was no difference in significant hemorrhage between the groups, and no clinical signs of progression of the thrombosis.In the second part of the study another 40 patients were randomized, followed with coagulation factor II, VII, IX and X and with repeated venograms. A stable therapeutic PT-level was achieved after 4.4 (“low-dose”) and 3.7 (“high-dose”) days, and heparin was discontinued after 5.4 and 4.4 days respectively. There were no clinical hemorrhages, the activity of the coagulation factors had dropped to the same level in both groups at the time when heparin was discontinued and no thromboembolic complications occurred.Our oral anticoagulation regimen with heparin treatment for an average of 4.4-5 days seems safe and reduces in-patient costs.

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Effects of Aspirin and Sulfinpyrazone on Thromboxane and Prostacyclin Synthesis in Rabbits

10.1055/s-0038-1665775 ◽

1979 ◽

Author(s):

J McDonald ◽

A Cerskus ◽

M Ali

Keyword(s):

Arachidonic Acid ◽

Platelet Aggregation ◽

Low Dose ◽

High Dose ◽

Prostacyclin Synthesis

Arachidonic acid (AA) or collagen were infused into rabbits causing intravascular platelet aggregation with thrombocytopenia, hypotension and death. Thromboxane and prostacyclin synthesis were measured by radioimmunoassay of plasma TXB2 and 6-keto-PGF1α. The effects of pretreatement with aspirin (ASA) or sulfinpyrazone(SPZ) were assessed.Death in drug-treated rabbits was always associated with elevations of plasma TXB2(1-40 ng/ml) and of 6-keto-PGF1α(1-20 ng/ml). Collagen produced only small elevations of plasma TXB2 compared to AA but protection by ASA correlated better with inhibition of TXB2 and 6-keto-PGF1α synthesis than with inhibition of aggregation. Low dose ASA produced less inhibition of prostacyclin synthesis than high dose ASA but was less effective in preventing thromboxane synthesis and death.

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