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Annals of Neurology Aug 2019Thymidine kinase 2, encoded by the nuclear gene TK2, is required for mitochondrial DNA maintenance. Autosomal recessive TK2 mutations cause depletion and multiple...
OBJECTIVE
Thymidine kinase 2, encoded by the nuclear gene TK2, is required for mitochondrial DNA maintenance. Autosomal recessive TK2 mutations cause depletion and multiple deletions of mtDNA that manifest predominantly as a myopathy usually beginning in childhood and progressing relentlessly. We investigated the safety and efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies.
METHODS
We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2-deficient patients under a compassionate use program.
RESULTS
In 5 patients with early onset and severe disease, survival and motor functions were better than historically untreated patients. In 11 childhood and adult onset patients, clinical measures stabilized or improved. Three of 8 patients who were nonambulatory at baseline gained the ability to walk on therapy; 4 of 5 patients who required enteric nutrition were able to discontinue feeding tube use; and 1 of 9 patients who required mechanical ventilation became able to breathe independently. In motor functional scales, improvements were observed in the 6-minute walk test performance in 7 of 8 subjects, Egen Klassifikation in 2 of 3, and North Star Ambulatory Assessment in all 5 tested. Baseline elevated serum growth differentiation factor 15 levels decreased with treatment in all 7 patients tested. A side effect observed in 8 of the 16 patients was dose-dependent diarrhea, which did not require withdrawal of treatment. Among 12 other TK2 patients treated with deoxynucleoside, 2 adults developed elevated liver enzymes that normalized following discontinuation of therapy.
INTERPRETATION
This open-label study indicates favorable side effect profiles and clinical efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies for TK2 deficiency. ANN NEUROL 2019;86:293-303.
Topics: Adult; Child; Child, Preschool; Compassionate Use Trials; Deoxyribonucleosides; Female; Humans; Male; Muscular Diseases; Thymidine Kinase; Walk Test
PubMed: 31125140
DOI: 10.1002/ana.25506 -
British Journal of Haematology Sep 2021The addition of molecularly targeted therapies to current chemotherapy regimens may improve acute lymphoblastic leukemia (ALL) outcomes and reduce acute and late...
The addition of molecularly targeted therapies to current chemotherapy regimens may improve acute lymphoblastic leukemia (ALL) outcomes and reduce acute and late toxicities. Checkpoint kinase 1 (CHK1) orchestrates cell cycle checkpoint control in the setting of DNA damage. CHK1 is expressed in both T- and B-ALL and represents a promising therapeutic target. Herein, we show that prexasertib, a targeted CHK1 inhibitor, exhibits significant single-agent efficacy using ALL patient-derived xenograft (PDX) models and synergizes with a nucleoside analog. These results support further clinical testing of prexasertib in ALL.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 1; Deoxycytidine; Drug Synergism; Humans; Mice; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Gemcitabine
PubMed: 34096630
DOI: 10.1111/bjh.17610 -
Archives of Biochemistry and Biophysics Oct 2022Alzheimer's disease (AD) is a progressive disease with a long duration and complicated pathogenesis. Thymidine (Thy) and 2'-deoxyuridine (2'-De) are pyrimidines...
Alzheimer's disease (AD) is a progressive disease with a long duration and complicated pathogenesis. Thymidine (Thy) and 2'-deoxyuridine (2'-De) are pyrimidines nucleotides that are associated with nervous system diseases. However, it remains unclear whether Thy and 2'-De exert neuroprotective effects in AD. Therefore, this study was conducted to explore the interventional effects and mechanisms of Thy and 2'-De on the Aβ-induced brain injury. Donepezil (Do, 10 mg/kg/d), Thy (20 mg/kg/d), and 2'-De (20 mg/kg/d) were administered for 4 weeks after the injection of Aβ peptides (200 μM, i.c.v.) to mice. UPLC-MS/MS method was performed to quantify Thy and 2'-De in the hippocampus of mice brain. The cognition ability, neuronal and mitochondria damage, and levels of Aβ/Aβ, p-Tau, Na K-ATPase, apoptosis, oxidative stress, immune cells, and Iba 1 were measured in Aβ-induced mice. The oxygen consumption (OCR) and extracellular acidification rate (ECAR) were measured using a seahorse analyzer in Aβ-induced N9 cells. Moreover, 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, was added to explore the mechanisms underlying the effects of Thy and 2'-De on Aβ-induced N9 cells. The expression of Iba 1 and levels of CD11b and reactive oxygen species (ROS) were measured after treatment with Thy (5 μM) and 2'-De (10 μM) against 2-DG (5 mM) in Aβ-induced N9 cells. The results suggested that Do, Thy, and 2'-De improved the cognition ability, attenuated the damage to hippocampus and mitochondria, downregulated the levels of Aβ/Aβ, p-Tau, Na K-ATPase, apoptosis, oxidative stress, and Iba 1, and regulated the immune response induced by Aβ against the brain injury. Furthermore, Do, Thy, and 2'-De increased ATP production and inhibited glycolysis in Aβ-induced N9 cells. Moreover, 2-DG enhanced the effects of drugs, reduced microglial activation, and attenuated oxidative stress to interfere with Aβ-induced N9 cells. In conclusion, Thy and 2'-De reduced microglial activation and improved oxidative stress damage by modulating glycolytic metabolism on the Aβ-induced brain injury.
Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Brain Injuries; Chromatography, Liquid; Deoxyglucose; Deoxyuridine; Donepezil; Glycolysis; Mice; Microglia; Neuroprotective Agents; Nucleotides; Oxidative Stress; Peptide Fragments; Pyrimidines; Reactive Oxygen Species; Tandem Mass Spectrometry; Thymidine
PubMed: 35998686
DOI: 10.1016/j.abb.2022.109377 -
Journal of Feline Medicine and Surgery Jun 2023Oxidative stress is associated with the development and progression of chronic kidney disease (CKD) in humans. The aim of this study was to evaluate the concentrations...
OBJECTIVES
Oxidative stress is associated with the development and progression of chronic kidney disease (CKD) in humans. The aim of this study was to evaluate the concentrations of oxidative stress markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA), in the plasma and urine of cats with different stages of CKD.
METHODS
Plasma and urine samples were collected from cats with CKD that were referred to the Veterinary Medical Center of the University of Tokyo between April 2019 and October 2022. Plasma and urine samples were collected from healthy cats (n = 6 at most), cats with stage 2 CKD (n = 8) and stage 3-4 CKD (n = 12), and cats with idiopathic cystitis (disease control, n = 5). Plasma and urine concentrations of 8-OHdG and MDA were measured using ELISA and thiobarbituric acid reactive substances assay kits, respectively.
RESULTS
The median plasma 8-OHdG concentrations were 0.156 ng/ml (<0.125-0.210 ng/ml) in the healthy group, <0.125 ng/ml (range <0.125 ng/ml) in the idiopathic cystitis group, 0.246 ng/ml (range 0.170-0.403 ng/ml) in cats with stage 2 CKD and 0.433 ng/ml (range 0.209-1.052 ng/ml) in cats with stage 3-4 CKD. Concentrations in stage 3-4 CKD were significantly higher than those in the healthy and disease control groups. Plasma MDA concentrations were low in the healthy and disease control groups and significantly higher in cats with stage 3-4 CKD. In every cat with CKD, plasma 8-OHdG and MDA concentrations were positively correlated with plasma creatinine concentrations (8-OHdG, = 0.68; MDA, = 0.67). Urinary 8-OHdG/urinary creatinine (u-CRE) and urinary MDA/u-CRE levels did not differ significantly between the groups; however, it was difficult to evaluate them because of the small sample size.
CONCLUSIONS AND RELEVANCE
This report shows that plasma 8-OHdG and MDA concentrations increase with the severity of feline CKD. These markers may be useful for assessing oxidative stress in cats with CKD.
Topics: Cats; Humans; Animals; 8-Hydroxy-2'-Deoxyguanosine; Deoxyguanosine; Creatinine; Malondialdehyde; Renal Insufficiency, Chronic; Patient Acuity; Cat Diseases
PubMed: 37318844
DOI: 10.1177/1098612X231173519 -
The Cochrane Database of Systematic... Jun 2023Hepatitis B virus (HBV)-human Immunodeficiency virus (HIV) co-infection promotes an aggressive disease course of HBV infection. In the only available non-Cochrane... (Review)
Review
BACKGROUND
Hepatitis B virus (HBV)-human Immunodeficiency virus (HIV) co-infection promotes an aggressive disease course of HBV infection. In the only available non-Cochrane systematic review on antiviral therapy during pregnancy for prevention of mother-to-child transmission of HBV, none of the women studied had HBV-HIV co-infection but were either HBV- or HIV-seropositive. Treatment of HBV alone may develop HIV-strains that are resistant to non-nucleoside reverse transcriptase inhibitors. Accordingly, co-treatment of the HIV infection is recommended.
OBJECTIVES
To evaluate the benefits and harms of tenofovir-based antiviral combination regimens versus placebo, tenofovir alone, or non-tenofovir-based antiviral regimen either alone or in combination with HBV for the prevention of mother-to-child transmission of HBV in HIV-positive pregnant women co-infected with HBV.
SEARCH METHODS
We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE Ovid, Embase Ovid, LILACS (Bireme), Science Citation Index Expanded (Web of Science), and Conference Proceedings Citation Index-Science (Web of Science) on 30 January 2023. We manually searched the reference lists of included trials, searched on-line trial registries, and contacted experts in the field and pharmaceutical companies for any further potential trials.
SELECTION CRITERIA
We aimed to include randomised clinical trials comparing tenofovir-based antiviral combination regimens (anti-HIV regimen with lopinavir-ritonavir therapy, or any other antiviral therapy, and two drugs with activity against HBV, specifically, tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF), plus lamivudine or emtricitabine) with placebo alone, or tenofovir alone, or non-tenofovir-based antiviral regimen (zidovudine, lamivudine, telbivudine, emtricitabine, entecavir, lopinavir-ritonavir, or any other antiviral therapy) either alone or in combination with at least two other antivirals.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Primary outcomes included all-cause infant mortality, proportion of infants with serious adverse events, proportion of infants with HBV mother-to-child transmission, all-cause maternal mortality, and proportion of mothers with serious adverse events. Secondary outcomes included proportion of infants with adverse events not considered serious, proportion of mothers with detectable HBV DNA (deoxyribonucleic acid) (before delivery), maternal hepatitis B e antigen (HBeAg) to HBe-antibody seroconversion (before delivery) and maternal adverse events not considered serious. We used RevMan Web to carry out analyses and presented results, where feasible, using a random-effects model and risk ratios (RR) with 95% confidence intervals (CIs). We performed sensitivity analysis. We assessed risk of bias using predefined domains, assessed the certainty of the evidence using GRADE, controlled risk of random errors with Trial Sequential Analysis, and presented outcome results in a summary of findings table.
MAIN RESULTS
Five completed trials were included, of which four trials contributed data to one or more of the outcomes. They included a total of 533 participants randomised to tenofovir-based antiviral combination regimens (196 participants) versus control (337 participants). The control groups received non-tenofovir-based antiviral regimens either as zidovudine alone (three trials) or as a combination of zidovudine, lamivudine and lopinavir-ritonavir (five trials). None of the trials used placebo or tenofovir alone. All trials were at unclear risk of bias. Four trials used intention-to-treat analyses. In the remaining trial, two participants in the intervention group and two in the control group were lost to follow-up. However, the outcomes of these four participants were not described. Tenofovir-based antiviral combination regimen versus control We are very uncertain about the effect of a tenofovir-based antiviral combination regimen versus control on all-cause infant mortality (RR 2.24, 95% CI 0.72 to 6.96; participants = 132; trials = 1; very low-certainty evidence); proportion of infants with serious adverse events (RR 1.76, 95% CI 1.27 to 2.43; participants = 132; trials = 1; very low-certainty evidence), and proportion of mothers with serious adverse events (RR 0.90, 95% CI 0.62 to 1.32; participants = 262; trials = 2; very low-certainty evidence). No trial reported data on the proportion of infants with HBV mother-to-child transmission and all-cause maternal mortality. We are also very uncertain about the effect of tenofovir-based antiviral combination regimens versus control on the proportion of infants with adverse events not considered serious (RR 0.94, 95% CI 0.06 to 13.68; participants = 31; trials = 1; very low-certainty evidence), and proportion of mothers with detectable HBV DNA (before delivery) (RR 0.66, 95% CI 0.42 to 1.02; participants = 169; trials = 2; very low-certainty evidence). No trial reported data on maternal hepatitis B e antigen (HBeAg) to HBe-antibody seroconversion (before delivery) and maternal adverse events not considered serious. All trials received support from industry.
AUTHORS' CONCLUSIONS
We do not know what the effects of tenofovir-based antiviral combination regimens are on all-cause infant mortality, proportion of infants with serious adverse events and proportion of mothers with serious adverse events, proportion of infants with adverse events not considered serious, and proportion of mothers with detectable HBV DNA before delivery because the certainty of evidence was very low. Only one or two trials, with insufficient power, contributed data for analyses. We lack randomised clinical trials at low risk of systematic and random errors, and fully reporting all-cause infant mortality, serious adverse events and reporting on clinical and laboratory outcomes, such as infants with HBV mother-to-child transmission, all-cause maternal mortality, maternal hepatitis B e antigen (HBeAg) to HBe-antibody seroconversion before delivery and maternal adverse events not considered serious.
Topics: Female; Humans; Infant; Pregnancy; Antiviral Agents; Coinfection; DNA, Viral; Emtricitabine; Hepatitis B e Antigens; Hepatitis B virus; HIV; HIV Infections; HIV Seropositivity; Infectious Disease Transmission, Vertical; Lamivudine; Lopinavir; Pregnant Women; Ritonavir; Tenofovir; Zidovudine
PubMed: 37306558
DOI: 10.1002/14651858.CD013653.pub2 -
International Journal of Biological... 2021Pancreatic cancer is a malignant tumor of the digestive system with a very high mortality rate. While gemcitabine-based chemotherapy is the predominant treatment for... (Review)
Review
Pancreatic cancer is a malignant tumor of the digestive system with a very high mortality rate. While gemcitabine-based chemotherapy is the predominant treatment for terminal pancreatic cancer, its therapeutic effect is not satisfactory. Recently, many studies have found that microorganisms not only play a consequential role in the occurrence and progression of pancreatic cancer but also modulate the effect of chemotherapy to some extent. Moreover, microorganisms may become an important biomarker for predicting pancreatic carcinogenesis and detecting the prognosis of pancreatic cancer. However, the existing experimental literature is not sufficient or convincing. Therefore, further exploration and experiments are imperative to understanding the mechanism underlying the interaction between microorganisms and pancreatic cancer. In this review, we primarily summarize and discuss the influences of oncolytic viruses and bacteria on pancreatic cancer chemotherapy because these are the two types of microorganisms that are most often studied. We focus on some potential methods specific to these two types of microorganisms that can be used to improve the efficacy of chemotherapy in pancreatic cancer therapy.
Topics: Animals; Antimetabolites, Antineoplastic; Bacteria; Carcinogenesis; Combined Modality Therapy; Deoxycytidine; Humans; Oncolytic Viruses; Pancreatic Neoplasms; Gemcitabine
PubMed: 34326701
DOI: 10.7150/ijbs.59117 -
Translational Psychiatry May 2022Previous studies have indicated that antidepressants that inhibit the serotonin transporter reduces oxidative stress. DNA and RNA damage from oxidation is involved in...
Previous studies have indicated that antidepressants that inhibit the serotonin transporter reduces oxidative stress. DNA and RNA damage from oxidation is involved in aging and a range of age-related pathophysiological processes. Here, we studied the urinary excretion of markers of DNA and RNA damage from oxidation, 8-oxodG and 8-oxoGuo, respectively, in the NeuroPharm cohort of 100 drug-free patients with unipolar depression and in 856 non-psychiatric community controls. Patients were subsequently treated for 8 weeks with escitalopram in flexible doses of 5-20 mg; seven of these switched to duloxetine by week 4, as allowed by the protocol. At week 8, 82 patients were followed up clinically and with measurements of 8-oxodG/8-oxoGuo. Contextual data were collected in patients, including markers of cortisol excretion and low-grade inflammation. The intervention was associated with a substantial reduction in both 8-oxodG/8-oxoGuo excretion (25% and 10%, respectively). The change was not significantly correlated to measures of clinical improvement. Both markers were strongly and negatively correlated to cortisol, as measured by the area under the curve for the full-day salivary cortisol excretion. Surprisingly, patients had similar levels of 8-oxodG excretion and lower levels of 8-oxoGuo excretion at baseline compared to the controls. We conclude that intervention with serotonin reuptake inhibitors in unipolar depression is associated with a reduction in systemic DNA and RNA damage from oxidation. To our knowledge, this to date the largest intervention study to characterize this phenomenon, and the first to include a marker of RNA oxidation.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; DNA; DNA Damage; Deoxyguanosine; Depressive Disorder; Humans; Hydrocortisone; Oxidative Stress; RNA
PubMed: 35577781
DOI: 10.1038/s41398-022-01969-z -
Annals of Oncology : Official Journal... Jan 2020
Topics: Colorectal Neoplasms; Drug Combinations; Humans; Neutropenia; Pyrrolidines; Thymine; Trifluridine; Uracil
PubMed: 31912790
DOI: 10.1016/j.annonc.2019.11.001 -
Clinical Pharmacokinetics Dec 2020Pyrimidine analogues can be considered as prodrugs, like their natural counterparts, they have to be activated within the cell. The intracellular activation involves... (Review)
Review
Pyrimidine analogues can be considered as prodrugs, like their natural counterparts, they have to be activated within the cell. The intracellular activation involves several metabolic steps including sequential phosphorylation to its monophosphate, diphosphate and triphosphate. The intracellularly formed nucleotides are responsible for the pharmacological effects. This review provides a comprehensive overview of the clinical studies that measured the intracellular nucleotide concentrations of pyrimidine analogues in patients with cancer. The objective was to gain more insight into the parallels between the different pyrimidine analogues considering their intracellular pharmacokinetics. For cytarabine and gemcitabine, the intracellular pharmacokinetics have been extensively studied over the years. However, for 5-fluorouracil, capecitabine, azacitidine and decitabine, the intracellular pharmacokinetics was only very minimally investigated. This is probably owing to the fact that there were no suitable bioanalytical assays for a long time. Since the advent of suitable assays, the first exploratory studies indicate that the intracellular 5-fluorouracil, azacitidine and decitabine nucleotide concentrations are very low compared with the intracellular nucleotide concentrations obtained during treatment with cytarabine or gemcitabine. Based on their pharmacology, the intracellular accumulation of nucleotides appears critical to the cytotoxicity of pyrimidine analogues. However, not many clinical studies have actually investigated the relationship between the intracellular nucleotide concentrations in patients with cancer and the anti-tumour effect. Only for cytarabine, a relationship was demonstrated between the intracellular triphosphate concentrations in leukaemic cells and the response rate in patients with AML. Future clinical studies should show, for the other pyrimidine analogues, whether there is a relationship between the intracellular nucleotide concentrations and the clinical outcome of patients. Research that examined the intracellular pharmacokinetics of cytarabine and gemcitabine focused primarily on the saturation aspect of the intracellular triphosphate formation. Attempts to improve the dosing regimen of gemcitabine were aimed at maximising the intracellular gemcitabine triphosphate concentrations. However, this strategy does not make sense, as efficient administration also means that less gemcitabine can be administered before dose-limiting toxicities are achieved. For all pyrimidine analogues, a linear relationship was found between the dose and the plasma concentration. However, no correlation was found between the plasma concentration and the intracellular nucleotide concentration. The concentration-time curves for the intracellular nucleotides showed considerable inter-individual variation. Therefore, the question arises whether pyrimidine analogue therapy should be more individualised. Future research should show which intracellular nucleotide concentrations are worth pursuing and whether dose individualisation is useful to achieve these concentrations.
Topics: Cytarabine; Deoxycytidine; Fluorouracil; Humans; Neoplasms; Phosphorylation; Prodrugs; Pyrimidines; Gemcitabine
PubMed: 33064276
DOI: 10.1007/s40262-020-00934-7 -
Basic & Clinical Pharmacology &... Jul 2023A combination of zidovudine (AZT), lamivudine (3TC) and lopinavir/ritonavir (LPV/r) is one of the most effective drugs for preventing mother-to-child transmission...
INTRODUCTION
A combination of zidovudine (AZT), lamivudine (3TC) and lopinavir/ritonavir (LPV/r) is one of the most effective drugs for preventing mother-to-child transmission (PMTCT) of HIV. However, limited information is available regarding its systemic toxicity. This study aimed to investigate its potential toxicity.
METHOD
An acute oral toxicity test was conducted to assess the potential acute toxicity of AZT + 3TC + LPV/r. Bacterial reverse mutation, mammalian erythrocyte micronucleus and mouse spermatogonia chromosomal aberration tests were conducted to assess its potential genotoxicity. A 28-day feeding test was conducted to assess the potential subacute toxicity.
RESULTS
In mice, the LD of the AZT + 3TC + LPV/r mixture was greater than 2000 mg/kg body weight (BW). The rate of micronucleated polychromatic erythrocytes (PCEs) increased in a dose-dependent manner in mice (P < 0.01). After treatment with AZT + 3TC + LPV/r for 28 days, the BW gain of male and female rats in the high-dose group was lower than that in the control group (P < 0.05); the relative weights of the liver, kidney, spleen and brain increased (P < 0.05); and pathological abnormalities appeared in the thyroid and spleen of male and female rats in the high-dose group. The haemoglobin (HGB) and red blood cells (RBCs) count in male and female rats decreased, but the white blood cells (WBCs) and lymphocyte apoptosis rates in male and female rats in the high-dose group increased (P < 0.05). The total protein, albumin, cholesterol and blood glucose levels of male and female rats in the high-dose group were significantly decreased (P < 0.05). The alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatinine (Cr) and blood urea nitrogen (BUN) levels of male and female rats in the medium- and high-dose groups increased significantly (P < 0.05).
CONCLUSION
The results suggest that AZT + 3TC + LPV/r may exhibit genotoxicity and subacute toxicity under experimental conditions.
Topics: Female; Male; Animals; Mice; Rats; Lamivudine; Zidovudine; Lopinavir; Ritonavir; Anti-HIV Agents; HIV Infections; Infectious Disease Transmission, Vertical; Mammals
PubMed: 37016497
DOI: 10.1111/bcpt.13870