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British Journal of Clinical Pharmacology Apr 2014The activity of the enzyme thiopurine methyltransferase (TPMT) is regulated by a common genetic polymorphism. One in 300 individuals lack enzyme activity and 11% are...
The activity of the enzyme thiopurine methyltransferase (TPMT) is regulated by a common genetic polymorphism. One in 300 individuals lack enzyme activity and 11% are heterozygous for a variant low activity allele and have an intermediate activity. The thiopurine drugs azathioprine, mercaptopurine and thioguanine are substrates for TPMT; these drugs exhibit well documented myelosuppressive effects on haematopoietic cells and have a track record of idiosyncratic drug reactions. The development of severe bone marrow toxicity, in patients taking standard doses of thiopurine drugs, is associated with TPMT deficiency whilst the TPMT heterozygote is at an increased risk of developing myelosuppression. Factors influencing TPMT enzyme activity, as measured in the surrogate red blood cell, are discussed in this review to enable an appreciation of why concordance between TPMT genotype and phenotype is not 100%. This is particularly important for lower/intermediate TPMT activities to avoid misclassification of TPMT status. TPMT testing is now widely available in routine service laboratories. The British National Formulary suggests TPMT testing before starting thiopurine drugs. Dermatologists were quick to adopt routine TPMT testing whilst gastroenterologists do not specifically recommend TPMT screening. TPMT testing is mandatory prior to the use of mercaptopurine in childhood leukaemia. Thiopurine drug dose and other treatment related influences on cell counts explain some of the differing recommendations between clinical specialities. TPMT testing is cost-effective and the major role is in the identification of the TPMT deficient individual prior to the start of thiopurine drugs.
Topics: Antimetabolites, Antineoplastic; Azathioprine; Cost-Benefit Analysis; Drug Hypersensitivity; Drug Labeling; Genetic Testing; Genotype; Humans; Mercaptopurine; Methyltransferases; Phenotype; Purine-Pyrimidine Metabolism, Inborn Errors; Thioguanine
PubMed: 23962279
DOI: 10.1111/bcp.12226 -
Drug Discoveries & Therapeutics Jul 2022We investigated adverse events in patients with prosthetic joint infections receiving combination therapy with linezolid, rifampicin, and clindamycin for ≥ 7 days....
We investigated adverse events in patients with prosthetic joint infections receiving combination therapy with linezolid, rifampicin, and clindamycin for ≥ 7 days. Twenty-two patients were evaluated. The combination therapy was administered for 15.5 (7-29) days at dosages of 1200, 450, and 450-1200 mg/day for linezolid, rifampicin, and clindamycin, respectively. Adverse events (gastrointestinal, eye, and skin disorders; liver damage; myelosuppression; hyponatremia, and others) were recorded. The incidence rates of leukopenia, neutropenia, anemia, thrombocytopenia, and hyponatremia were 36.4%, 31.8%, 40.9%, 18.2%, and 18.2%, respectively. Common Terminology Criteria for Adverse Events version 5.0 Grade 3 neutropenia, anemia, and hyponatremia were observed. The incidence rate of myelosuppression was higher following combination therapy compared with that previously reported following single-drug administration. All patients were discharged after the infection was under control. It is important to monitor these adverse events during combination therapy with the aforementioned agents; these conditions may be relieved by discontinuing linezolid.
Topics: Anemia; Anti-Bacterial Agents; Arthritis, Infectious; Clindamycin; Humans; Hyponatremia; Linezolid; Neutropenia; Rifampin
PubMed: 35753771
DOI: 10.5582/ddt.2022.01038 -
Scientific Reports Apr 2021This study aimed to investigate the influence of TPMT*3C, ITPA, NUDT15, and 6-thioguanine nucleotides (6-TGN) on azathioprine (AZA)-induced myelosuppression in Southwest...
This study aimed to investigate the influence of TPMT*3C, ITPA, NUDT15, and 6-thioguanine nucleotides (6-TGN) on azathioprine (AZA)-induced myelosuppression in Southwest China patients with autoimmune hepatitis (AIH). A total of 113 Chinese patients with AIH receiving AZA maintenance treatment were evaluated. The relevant clinical data of the patients were collected from the hospital information system. Genotyping of TPMT*3C(rs1142345), ITPA (rs1127354) and NUDT15(rs116855232) was conducted using a TaqMan double fluorescent probe. The concentration of 6-TGN was determined using UPLC-MS/MS. Among AIH patients treated with AZA, 40 (35.4%) exhibited different degrees of myelosuppression. The NUDT15 variant was associated with leukopenia (P = 8.26 × 10; OR = 7.5; 95% CI 3.08-18.3) and neutropenia (P = 3.54 × 10; OR = 8.05; 95% CI 2.96-21.9); however, no significant association with myelosuppression was observed for TPMT*3C and ITPA variants (P > 0.05). There was no significant difference in 6-TGN concentration between AIH patients with or without myelosuppression (P = 0.556), nor was there a significant difference between patients with variant alleles of TPMT*3C, ITPA, or NUDT15 and wild-type patients (P > 0.05). Interestingly, it was found that patients with a lower BMI had higher adjusted 6-TGN levels and a higher incidence of myelosuppression (P = 0.026 and 0.003). This study confirmed that NUDT15 variants are a potential independent risk predictor for AZA-induced leukopenia and neutropenia. BMI may be a crucial non-genetic factor that affects the concentration of AZA metabolites and myelosuppression. In addition, the 6-TGN concentration in red blood cells does not reflect the toxicity of AZA treatment, and new biomarkers for AZA therapeutic drug monitoring need further research.
Topics: Adult; Aged; Alleles; Azathioprine; China; Female; Genetic Association Studies; Guanine Nucleotides; Hepatitis, Autoimmune; Humans; Leukopenia; Male; Methyltransferases; Middle Aged; Mutation; Phenotype; Pyrophosphatases; Thionucleotides
PubMed: 33846471
DOI: 10.1038/s41598-021-87095-0 -
Infection and Drug Resistance 2022Linezolid is classed as oxazolidinone antibiotics which can be used to treat severe infections caused by vancomycin-resistant Enterococcus faecium, hospital-acquired...
BACKGROUND
Linezolid is classed as oxazolidinone antibiotics which can be used to treat severe infections caused by vancomycin-resistant Enterococcus faecium, hospital-acquired pneumonia caused by Staphylococcus aureus, complicated skin, and uncomplicated skin structure infections (SSSIs) caused by methicillin-susceptible S. aureus or Streptococcus pyogenes, and community-acquired pneumonia caused by Streptococcus pneumoniae. However, many studies have suggested it can also cause thrombocytopenia and pancytopenia.
PATIENTS AND METHODS
We report on three patients with linezolid-pancytopenia. Patients in cases 1 and 2 were diagnosed with heart failure with preserved ejection fraction (HFpEF) and were both administered with dapagliflozin, one of the sodium-dependent glucose transporters 2 inhibitors (SHLT-2i).
RESULTS
Two patients were diagnosed with type 2 diabetes, pneumonia, and hyponatremia. Severe myelosuppression occurred in both patients, with a severe decrease in leukocytes and platelets and a moderate decrease in hemoglobin, who eventually passed away despite the discontinuation of linezolid and adopting appropriate treatment measures. The patient in case 3 was diagnosed with pneumonia, type 2 diabetes, and sequelae of cerebral thrombosis. After twelve days of treatment, the patient developed moderate thrombocytopenia and anemia. She recovered without any additional treatment after the discontinuation of linezolid.
CONCLUSION
In this case series, two patients with irreversible myelosuppression were treated with both linezolid and SGLT-2i, and one diabetic patient with single linezolid use presented with reversible pancytopenia, suggesting that SGLT-2i may exacerbate myelosuppression of linezolid. Linezolid should be used with caution in infectious patients with a history of SGLT-2i. We will conduct relevant animal experiments to clarify the interaction between the two drugs.
PubMed: 36158232
DOI: 10.2147/IDR.S375694 -
Asia Pacific Journal of Clinical... Mar 2024To evaluate the potential benefits of Bacteroides fragilis 839 (BF839), a next-generation probiotics, in reducing myelosuppression and gastrointestinal toxicity... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
To evaluate the potential benefits of Bacteroides fragilis 839 (BF839), a next-generation probiotics, in reducing myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patient.
METHODS AND STUDY DESIGN
40 women with early breast cancer were randomly assigned to the BF839 (n=20) or placebo (n=20) during the administration of adjuvant chemotherapy (4 cycles of epirubicin 100mg/m2 and cyclophosphamide 600mg/m2). Myelosuppression and gastrointestinal adverse effects were monitored in both groups.
RESULTS
Throughout the four treatment cycles, the percentage of patients experiencing myelosuppression was 42.5% in the BF839 group, significantly lower than the 66.3% observed in the control group (p=0.003). Two patients in the BF839 group and three patients in the placebo group received recombinant human granulocyte colony-stimulating factor (rhG-CSF) due to leuko-penia/neutropenia. When considering an ITT analysis, which included all patients regardless of rhG-CSF treatment, the BF839 group exhibited less reduction from baseline in white blood cells (-0.31±1.19 vs -1.15±0.77, p=0.012) and neutrophils (0.06±1.00 vs -0.84±0.85, p=0.004) compared to the placebo group. The difference became even more significant when excluding the patients who received rhG-CSF injections. Throughout the four treatment cycles, compared to the placebo group, the BF839 group had significantly lower rates of 3-4 grade nausea (35.0% vs 71.3%, p=0.001), vomiting (20.0% vs 45.0%, p=0.001), and diarrhea (15.0% vs 30.0%, p=0.023).
CONCLUSIONS
These findings suggest that BF839 has the potential to effectively mitigate myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patients.
Topics: Female; Humans; Antineoplastic Agents; Bacteroides fragilis; Breast Neoplasms; Cyclophosphamide; Epirubicin; Granulocyte Colony-Stimulating Factor; Recombinant Proteins
PubMed: 38494684
DOI: 10.6133/apjcn.202403_33(1).0003 -
Advances in Therapy Aug 2020Chemotherapy-induced myelosuppression (CIM) is one of the most common dose-limiting complications of cancer treatment, and is associated with a range of debilitating...
INTRODUCTION
Chemotherapy-induced myelosuppression (CIM) is one of the most common dose-limiting complications of cancer treatment, and is associated with a range of debilitating symptoms that can significantly impact patients' quality of life. The purpose of this study was to understand patients' perspectives on how the side effects of CIM are managed in routine clinical practice.
METHODS
An online survey was conducted of participants with breast, lung, or colorectal cancer who had received chemotherapy treatment within the past 12 months, and had experienced at least one episode of myelosuppression in the past year. The survey was administered with predominantly close-ended questions, and lay definitions of key terms were provided to aid response selection.
RESULTS
Of 301 participants who completed the online survey, 153 (51%) had breast cancer, 100 (33%) had lung cancer, and 48 (16%) had colorectal cancer. Anemia, neutropenia, lymphopenia, and thrombocytopenia were reported by 61%, 59%, 37%, and 34% of participants, respectively. Most participants (79%) reported having received treatment for CIM, and 64% of participants recalled chemotherapy dose modifications as a result of CIM. Although most participants believed their oncologist was aware of the side effects of CIM, and treated them quickly, 30% of participants felt their oncologists did not understand how uncomfortable they were due to the side effects of CIM. Overall, 88% of participants considered CIM to have a moderate or major impact on their lives.
CONCLUSION
The data highlight that despite the various methods used to address CIM, and the patient-focused approach of oncologists, the real-world impact of CIM on patients is substantial. Improving communication between patients and health care providers may help improve patients' understanding of CIM, and foster shared decision-making in terms of treatment. Additional insights from patients should be obtained to further elucidate the totality of life burden associated with CIM.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Colorectal Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Lung Neoplasms; Male; Middle Aged; Surveys and Questionnaires; United States; Young Adult
PubMed: 32642965
DOI: 10.1007/s12325-020-01419-6 -
Cancer Jan 2004Cytotoxic chemotherapy suppresses the hematopoietic system, impairing host protective mechanisms and limiting the doses of chemotherapy that can be tolerated.... (Review)
Review
Cytotoxic chemotherapy suppresses the hematopoietic system, impairing host protective mechanisms and limiting the doses of chemotherapy that can be tolerated. Neutropenia, the most serious hematologic toxicity, is associated with the risk of life-threatening infections as well as chemotherapy dose reductions and delays that may compromise treatment outcomes. The authors reviewed the recent literature to provide an update on research in chemotherapy-induced neutropenia and its complications and impact, and they discuss the implications of this work for improving the management of patients with cancer who are treated with myelosuppressive chemotherapy. Despite its importance as the primary dose-limiting toxicity of chemotherapy, much concerning neutropenia and its consequences and impact remains unknown. Recent surveys indicate that neutropenia remains a prevalent problem associated with substantial morbidity, mortality, and costs. Much research has sought to identify risk factors that may predispose patients to neutropenic complications, including febrile neutropenia, in an effort to predict better which patients are at risk and to use preventive strategies, such as prophylactic colony-stimulating factors, more cost-effectively. Neutropenic complications associated with myelosuppressive chemotherapy are a significant cause of morbidity and mortality, possibly compromised treatment outcomes, and excess healthcare costs. Research in quantifying the risk of neutropenic complications may make it possible in the near future to target patients at greater risk with appropriate preventive strategies, thereby maximizing the benefits and minimizing the costs.
Topics: Aged; Antineoplastic Agents; Colony-Stimulating Factors; Fever; Humans; Neutropenia; Opportunistic Infections; Risk Factors
PubMed: 14716755
DOI: 10.1002/cncr.11882 -
Asian Pacific Journal of Cancer... 2011The aim of this study was to investigate the therapeutic effects of the combination of paeoniflorin and albiflorin (CPA) extracted from Paeonia radix on radiation and...
The aim of this study was to investigate the therapeutic effects of the combination of paeoniflorin and albiflorin (CPA) extracted from Paeonia radix on radiation and chemotherapy induced myelosuppression in two animal models: mice and rabbits. Mice were exposed to X-ray radiation (400 Roentgen), and both mice and rabbits were intraperitoneally injected with cyclophosphamide (100.0 mg/kg) and cytarabine chloride (92.7 mg/kg), respectively, for 3 days to induce myelosuppression. CPA was subsequently administrated intravenously at low (15.0 mg/kg for mice, 6.00 mg/kg for rabbits), intermediate (30.0 mg/kg for mice, 12.0 mg/kg for rabbits) and high (60.0 mg/kg for mice, 24.0 mg/kg for rabbits) doses, as well as orally (60.0 mg/kg for mice, 24.0 mg/kg for rabbits) for 7 days. Shenqi tablets were used as positive controls (oral administration of 936.0 mg/kg for mice, 336.0 mg/kg for rabbits). The administration of CPA significantly ameliorated myelosuppression in all cases. For the X-ray irradiated mice and the chemotherapy treated mice and rabbits, high dosages of CPA resulted in the recovery of, respectively, 94.4%, 95.3% and 97.7% of hemoglobin content; 67.7%, 92.0% and 94.3% of platelet numbers; 26.8%, 137.1% and 107.3% of white blood cell counts; as well as a reversal in the reduction of peripheral differential white blood cell counts. There was also a recovery of 50.9%, 146.1% and 92.3%, respectively, in the animals' relative spleen weight. Additionally, a recovery of 35.7% and 87.2% in the number of bone marrow nucleated cells was observed in the radio- and chemotherapy treated mice, respectively. Bone marrow white blood cell counts also resumed to normal levels. These results substantiate the marked therapeutic effects of CPA to ameliorate myelosuppression induced by radio and chemotherapy.
Topics: Animals; Benzoates; Blood Platelets; Bone Marrow Cells; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Cytarabine; Drug Synergism; Drugs, Chinese Herbal; Female; Glucosides; Hemoglobins; Herb-Drug Interactions; Leukocytes; Male; Mice; Mice, Inbred BALB C; Monoterpenes; Paeonia; Plant Extracts; Plant Roots; Rabbits; X-Rays
PubMed: 22292646
DOI: No ID Found -
Scientific Reports Jun 2024This study aimed to investigate impacts of Omicron infection on cancer patients in China. A retrospective study was conducted, including 347 cancer patients undergoing...
Completion rates and myelosuppression degrees of cancer patients receiving radiotherapy or chemoradiotherapy unchanged regardless of delay duration after Omicron infection.
This study aimed to investigate impacts of Omicron infection on cancer patients in China. A retrospective study was conducted, including 347 cancer patients undergoing radiotherapy or chemoradiotherapy between July 2022 and March 2023. Three groups involved: 108 patients without SARS-CoV-2 infection (non-COVID-19 group), 102 patients beginning treatment 10 days after first SARS-CoV-2 infection (≥ 10 days COVID-19 group), and 137 patients beginning treatment less than 10 days after first SARS-CoV-2 infection (< 10 days COVID-19 group). SAA, hsCRP, ALT, etc., were used to assess COVID-19 infection. Serum levels of SAA, hsCRP and IL-6 were all raised in two COVID-19-infected groups (SAA < 0.01, hsCRP < 0.01, IL-6 < 0.05), but PCT, ALT, LDH and HBDH levels were only elevated in ≥ 10 days COVID-19 group (PCT = 0.0478, ALT = 0.0022, LDH = 0.0313, HBDH = 0.0077). Moreover, moderate and severe infected cases were higher in ≥ 10 days COVID-19 group than < 10 days COVID-19 group (12/102 vs 5/137, p = 0.0211), but no significance in myelosuppression and completion rates among three groups. Omicron infection led to inflammation, liver and cardiovascular injury on cancer patients, but delay duration of radiotherapy or chemoradiotherapy after infection did not affect the completion rates and myelosuppression of current therapy. Besides, severity of Omicron infection was even worse among cancer patients who received delayed treatment.
Topics: Humans; COVID-19; Female; Male; Middle Aged; Neoplasms; Chemoradiotherapy; Retrospective Studies; Aged; SARS-CoV-2; Adult; China
PubMed: 38902401
DOI: 10.1038/s41598-024-65019-y -
Plants (Basel, Switzerland) Dec 2022Myelosuppression is a major adverse effect of chemotherapy. With the increasing number of cancer patients worldwide, there is a growing interest in therapeutic...
Myelosuppression is a major adverse effect of chemotherapy. With the increasing number of cancer patients worldwide, there is a growing interest in therapeutic approaches that reduce the adverse effects of chemotherapy. Nakai (AGN) roots have been widely used in oriental medicine to treat blood-related diseases, including cancer. However, the effects of AGN on myelosuppression have not been studied. Here, we investigated the effects of AGN ethanol extract (AGNEX) on cyclophosphamide-induced myelosuppression. AGNEX treatment significantly decreased white blood cell levels while increasing red blood cell and platelet levels in the peripheral blood. It inhibited thymus and spleen atrophy. It also enhanced serum levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α. qRT-PCR results showed that AGNEX decreased the expression of IL-1b and stem cell factor (SCF) in the bone marrow (BM) while increasing the mRNA expression of IL-3 and IL-6 in the spleen. Although AGNEX did not significantly decrease apoptosis and cell cycle arrest in the BM and splenocytes, AGNEX plays a positive role in cyclophosphamide-induced myelosuppression. AGNEX administration increased BM cells in the femur while decreasing apoptotic BM cells. These findings suggest that AGNEX could be used to treat myelosuppression and as a combination therapy in cancer patients.
PubMed: 36559587
DOI: 10.3390/plants11243476