ABSTRACT
Acute exposure to high doses of radiation leads to severe myelosuppression, but few treatments are currently available to treat hematopoietic syndrome of acute radiation syndrome. Granulocyte colony stimulating factors (e.g., filgrastim) stimulate proliferation of neutrophil precursors and enhance mature neutrophil function. Owing to ethical constraints on conducting clinical research in lethally irradiated humans, we developed a model-based strategy to integrate preclinical experience in irradiated nonhuman primates (NHPs) and other clinical myelosuppressive conditions to inform filgrastim dosing to treat hematopoietic syndrome of acute radiation syndrome. Models predicting neutrophil counts and overall survival based on drug exposures were calibrated and scaled from NHPs to adult and pediatric human subjects. Several scenarios were examined investigating variations in filgrastim doses, dose frequency, treatment initiation, and duration, as well as the effect of age and radiation dose rate. Model-based simulations and established safety profiles supported that a subcutaneous filgrastim dose of 10 µg/kg once daily provides a significant survival benefit (50%) over placebo in both adults and children, provided that the treatment is initiated within 1-14 days after radiation exposure and lasts 2-3 weeks. For treatment durations of longer than 3 weeks, filgrastim treatment is not expected to provide significantly greater benefit. This survival benefit is expected to hold for the wide range of radiation doses and dose rates (0.01-1,000 Gy/hours) examined.
Subject(s)
Acute Radiation Syndrome/drug therapy , Filgrastim/administration & dosage , Hematologic Agents/administration & dosage , Acute Radiation Syndrome/mortality , Adult , Age Factors , Animals , Child , Computer Simulation , Disease Models, Animal , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Drug Evaluation, Preclinical , Female , Granulocyte Precursor Cells/drug effects , Humans , Injections, Subcutaneous , Macaca mulatta , Male , Myelopoiesis/drug effects , Risk Assessment/methods , Treatment OutcomeABSTRACT
OBJECTIVE: To study the efficacy and safety of Shuanghuang Shengbai Granule (, SSG), a traditional Chinese herbal medicine, on myelosuppression of cancer patients caused by chemotherapy. METHODS: A total of 330 patients were randomly assigned to the treatment group (220 cases, analysed 209 cases) and the control group (110 cases, analysed 102 cases) with a 2:1 ratio by envelope method. The patients in the treatment group at the first day of chemotherapy started to take SSG for 14 days, while the patients in the control group took Leucogon Tablets. The changes of the blood routine, clinical symptoms and immune function in both groups were observed for safety and efficacy evaluation. RESULTS: At the 7th day of chemotherapy, the white blood cells (WBCs) level in the treatment group was significantly higher than that in the control group (P<0.05). After treatment, the WBCs rate in the normal range accounted for 50.2% in the treatment group, the myelosuppression of WBCs and neutrophil were mainly grade I, while 8.1% and 5.7% of patients emerged grade III and grade IV myelosuppression, respectively. The incidence of myelosuppression of the treatment group was significantly lower than that of the control group (P<0.05). The total effective rate of Chinese medicine syndrome in the treatment group was significantly higher than that in the control group (84.2% vs. 72.5%, P<0.05). The immune cell levels in both groups were maintained in the normal range. Compared with that before treatment, the levels of CD3+ and CD4+ cells were significantly increased in the treatment group after treatment (P<0.05). The discrepancy of CD3+ and CD4+ cell activity before and after treatment in both groups were significantly different (P<0.05). No obvious adverse event occurred in both groups. CONCLUSION: SSG had a protection effect on bone marrow suppression, and alleviated the clinical symptoms together with clinical safety.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drugs, Chinese Herbal/therapeutic use , Granulocyte Precursor Cells/drug effects , Immune Tolerance/drug effects , Neoplasms/drug therapy , Pancytopenia/prevention & control , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Humans , Male , Medicine, Chinese Traditional , Middle Aged , Pancytopenia/chemically induced , Treatment OutcomeABSTRACT
Aging is associated with a decline in immune function (immunosenescence), a condition known to correlate with increased incidence of cancer as well as infectious and degenerative diseases. Innate, cellular and humoral immunity all exhibit increased deterioration with age. Circulating melatonin decreases with age, and in recent years much interest has been focused on its immunomodulatory effect. Melatonin stimulates the production of progenitor cells for granulocytes and macrophages. It also stimulates the production of natural killer cells and CD4+ cells and inhibits CD8+ cells. The production and release of various cytokines from natural killer cells and T helper lymphocytes are enhanced by melatonin. Melatonin has the potential therapeutic value to enhance immune function in aged individuals.
Subject(s)
Aging/physiology , Immune System/physiology , Melatonin/physiology , Neuroimmunomodulation/physiology , Adjuvants, Immunologic/therapeutic use , Aged , Aged, 80 and over , Circadian Rhythm , Cytokines/physiology , Granulocyte Precursor Cells/cytology , Granulocyte Precursor Cells/drug effects , Humans , Immunity, Innate/drug effects , Immunity, Innate/physiology , Immunocompetence , Killer Cells, Natural/metabolism , Melatonin/deficiency , Melatonin/metabolism , Melatonin/therapeutic use , Pineal Gland/metabolism , Receptors, Melatonin/drug effects , Receptors, Melatonin/physiology , Secretory Rate , Sleep/physiology , Superior Cervical Ganglion/physiology , Sympathetic Fibers, Postganglionic/physiology , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/metabolismABSTRACT
Asparagus-P is a traditional herbal medicinal product consisting of a combination of dried and pulverized asparagus roots and parsley leaves in equal parts. It is commonly used to support aquaretic kidney function, i.e. the increased excretion of water from the kidneys without affecting electrolyte balance. The mechanisms of this aquaretic effectiveness are widely unknown and are controversial. By using two different kidney cell lines (distal tubule-derived Madin-Darby bovine kidney (MDBK) cells and proximal tubule-derived opossum kidney (OK) cells) the study investigated whether a stimulation of basal kidney cell metabolism might be responsible for the increased excretion of water from the kidneys. The results demonstrate that Asparagus-P was able to stimulate the metabolism of both kidney cell lines in a dose-dependent manner with a maximum stimulation at the recommended daily dosage after distribution in the whole body fluid. Metabolic stimulation was much more pronounced for OK than for MDBK cells. Whether a stimulation of cell metabolism correlates with an increased water excretion is currently unknown, but in vitro data might deliver the first evidence for a better understanding of the mechanism of action. Moreover, Asparagus-P inhibited the metabolism of inflammation-mediating cells (differentiated human promyelocytes). This increases the information on the antiinflammatory efficacy of Asparagus-P as already shown by its potential to inactivate reactive oxygen radicals.
Subject(s)
Asparagus Plant/chemistry , Granulocyte Precursor Cells/metabolism , Kidney Tubules, Distal/metabolism , Kidney Tubules, Proximal/metabolism , Petroselinum/chemistry , Water/metabolism , Animals , Anti-Inflammatory Agents/pharmacology , Cattle , Cell Line , Granulocyte Precursor Cells/drug effects , Humans , Kidney Tubules, Distal/drug effects , Kidney Tubules, Proximal/drug effects , Opossums , Phytotherapy , Plant Leaves/chemistry , Plant Roots/chemistry , Time FactorsABSTRACT
Breast cancer, the most commonly occurring cancer in women in the United States, is the second most common cause of cancer-related mortality. Mortality rates in breast cancer have, however, declined by 2.3% per year from 1990 to 2001, partly because of the development of better chemotherapy agents and regimens, which have resulted in major changes in the standards of care. To study the changes in the past decade in expert opinion about the preferred chemotherapy for breast cancer, we compared the treatment guidelines of the National Comprehensive Cancer Network (NCCN) for 1996, 2000, and 2005. The myelotoxicity associated with the NCCN-recommended agents was also assessed by using data from the prescribing information for the drugs. This review showed that many of the agents, combinations of agents, and new dosing schedules currently recommended in the NCCN guidelines for the treatment of breast cancer are associated with myelosuppression. Many of these myelosuppressive regimens, which were used in the past to treat advanced-stage or metastatic disease, are now prescribed for early-stage disease. Furthermore, the cytotoxic agents and regimens recommended by the NCCN are more myelosuppressive than those recommended a decade ago. Many oncologists are aware of this trend toward the more intensive treatment of patients with cancer and take proactive steps to minimize the risk of myelosuppression and its complications.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Granulocyte Precursor Cells/drug effects , Neoadjuvant Therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/surgery , Chemotherapy, Adjuvant , Dose-Response Relationship, Drug , Female , Humans , Mastectomy/methods , Middle Aged , Myeloablative Agonists/adverse effects , Myeloablative Agonists/therapeutic use , Patient Selection , Prognosis , Randomized Controlled Trials as Topic , Risk Assessment , Survival Analysis , Treatment OutcomeABSTRACT
Curcuma longa has been commonly used as a traditional remedy for a variety of symptoms such as inflammation, gastritis and gastric ulcer. When C. longa extract was administered per os to pylori-ligated rat stomachs, it reduced gastric acid secretion and protected against the formation of gastric mucosal lesions. We therefore tested whether C. longa extract inhibits gastric ulcers by blocking the H(2) histamine receptor. Dimaprit, a H(2) histamine receptor agonist, induced intracellular cAMP production in U937 and HL-60 promyelocytes. Pretreatment with C. longa extract significantly blocked dimaprit-induced cAMP production in a concentration dependent manner, but had no effect on the elevation of cAMP levels triggered by isoproterenol-induced beta(2)-adrenoceptor activation in U937 cells. To identify the active component(s) of C. longa extract, we sequentially fractionated it by extraction with ethyl acetate, n-butanol and water. We found that the ethyl acetate extract showed the most potent H(2)R antagonistic effect against dimaprit-induced cAMP production. However, curcumin, a major component of C. longa extract, showed no H(2)R blocking effect. C. longa ethanol extract and ethylacetate extract also blocked the binding of [(3)H]-tiotidine to membrane receptors on HL-60 cells. These findings suggest that the extract from C. longa specifically inhibits gastric acid secretion by blocking H(2) histamine receptors in a competitive manner.
Subject(s)
Anti-Ulcer Agents/pharmacology , Curcuma , Plant Extracts/pharmacology , Receptors, Histamine H2/drug effects , Stomach Ulcer/prevention & control , Acetates/chemistry , Acetates/pharmacology , Animals , Cyclic AMP/antagonists & inhibitors , Cyclic AMP/metabolism , Dimaprit/antagonists & inhibitors , Dimaprit/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Gastric Mucosa/injuries , Gastric Mucosa/metabolism , Granulocyte Precursor Cells/drug effects , Granulocyte Precursor Cells/pathology , HL-60 Cells , Histamine H2 Antagonists/isolation & purification , Histamine H2 Antagonists/pharmacology , Histamine H2 Antagonists/therapeutic use , Humans , Male , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Ranitidine/pharmacology , Rats , Rats, Sprague-Dawley , Stomach Ulcer/drug therapy , U937 CellsABSTRACT
OBJECTIVE: To explore the effects of xue-bao capsules on injury of radio-or chemo-therapy in mice, in order to provide rationale behind clinical trials. METHOD: xue-xu (deficiency of blood) model in mice was induced by radiation or cyclophosphamide. Leucocyte (WBC), erythrocyte (RBC), hemoglobin (Hb) and platelet (Pt) in peripheral blood as well as CFU-E and CFU-Gm in bone marrow were counted. RESULT: CFU-E and CFU-Gm in normal mice were promoted by this drug. The reduction of WBC, RBC and Hb in peripheral blood as well as CFU-E and CFU-Gm in bone marrow owing to the 3.5 Gy of 60Co radiation were antagonized by the drug. It had also antagonized cyclophosphamide induced the reduction of WBC, RBC and Pt in peripheral blood. CONCLUSION: xue-bao capsules has the effects against the adverse reactions of radio-or-chemo-therapy.
Subject(s)
Bone Marrow Cells , Drugs, Chinese Herbal/pharmacology , Plants, Medicinal , Radiation Injuries, Experimental/pathology , Animals , Bone Marrow Cells/cytology , Bone Marrow Cells/drug effects , Bone Marrow Cells/radiation effects , Capsules , Cell Count , Cells, Cultured , Cyclophosphamide/toxicity , Drug Combinations , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/isolation & purification , Erythrocyte Count , Erythroid Precursor Cells/drug effects , Erythroid Precursor Cells/radiation effects , Female , Granulocyte Precursor Cells/drug effects , Granulocyte Precursor Cells/radiation effects , Leukocyte Count , Male , Mice , Plants, Medicinal/chemistry , Platelet Count , Radiation Injuries, Experimental/blood , Random Allocation , Whole-Body Irradiation/adverse effectsABSTRACT
Okinawa prefecture in Japan is a distinct area characterized by unique traditional food habits and longevity. Prolonged exposure to activated leukocytes, playing pivotal roles in chronic inflammation-associated carcinogenesis, is known to lead to oxidative and nitrosative damage to macromolecules in the body since they are primary sources of free radicals, such as superoxide anion (O(2)(-)) and nitric oxide (NO). In this study, we estimated anti-oxidative and anti-nitrosative activities of Okinawan food items by employing two cellular experimental systems: (1) phorbol ester-induced O(2)(-) generation from differentiated HL-60 human promyelocytic leukemia cells; and (2) lipopolysaccharide (LPS)-induced NO generation in RAW264.7 murine macrophages. A total of 138 food items, consisting of 42 samples unique to Okinawa and 96 common in the Japanese main island, were purchased at local markets in Okinawa and extracted with chloroform. When tested at a concentration of 100 microg/ml, 38% (16/42) of the former showed 70% or more inhibition of O(2)(-) generation while 21% (20/96) of the latter did so. In parallel, 64% (27/42) of the former showed significant NO generation suppression in contrast to 48% (46/96) of the latter . Twenty-one active species were further tested at a concentration of 20 mug/ml, and eleven species, including sugar cane, wild turmeric, and zedoary, were indicated to be most promising items with anti-oxidative and anti-nitrosative properties. In addition, some of the active constituents (chebulagic acid, a resveratrol derivative, and sesquiterpenoids) were identified. Our results suggest that food items typical in the Okinawa area have higher cancer preventive potential than those common in Japan.