Protein kinases are intimately involved in the pathogenesis of many diseases such as cancer, inflammation, and autoimmune and neurological diseases. Therefore, kinases have been widely studied as drug targets over the past three decades. As of April, 2020, the FDA had approved 59 small molecule kinase inhibitors (SMKIs) in the emerging field of targeted drug therapy. This paper focuses on the biochemistry and pharmacology of these 59 SMKIs and 121 SMKIs for which structures can be retrieved and that are now in phase Ⅱ and Ⅲ clinical trials. In addition, this paper also conducts a simple analysis of several popular targets and their inhibitors.

Abstract: Objective　To investigate the clinical and laboratory characteristics of pulmonary infection caused by Nocardia otitidiscaviarum. Methods　The clinical data of a patient with pulmonary infection caused by Nocardia otitidiscaviarum were reported, and the clinical characteristics, laboratory characteristics and drug sensitivity of pulmonary infection caused by Nocardia otitidiscaviarum were summarized in combination with the relevant literature at home and abroad from January 2010 to December 2022. Results　A 67-year-old female patient was admitted to the hospital on June 30, 2020 because of "repeated chest tightness and shortness of breath for 3 years, aggravated cough, expectoration and fever". The sputum, alveolar lavage fluid and blood of the patient were collected for culture, and the detected pathogenic bacteria were identified. There are pathogenic bacteria growing in sputum and alveolar lavage fluid, which are identified as Nocardia otitidiscaviarum by Autof ms mass spectrometer. According to the results of pathogenic bacteria and the patient's condition, meropenem combined with compound sulfamethoxazole tablets were given anti-infection treatment, and the patient's condition improved and discharged. Conclusion　The clinical manifestations and imaging features of nocardiosis are lack of specificity, and are prone to misdiagnosis and missed diagnosis. Etiology is the key to disease diagnosis, and clinical examination and culture should be conducted in time.

Objective: This study aimed to determine the effect of radiotherapy (RT) on the risk of herpes zoster (HZ) in patients with gynecological cancers via a nationwide population-based study. Methods: Based on patient data obtained from the National Health Insurance Research Database, 1928 gynecological cancer patients were identified with 1:1 matching for RT and non-RT cohorts by age, index date, and cancer type. Another cohort consisting of 964 noncancer individuals matched was used as normal control. The incidence of HZ was compared between cancer patients with and without RT. Age, comorbidities, cancer-related surgery and chemotherapy (CT), and cancer type were adjusted as confounders. Results: The risk of HZ in cancer patients was higher than that of non-cancer individuals (14.23 versus 8.34 per 1,000 person-years [PY], the adjusted hazard ratio [aHR]=1.38, p=0.044). In the cancer population, the incidence of HZ for the RT and non-RT cohorts was 20.55 versus 10.23 per 1,000 PY, respectively (aHR=1.68, p=0.009). Age >50 years was an independent factor for developing HZ. The 5-year actuarial incidence for patients receiving neither RT nor CT, RT alone, CT alone, and combined modalities was 5.4%, 6.9%, 3.7%, and 9.9%, respectively (p<0.001). In the RT cohort, the risk rose rapidly in the first year, becoming steady thereafter. Conclusion This population-based study showed that gynecological cancer patients receiving RT combined with CT had the highest cumulative risk of HZ. Health care professionals should be aware of the potential toxicities.

Choosing the right solvent and timely use is the basis of rational drug use and the most direct and efficient way to improve the safety of traditional Chinese medicine injections. This study aimed to evaluate the influence of solvent and drug preparation time on Shuanghuanglian injection inducing pseudo-allergic reactions with mouse mode. The two tests were carried out: (1) Comparative experiment between different solvent: Shuanghuanglian injection preparation to the appropriate concentration with 0.9% sodium chloride injection and 5% dextrose injection, mixed with Evans blue, at one time intravenous injected into mice, 30 minutes later, the mouse ears vascular permeability were observed and compared. (2) Comparative experiment among different preparation time: placed 10 min, 2.5 h, 6 h and 24 h after Shuanghuanglian injection were prepared and then to detect the pseudo-allergic reactions in mice using the same methods as in (1). The results showed that there was no significant difference in the pseudo-allergic reactions in mice which induced by the same dose of Shuanghuanglian injection, respectively with 0.9% sodium chloride injection and 5% dextrose injection preparation, and with the extension of preparation time, the degree of pseudo-allergic reactions of Shuanghuanglian injection was gradually severe.
Animals ; Drug Compounding ; Drug Hypersensitivity ; etiology ; Drugs, Chinese Herbal ; adverse effects ; Injections ; Male ; Mice ; Mice, Inbred ICR ; Solvents ; Time Factors

To evaluated the pseudo-allergic reactions of cordate houttuynia, pulse-activating and Qingkailing injection in mice, the ICR mouse were divided into different test groups, then were intravenously injected with three traditional Chinese medicine injections, positive control compound 48/80 and physiological saline as normal control. All test substances were mixed with 0.4% Evans blue. The reaction and vascular permeability of the ears were observed and measured 30 min after injection. At the same time, the mechanisms of the traditional Chinese injections' pseudo-allergic reactions was studyed. ICR mice were injected with the test substances as above without EB, blood in a part of mice were collected after 5 min, and the level of histamine in the plasma were measured. Blood in the other part of mice were collected after 30 min, and the level of VEGF, TNF-α and IL-10 in the serum were measured. The reasults showed that except the cordate houttuynia injection, pulse-activating injection in 1. 5 times clinical concentration and Qingkailing injection in 3.3 times clinical concentration caused mild pseudo-allergic reactions mainly for vascular permeability, no pseudo-allergic reactions occurred when the concentration of the two injections was below the concentration metioned above; 5 minutes after intravenous injection of the three TCM injections into ICR mice with the highest dose, the levels of histamine in plasma of pulse-activating injection and Qingkailing injection groups were increased significantly, 30 minutes later, the levels of VEGF, TNF-α and IL-10 in the serum of all groups were no significant change compared to normal group. The mouse of pulse-activating and Qingkailing injection groups showed inflammatory changes in ear and lung tissues. It can be conluded that when the dose or concentration increased to a certain extent, pulse-activating and Qingkailing injection could induce pseudo-allergic reactions on ICR mice, the increased histamine realease maybe the main reason for pseudo-allergic reactions of the two traditional Chinese medicine injections. In addition the author preliminary thought that inflammatory mechanisms leading to hyperpermeabilities were the main reason of the traditional Chinese medicine injection's pseudo-allergic reaction.
Animals ; Drug Hypersensitivity ; etiology ; Humans ; Injections ; Interleukin-10 ; blood ; Male ; Medicine, Chinese Traditional ; adverse effects ; Mice ; Mice, Inbred ICR

Objective To study the sources and the relationship between the management and the outcome of hemorrhage after cephalic pancreatoduodenectomy.Methods The clinical data of 370 patients who underwent pancreatic resection at the Lihuili Hospital and the Second Affiliated Hospital of Zhejiang University were retrospectively analyzed.Results Postoperative bleeding occurred in 35 patients with 11 deaths.Among those intraabominal bleeding occurred in 14 cases and gastrointestinal hemorrhage occurred in 22,with one case suffering from both.Bleediug developing within 72 hours after operation in 12 cases (early-stage group),which was caused by improper intraoperative homeostasis.In other 23 cases,bleeding 72 hours after operation(later stage group)was caused by the erosion following pancreatic and/or bile leakage.Relaparotomy was performed in 13 cases and endoscopic homeostasis was performed in 3. Relaparotomy or endoscopic homeostasis was superior to that of conservative therapy in the early-stage group (P0.05).Pancreatic or bile leakage was identified as the significant risk factors for the postoperative bleeding.Conclusions In order to prevent the postoperative hemorrhage and to reduce the mortality of pancreatic resection,skillful techniques,expeditious homeostasis,proper management of stump pancreas and the prevention of pancreatic and bile leakage are essential.

OBJECTIVETo study the changes and significance of Toll-like receptor-2 (TLR2) and Toll-like receptor-4 (TLR4) on platelets, CD86 on lymphocytes and concentrations of IL-2, IFN-gamma, IL-4 and IL-10 in serum in children with idiopathic thrombocytopenic purpura (ITP).

METHODSPeripheral blood samples were collected from 24 children with acute idiopathic thrombocytopenic purpura (AITP), 21 children with chronic idiopathic thrombocytopenic purpura (CITP) and 20 normal children (control group). Expression of TLR2 and TLR4 on platelets and CD86 on lymphocytes were detected by flow cytometry. Serum concentrations of IL-2, IL-4, IL-10 and IFN-gamma were measured using ABC-ELISA.

RESULTSThe expression of CD41+TLR2+ and CD61+TLR4+ in the AITP and the CITP groups were significantly lower than those in the control group (p<0.01). The AITP group had lower expression of CD41+TLR2+ and CD61+TLR4+ than the CITP group (p<0.01). The expression of CD86+ in the AITP and the CITP groups was significantly higher than that in the control group (p<0.01). The serum concentrations of IL-2, IL-4, IL-10 and IFN-gamma in the AITP and the CITP groups were significantly higher than those in the control group (p<0.05). There was a positive correlation between CD41+TLR2+ and CD61+TLR4+ expression. CD41+TLR2+ and CD61+TLR4+ expression were negatively correlated with CD86+ expression and serum concentrations of IL-2, IL-4 and IL-10.

CONCLUSIONSThe detections of TLR2 and TLR4 on platelets, CD86 on lymphocytes and serum concentrations of IL-2, IFN-gamma, IL-4 and IL-10 are of great value in understanding the pathogenesis and predicting types of ITP in children.

Adolescent ; B7-2 Antigen ; blood ; Blood Platelets ; chemistry ; Child ; Child, Preschool ; Cytokines ; blood ; Humans ; Infant ; Purpura, Thrombocytopenic, Idiopathic ; immunology ; Toll-Like Receptor 2 ; blood ; Toll-Like Receptor 4 ; blood

Drug allergy and pseudoallergic reactions are main adverse drug reactions. Allergy is mainly induced by the immunogenicity of drug, drug metabolic products or drug additive. Pseudoallergic reactions may result from the irritation or activation of inflammatory material release. Pre-clinical evaluation of drug allergy and pseudoallergic reactions is included in immunotoxicity evaluation. Now there is no in vivo or in vitro method that could predict all kinds of allergy or pseudoallergic reactions due to the different mechanisms. In the past few years, FDA, SFDA OECD, ICH and WHO have published several guidelines on per-clinical immunotoxicity evaluation, however, no agreement has been reached on allergy and pseudoallergic reactions evaluation. This article reviews the requirements of allergy and pseudoallergic reactions in pre-clinical evaluation.
Drug Hypersensitivity ; diagnosis ; Humans ; Immune System ; drug effects ; Practice Guidelines as Topic

The purpose of this study was to investigate whether pretransplant infusion of reactive natural killer cells (NK cells) from donor or recipient can reduce graft-versus-host disease (GVHD) and enhance engraftment in bone marrow transplantation (BMT). Recipient BALB/c mice were divided into 4 groups after received 6.5 Gy total-body irradiation (TBI): control group 1 was treated with nothing, control group 2 received BMT alone, experiment group 1 received BMT and autoreactive NK cells, experiment group 2 received BMT and alloreactive NK cells. Life span, clinical and pathologic changes of GVHD and chimerism rate of each group were evaluated. The results showed that all mice were survival in control group 1. The life span was shorter in experiment group 1 than that in control group 2 (P < 0.05) and longer in experiment group 2 than that in control group 2 (P < 0.01). GVHD was higher in score of experiment group 1 than in control group 2 (P < 0.05) but lower in experiment group 2 than that in control group 2 (P < 0.01). The donor chimerism rate in both two experiment groups were higher than that in control group 2 (P < 0.05), however, the donor chimerism rate was higher in experiment group 2 than that in experiment group 1 (P < 0.01). It is concluded that pretransplant infusion of alloreactive donor NK cells can prolong life span, reduce the degree of GVHD and enhance engraftment. But autoreactive recipient NK cells can shorten life span, aggravate the degree of GVHD and also enhance engraftment, which is weaker than that using alloreactive donor NK cells.
Animals ; Bone Marrow Transplantation ; adverse effects ; Graft Survival ; immunology ; Graft vs Host Disease ; prevention & control ; Killer Cells, Natural ; transplantation ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Whole-Body Irradiation

Reproductive toxicity research takes an important place in traditional Chinese medicine pre-clinical safety evaluation. Modern reproductive toxicity experiment includes drug-related miscarriage, fetal death, teratism, and adverse effects on fertility, genital system, embryonic development and fetus, which is different from contraindicated in pregnancy in traditional Chinese medicine theory. Now the three-phases reproductive toxicity study is the method mainly applied in traditional Chinese medicine reproductive toxicity evaluation. Besides that, alternative methods of whole embryos culture and embryonic stem cell test are also used in traditional Chinese medicine embryo toxicity evaluation. This article reviews research progress and pre-clinical evaluation on reproductive toxicity of traditional Chinese medicine.
Animals ; Drug-Related Side Effects and Adverse Reactions ; Drugs, Chinese Herbal ; toxicity ; Embryonic Development ; drug effects ; Embryonic Stem Cells ; drug effects ; Female ; Humans ; Medicine, Chinese Traditional ; Pregnancy ; Reproduction ; drug effects ; Toxicity Tests