Idiosyncratic adverse drug reactions (IDR) induce severe medical complications or even death in patients. Alert structure in drugs can be metabolized as reactive metabolite (RM) in the bodies, which is one of the major factors to induce IDR. Structure modification and avoidance of alert structure in the drug candidates is an efficient method for reducing toxicity risks in drug design. This review briefly summarized the recent development of the methodologies for structure optimization strategy to reduce the toxicity risks of drug candidates. These methods include blocking metabolic site, altering metabolic pathway, reducing activity, bioisosterism, and prodrug.
Binding Sites ; Cytochrome P-450 Enzyme System ; metabolism ; Drug Design ; Drug Discovery ; methods ; Drug Recalls ; Drug-Related Side Effects and Adverse Reactions ; prevention & control ; Humans ; Structure-Activity Relationship

To further uncover the scientific significance and molecular mechanism of the Chinese herbs with pungent hot or warm natures, endogenous and exogenous expression systems were established by isolation of dorsal root ganglion (DRG) neurons and transfection of HEK293 cells with TRPV1 channel gene separately. On this basis, the regulation action of capsaicin, one main ingredient from chili pepper, on TRPV1 channel was further explored by using confocal microscope. Besides, the three-sites one-unit technique and method were constructed based on the brown adipose tissue (BAT), anal and tail skin temperatures. Then the effect of capsaicin on mouse energy metabolism was evaluated. Both endogenous and exogenous TRPV1 channel could be activated and this action could be specifically blocked by the TRPV1 channel inhibitor capsazepine. Simultaneously, the mice's core body temperature and BAT temperature fall down and then go up, accompanied by the increase of temperature of the mice's tail skin. Promotion of the energy metabolism by activation of TRPV1 channel might be the common way for the pungent-hot (warm) herbs to demonstrate their natures.
Adipose Tissue, Brown ; drug effects ; physiology ; Animals ; Capsaicin ; analogs & derivatives ; pharmacology ; Energy Metabolism ; Ganglia, Spinal ; cytology ; HEK293 Cells ; Humans ; Mice ; Neurons ; drug effects ; physiology ; Plants, Medicinal ; chemistry ; TRPV Cation Channels ; physiology ; Temperature ; Thermogenesis

OBJECTIVETo investigate the feasibility and the mid-term effects of unilateral pedicle screw fixation and transforaminal lumbar interbody fusion in treating lumbar degenerative diseases.

METHODSFrom August 2005 to May 2010, 56 patients with lumbar degenerative diseases underwent lumbar posterolateral fusion,their clinical data were retrospective analyzed. The patients were divided into two groups (unilateral group and bilateral group) according to fixation methods,27 patients in unilateral group who were underwent unilateral pedicle screw fixation, including 18 males and 9 females with a mean age of (57.5 ± 7.1) years old (ranged from 41 to 66 years); and 29 patients in bilateral group who were treated with bilateral pedicle screw fixation (on the basis of the above, with contralateral vertebral pedicle screw fixation), including 19 males and 10 females with a mean age of (54.6 ± 5.1) years old (ranged from 43 to 68 years). The clinical data such as operation time, blood loss volume, hospitalization time and cost were compared between two groups. JOA score system was used to evaluate the neurological function. And fusion status and cage-related complication were also analyzed.

RESULTSAll patients were followed up from 36 to 60 months with an average of 45.8 months. No iatrogenic nerve, blood vessels or organs injury were found during operation. Operation time, blood loss volume, hospitalization time and cost in unilateral group were better than that of bilateral group (P < 0.05). There was no significant difference in JOA score between two groups (P > 0.05). Two patients in unilateral group developed with cage related complications, 1 case was cage displacement and 1 case was cage subsidence, while 2 patients in bilateral group developed with complications of no-fusion, and there was no significant differences between two groups (P = 0.58).

CONCLUSIONUnilateral pedicle screw fixation is a satisfactory method and can obtain good effects in treating lumbar degenerative diseases in mid-term, however, the indications should be well considered.

Adult ; Aged ; Biomechanical Phenomena ; Female ; Humans ; Intervertebral Disc Degeneration ; physiopathology ; surgery ; Lumbar Vertebrae ; surgery ; Male ; Middle Aged ; Pedicle Screws ; Spinal Fusion ; methods

The methyl group plays an important role in the rational drug design. Introducing methyl into small molecules has become an important strategy of lead compound optimization. The application of methyl in drug design is reviewed in this paper. Methyl can modulate the physicochemical, pharmacodynamic, and pharmacokinetic properties by ortho effect, inductive effect, and conformational effect. It also improves the metabolic stability as a soft metabolic point. In addition, introducing methyl into drug molecules can also be applied as a strategy in new uses of old drugs and generate me-too drugs.
Drug Design ; Hydrophobic and Hydrophilic Interactions ; Lipid Metabolism ; Methylation ; Pharmaceutical Preparations ; chemical synthesis ; chemistry ; metabolism ; Solubility ; Stereoisomerism ; Structure-Activity Relationship

OBJECTIVETo observe the efficacy and safety of modified Shengma Biejia Decoction (MSBD) combined with CAG program in treating elderly acute myeloid leukemia (AML) patients with yin deficiency toxin stasis syndrome (YDTSS).

METHODSTotally 46 elderly AML patients were assigned to the treatment group (24 cases; treated with MSBD + CAG) and the control group (22 cases; treated with CAG + placebos of Chinese medicine) according to random digit table. The therapeutic course of CM placebo or MSBD was 21 days. The clinical efficacy and adverse reactions were observed. Meanwhile, physical state (ECOG Score), transfusion dependency, and TCM syndrome score were compared before and after treatment.

RESULTS(1) The complete remission rate was 54% (13/24) and the objective response rate (ORR) was 71% (17/24) in the treatment group, obviously higher than those of the control group [36% (8/22); 54% (13/24)], with statistical difference (P = 0.036, 0.042). When comparing the efficacy based on risk level, the moderate and poor ORR was 71% (10/14) and 67% (6/9) in the treatment group, and 57% (8/14) and 33% (2/6) in the control group, with statistical difference between the two groups (P = 0.048; P = 0.010). (2) Compared with before treatment in the same group, the ECOG score significantly decreased, the average infusion time of red cells and platelets were markedly prolonged in the treatment group after treatment (P < 0.05). ECOG score, the average infusion time of red cells and platelets were significantly better in the treatment group than in the control group after treatment (P < 0.05). (3) Compared with before treatment in the same group, scores of fever, hemorrhage, and bone pain were markedly reduced in the control group (P < 0.05); scores of fever, fatigue, hemorrhage, dry mouth, and bone pain were markedly reduced in the treatment group (P < 0.05). Better effect in relief of fever, fatigue, hemorrhage, dry mouth, and so on was obtained in the treatment group than in the control group (P < 0.05). (4) In aspect of hematotoxicity, the incidence of neutropenia, anemia, thrombocytopenia was obviously lower in the treatment group than in the control group [29.2% (7/24) vs 54.5% (12/22); 16.7% (4/ 24) vs 45.5% (10/22); 33.3% (8/24) vs 63.6% (14/22); P < 0.05]. The incidence of fatigue and anorexia was obviously lower in the treatment group than in the control group [37.5% (9/24) vs 63.6% (14/22), 37.5% (9/24) vs 81.8% (18/22); P < 0.05].

CONCLUSIONMSBD combined with CAG program in treating elderly AML patients with YDTSS, with efficacy enhancing toxicity reducing effect, had distinct advantages in improving physical condition and clinical symptoms, and reducing transfusion dependency.

Aclarubicin ; therapeutic use ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Cytarabine ; therapeutic use ; Drugs, Chinese Herbal ; therapeutic use ; Granulocyte Colony-Stimulating Factor ; therapeutic use ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; Medicine, Chinese Traditional ; Phytotherapy ; Yin Deficiency ; drug therapy

Acyclovir ; therapeutic use ; Anti-Inflammatory Agents ; therapeutic use ; Antiviral Agents ; therapeutic use ; Brain Stem ; pathology ; virology ; Encephalitis ; complications ; diagnosis ; drug therapy ; virology ; Herpes Zoster ; complications ; diagnosis ; drug therapy ; virology ; Herpes Zoster Oticus ; diagnosis ; drug therapy ; etiology ; virology ; Humans ; Male ; Methylprednisolone ; therapeutic use ; Middle Aged

OBJECTIVETo investigate the clinical application of a new temporary abdominal wound closure,vacuum system for temporary management of the open abdomen.

METHODSVacuum pack system consisted of polyethylene sheet,surgical towel,silicone drain, adhesive plastic drape. Clinical data of the patients undergoing exploratory celiotomy were recorded,and the indications for such temporary abdominal closure and its complications were reviewed.

RESULTSThirteen trauma patients underwent such vacuum abdominal closure for 15 times, including 5 times (33.3%) for increased intra- abdominal pressure so that tension-free fascial closure was unable to achieve, 4 times (26.7%) for reexploration, 2 times (13.3%) for damage control, and 4 times (26.7%) for combined factors. Finally, seven patients (53.8%) received direct closure and 5 patients (38.5%) received skin grafting after granulation because the defect could not be closed directly. One patient (7.7%) died before abdominal closure was attempted. None of the patients developed enterocutaneous fistula and evisceration. Three patients (23.1%) developed intra-abdominal abscess.

CONCLUSIONSThe vacuum pack is a better temporary abdominal wound closure device, and primary closure can be achieved in most of the patients. The technique is simple and easily mastered with a low complication rate.

Abdominal Injuries ; surgery ; Adolescent ; Adult ; Bandages ; Female ; Humans ; Laparotomy ; instrumentation ; methods ; Male ; Middle Aged ; Vacuum ; Young Adult

OBJECTIVETo investigate the significance of Rac subfamily members in the gastrointestinal carcinogenesis and progression.

METHODSThe mRNA expression of Rac1, Rac2 and Rac3 in 12 kinds of gastrointestinal cancer cell lines was examined by semi-quantitative RT-PCR. The activities of Rac1 protein in 5 kinds of gastric cancer cell lines were tested by pull-down assay.

RESULTSCompared with the normal gastric mucosa and intestinal epithelial cell line, the mRNA expression of Rac1 and Rac3 was up-regulated in most of gastrointestinal cancer cell lines. The activities of Rac1 protein increased markedly in gastric cancer cell lines.

CONCLUSIONThe increased mRNA expression of Rac1 and Rac3 in gastrointestinal cancer cell lines and the abnormal activation of Rac1 protein in gastric cancer cell lines might be correlated with the carcinogenesis of gastrointestinal cancer.

Cell Line, Tumor ; Gastrointestinal Neoplasms ; metabolism ; Humans ; RNA, Messenger ; analysis ; Reverse Transcriptase Polymerase Chain Reaction ; rac GTP-Binding Proteins ; genetics ; rac1 GTP-Binding Protein ; analysis ; genetics

OBJECTIVETo detect the expression of stem cell transcription factor Oct-4 in squamous cell carcinoma (SCC) and seborrheic keratosis (SK) and its association with cancer stem cells.

METHODSImmunohistochemistry was used to detect Oct-4 expression in 35 SCC cases, 21 SK cases and 15 normal control skin tissues.

RESULTSOct-4 expression was negative in normal skin and showed a significant difference between SCC and SK tissues (P<0.05).

CONCLUSIONThe Oct-4-positive cells in SCC and SK are probably tumor stem cells. Oct-4 expression may provide an important evidence for isolation and identification of human SCC and SK stem cells.

Adult ; Aged ; Carcinoma, Squamous Cell ; metabolism ; pathology ; Case-Control Studies ; Female ; Humans ; Keratosis, Seborrheic ; metabolism ; pathology ; Male ; Middle Aged ; Octamer Transcription Factor-3 ; metabolism ; Skin Neoplasms ; metabolism ; pathology ; Young Adult