The new HIV-1 NNRTI drug Etravirine (TMC125) and a promising drug candidate Rilpivirine (TMC278) in phase III clinical trial are compounds belonging to the diarylpyrimidine (DAPY) family. They are extremely high potent against both wild-type and many drug-resistant HIV-1 strains, providing new hope for HIV-infected patients who fail to use current drugs due to the emergence of drug-resistant HIV mutants. The discovery and development of DAPY derivatives as next-generation NNRTI drugs depend on multidisciplinary coordination and their success has encouraged new researches to explore more next-generation NNRTIs with new scaffolds. This review described the story of discovery and development of DAPY derivatives as next-generation NNRTIs and related progress.
Anti-HIV Agents ; chemical synthesis ; chemistry ; pharmacology ; Drug Resistance, Viral ; HIV Infections ; drug therapy ; HIV-1 ; drug effects ; Humans ; Molecular Structure ; Nitriles ; chemical synthesis ; chemistry ; pharmacology ; Pyridazines ; chemical synthesis ; chemistry ; pharmacology ; Pyrimidines ; chemical synthesis ; chemistry ; pharmacology ; Reverse Transcriptase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Rilpivirine

Rhynchosia volubilis Lour has been a major drug in a folk prescription for contraception in China, whereas its mechanism remains unknown. Its antifertility effects on male mice and antimicrobial activities on sexually transmitted infection (STI) pathogens were previously reported. This study was undertaken to develop the n-Butanol extract of Rhynchosia volubilis Lour (BERVL) as a spermicidal agent with STI prevention. The spermicidal activities of BERVL with different doses were assessed using selected high-motile sperms of normal human semen samples, and their inhibitory effects on Lactobacillus acidophilus were determined. The mechanism of the spermicidal activity was explored by aqueous Eosin Y and Hoechst 33342/PI staining. The results showed spermicidal activities and inhibitory effects of BERVL on Lactobacillus acidophilus were dose-dependent. Dose of 90 mg/mL BERVL terminated all progressive sperm motility within 2 min, and had slight inhibitory effect on Lactobacillus acidophilus, suggesting it was an effective and safe dose for contraception use. About 80% sperms exposed to BERVL displayed changes consistent with high permeability of head membrane. It is concluded that BERVL as spermicide has advantages over N-9 with strong ability to instantaneously kill human sperm and possesses light inhibitory effect on Lactobacillus acidophilus.

Objective To evaluate the efficiency and safety of exercise interventions on cancer related fatigue. Methods Cochrane Library, JBI Database of Systematic Reviews, MEDLINE, EMbase, CINAHL, Chinese Journal Full- text Database, Chinese Biomedical Literature Database, and Wanfang Databse were searched from the inception to November 2014 to screen the systematic review and Meta-analysis conforming to the inclusion criteria. Two authors independently appraised their methodological qualities with Overview Quality Assessment Questionnaire (OQAQ), and analyzed the data using descriptive analysis. The primary outcome included the scaling of cancer related fatigue, the secondary outcome included adherence to exercise intervention and the incidence of adverse events. Results Fourteen systematic review/Meta-analysis were identified, twelve of them had a high methodological quality (Scoring 5-7). Six systematic review/Meta-analysis found that aerobic exercise could effectively alleviate cancer related fatigue, especially for breast cancer patients;seven articles showed that exercise could modulate cancer related fatigue of patients under active treatments;seven articles reported the compliance to the exercise intervention, four articles reported adverse events occurring during the intervention, very few of them resulted directly from the exercise intervention. Conclusions Exercise intervention can modulate cancer related fatigue with good safety.

Objective To study the characteristics of dynamic susceptibility-contrast(DSC)MR perfusion curves,color images and perfusion values in pre-operative brain metastasis.Methods Twenty- eight brain metastases underwent DSC MR perfusion imaging by using a first-pass T_2~* echo-planar sequence. The patients' data were transferred to on-line workstation.Time-signal intensity curves,color perfusion maps and rCBV,rMTT values in both tumor parenchyma and peri-tumor edema were analyzed,and independent t- test was used and P0.05).Conclusion Different originated brain metastases have nearly same characteristics in DSC MR perfusion imaging.

Objective To study the effect of Sinisan on the ultra structure of hippo-campus to the intervention in rats with post-traumatic stress disorder(PTSD).Methods SD rats were divided equally into 5 groups,each group had ten rats:blank control group,model group,negative control group,positive control group and experimental group.The blank control group did not copy the model,the normal feeding.Model group,repetitive post-traumatic stress disorder model was induced by current stimulation,but not treated.Negative control group,equal volume of 0.9％ NaC1.Positive control group (paroxetine hydrochloride 0.42 mg · mL-1) and experimentalgroup (Sinisan,containing crude drug 0.24 g · mL-1).It given to drugs 1 h before the model establishment.The rats were administered with 10 mL · kg-1,once a day,for a total of 7 d.In each group,rats was cardiac perfusion and the hippo-campus tissue was collected.The changes of ultra structure of CA1 and CA3 area in hippo-campus with rats were observed by transmission electron microscope.Results In the blank control group,the CA1 and CA3 neurons in the hippocampus were rich in cytoplasmic organelles,and the mitochondria were round or long,the structure of the mitochondrial cristae was clear,the rough endoplasmic reticulum was like a cord like distribution,and the ribosome was abundant.Compared with the blank control group,the organelle of CA1 and CA3 area in hippo-campus of the model group were significantly damaged,the cytoplasm was open,the mitochondria were swollen,the mitochondrial membrane and cristae disappeared,and the rough endoplasmic reticulum was dilated.The results showed that the damage of the organelles in the hippocampal neurons of rats was induced by the electric shock.The model group was similar to the negative control group,which indicated that there was no significant effect on the stress of rats after intragastric administration.The intracellular organelles in the CA1 and CA3 neurons in the hippocampus of the positive control group and the experimental group were significantly recovered,and the changes in the two groups were similar.These results suggest that both paroxetine hydrochloride and Sinisan can significantly improve the structure of CA1 and CA3 neurons in the hippocampus of PTSD rats.Conclusion Snisan as traditional Chinese medicine compound can significantly improve the hippocampus of rats with PTSD CA1 and CA3 neurons.

Objective To study on intervene function of Sinisan with the ultra structure of hippo-campus in rats with sleep disorder induced by post traumatic stress disorder.Methods Fifty SD rats were divided equally into five groups:blank control group,model group,negative control group,positive control group and experimental group.The control blank group did not copy the model,do not receive drugs,the normal feeding.Model group,repetitive post-traumatic stress disorder model was induced by current stimulation,but not receive drugs.Negative control group,equal volume of 0.9％ NaCl.Positive control group (paroxetine hydrochloride 0.42 mg ·mL-1) and experimental group (Sinisan,containing crude drug 0.24 g · mL-1).It given to drugs 1 h before the model establishment.The rats were administered with 10 mL · kg-1,once a day,for a total of 7 d.The changes of ultra structure of CA1 and CA3 area in hippo-campus with rats were observed by transmission electronmicroscope.Results In the blank control group,the hippocampal neurons were clearly defined,and the synaptic space was obvious in the CA1 and CA3 area.Compared with the blank control group,in the model group,the synaptic structure of hippocampal neurons was significantly changed,the synaptic vesicles were reduced and the synaptic structure was not clear in the CA1 and CA3 area.Compared with the model group,the negative control group was same too,which indicated that there was no significant stress effect on the rats after intragastric administration of saline.Compared with the negative control group,positive control group and experimental group hippocampal neurons synapse structure was restored,and the two groups were similar in the CA1 and CA3 area.Conclusion Transmission electronmicroscope was used to study the ultra structure of CA1 and CA3 in rats hippo-campus with characteristic difference.

Objective To study the effects of sleep latency to the intervention of Sinisan in rats with post-traumatic stress and sleep disorder (PTSD).Methods Fifty SD rats were divided equally into 5 groups:sham operation group,model group,negative control group group,positive control group and experimental group.PTSD model was made by claustrophobia,but not in sham operation group.The model group was not given the drug,the negative control group was given equal volume 0.9％ NaC1,and the positive control group was given paroxetine hydrochloride 0.42 mg · mL-1.The experimental group was perfused with the decoction of Sinisan (containing 0.24 g · mL-1) 10 mL · kg-1.The drug was administered 1 h before the stress model was administered once a day for a total of 7 d.After intervention on the 7th day,nonrapid eye movements sleep (NREMS) and eye movements sleep (REMS) were detected.Results The REMS and NREMS of sham operation group and model group were respectively (8.66 ± 3.04),(23.27 t 10.15) min;(65.90 ± 25.08),(109.36 ± 43.43) min,the differences between groups were statistically significant(all P ＜ 0.01);the result suggest that difficulty in falling asleep appears in rats after modeling.The REMS and NREMS of the positive control group and the experimental group were respectively (8.17 ±2.29),(6.83 ±2.84) min;(162.29 ±46.19),(195.24 ±67.96) min.Comparison between the drugs groups and model group,the difference was statistically significant (P ＜0.05,P ＜0.01).These Results suggested that both paroxetine hydrochloride and Sinisan can significantly promote the sleep of rats.Conclusion Traditional Chinese medicine compound Sinisan can obviously promote the rats with sleep disorder caused by PTSD.

Object To design a casualty sorting unit with chest integrated with table in the tent-form field medical system.Methods The unit was designed with virtual prototype simulation and CAD, which took considerations on the service orientation, the types and quantity of equipment and devices as well as the requirements for packaging box's size and dimensions of the tent-form field medical system.Results The unit had a size of 1795 mm ×600 mm ×600 mm when deployed, and could be used as the field diagnostic and treatment table; the size was 800 mm ×600 mm ×600 mm when withdrawn, when the module met the requirements of the tent-form field medical system for the packaging box and could be used to hold valuable devices such as color Doppler ultrasound and ECG machine. Finite element simulation and check verified that the module had shape and stress changes due to austere force satisfy the desired requirements.Conclusion The unit gains advantages in deployment and withdrawal, materials, mechanical structure and ergonomics-based operation, accords with the requirements for modularity and multi function integrated into one decice, and enhances the efficiency of casualty sorting in the tent-form field medical system.

OBJECTIVETo investigate the effect of Bushengzhuyang Fang (Yangjing Capsule, YJC) on penile erectile function and its action mechanisms in rats.

METHODSFifty-six male SD rats were randomly divided into seven groups of equal number: blank control, daidzein, daidzein + testosterone, daidzein + sildenafil, daidzein + low-dose YJC, daidzein + medium-dose YJC, and daidzein + high-dose YJC. The rats in the blank control group were treated intragastrically with normal saline and those in the other groups with daidzein at the dose of 100 mg per kg per day for 30 days. Then the last five groups received additionally testosterone (4 mg per kg per day), sildenafil (2.5 mg per kg per day), low-dose YJC, (0.315 mg per kg per day), medium-dose YJC (0.63 mg per kg per day), and high-dose YJC (1. 26 mg per kg per day), respectively. At 0, 30 and 60 days of treatment, we observed the apomorphine-induced spontaneous erectile response and pathological changes in the corpus cavernosum of the rats, recorded the number of penile erection and erectile incubation period, and determined the serum levels of testosterone (T) and luteinizing hormone (LH).

RESULTSAt 30 days of treatment, the number of apomorphine-induced erections was decreased, the erectile incubation period prolonged, and the serum levels of T and LH reduced remarkably in all groups of rats (P < 0.05). Compared with the findings at 30 days, the number of penile erections was significantly decreased at 60 days in the daidzein group (1.39 ± 0.42 vs 2.67 ± 0.33, P < 0.05) and daidzein + low-dose YJC group (1.33 ± 0.49 vs 2.83 ± 0.61, P < 0.05); the erectile incubation period was markedly ex- tended ([16.33 ± 3.11] vs [8.50 ± 0.93] min and [15.50 ± 3.21] vs [8.63 ± 1.54] min, P < 0.05); and the serum levels of T ([5.34 ± 0.89] vs [1.24 ± 0.30] ng/ml and [5.28 ± 1.12] vs [2.07 ± 0.76] ng/ml, P < 0.05) and LH ([3.62 ± 0.37] vs [2.09 ± 0.12] ng/ml and [3.79 ± 0.28] vs [2.17 ± 0.33] ng/ml, P < 0.05) were significantly reduced in the daidzein and daidzein + low-dose YJC groups, respectively. Pathological examination revealed slightly decreased cavernous sinuses and blood vessels in the corpus cavernosum of the rats in the daidzein + testosterone, daidzein + sildenafil, daidzein + medium-dose YJC, and daidzein + high-dose YJC groups as compared with those in the blank control group.

CONCLUSIONHigh-dose Yangjing Capsule is efficacious for the recovery of erectile function in rats, especially for phytoestrogen-induced erectile dysfunction.

Animals ; Apomorphine ; pharmacology ; Drugs, Chinese Herbal ; therapeutic use ; Erectile Dysfunction ; chemically induced ; drug therapy ; Humans ; Isoflavones ; pharmacology ; Luteinizing Hormone ; Male ; Penile Erection ; drug effects ; physiology ; Penis ; drug effects ; pathology ; Phytoestrogens ; Phytotherapy ; Piperazines ; therapeutic use ; Purines ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Sildenafil Citrate ; Sulfonamides ; therapeutic use ; Testosterone ; therapeutic use ; Vasodilator Agents ; therapeutic use

OBJECTIVEThis review aimed to summarize the relationship between intestinal microbiota metabolism and cardiovascular disease (CVD) and to propose a novel CVD therapeutic target.

DATA SOURCESThis study was based on data obtained from PubMed and EMBASE up to June 30, 2015. Articles were selected using the following search terms: "Intestinal microbiota", "trimethylamine N-oxide (TMAO)", "trimethylamine (TMA)", "cardiovascular", and "atherosclerosis".

STUDY SELECTIONStudies were eligible if they present information on intestinal microbiota metabolism and atherosclerosis. Studies on TMA-containing nutrients were also included.

RESULTSA new CVD risk factor, TMAO, was recently identified. It has been observed that several TMA-containing compounds may be catabolized by specific intestinal microbiota, resulting in TMA release. TMA is subsequently converted to TMAO in the liver. Several preliminary studies have linked TMAO to CVD, particularly atherosclerosis; however, the details of this relationship remain unclear.

CONCLUSIONSIntestinal microbiota metabolism is associated with atherosclerosis and may represent a promising therapeutic target with respect to CVD management.

Atherosclerosis ; metabolism ; microbiology ; Gastrointestinal Microbiome ; physiology ; Humans ; Methylamines ; metabolism