Biodiversity Risk and Opportunity Assessment in BAT Cooperative Tobacco-growing Areas

Using the method in Biodiversity Risk and Opportunity Assessment Handbook of British American Tobacco Biodiversity Partnership,we assess biodiversity risks and opportunities in BAT and China's cooperative tobacco-growing areas. The assessment results indicate that there are 8 risks and 1 opportunity. Action and monitoring plans have been made for medium and high risks as well as opportunity,to reduce impact on biodiversity.

In vitro screening of reversible and time-dependent inhibition on CYP3A by TM208 and TM209 in rat liver microsomes

TM208 and TM209,dithiocarbamate derivatives with potential anti-cancer effects,were evaluated in reversible and time-dependent cytochrome P450(CYP)3A inhibition assays in rat liver microsomes using testosterone as probe substrate.Both compounds were found to be weak reversible inhibitors and moderate mechanism-based inhibitors of rat CYP3A.For reversible inhibition on rat CYP3A,the Ki values of competitive inhibition model were 12.10±1.75 and 13.94±1.31 μM,respectively.For time-dependent inhibition,the inactivation constants(K_(l))were 31.93±12.64 and 32.91±15.58 μM,respectively,and the maximum inactivation rates(kinact)were 0.0349770.0069 and 0.0725970.0172 min^(-1) respectively.These findings would provide useful in vitro information for future in vivo DDI studies on TM208 or TM209。

Discovery of novel diarylamides as orally active diuretics targeting urea transporters

Urea transporters(UT)play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing diuretics.Thus,UT inhibitors are promising for development as novel diuretics.In the present study,a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput screening.Optimization of the inhibitor led to the identifi-cation of a promising preclinical candidate,N-[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide(1 H),with excellent in vitro UT inhibitory activity at the submicromolar level.The half maximal inhibitory concentrations of 1 H against UT-B in mouse,rat,and human erythrocyte were 1.60,0.64,and0.13 mmol/L,respectively.Further investigation suggested that 8 mmol/L 1 H more powerfully inhibited UT-A1 at a rate of 86.8%than UT-B at a rate of 73.9%in MDCK cell models.Most interestingly,we found for the first time that oral administration of 1 H at a dose of 100 mg/kg showed superior diuretic effect in vivo without causing electrolyte imbalance in rats.Additionally,1 H did not exhibit apparent toxicity in vivo and in vitro,and possessed favorable pharmacokinetic characteristics.1 H shows promise as a novel diuretic to treat hyponatremia accompanied with volume expansion and may cause few side effects.

Outcome of multimodal MRI-guided intravenous thrombolysis in patients with stroke with unknown time of onset

Objective Intravenous tissue plasminogen activator(tPA)is the standard therapy for patients with acute ischaemic stroke(AIS)within 4.5 hours of onset.Recent trials have expanded the endovascular treatment window to 24 hours.We investigated the efficacy and safety of using multimodal MRI to guide intravenous tPA treatment for patients with AIS of unknown time of onset(UTO).Methods Data on patients with AIS with UTO and within 4.5 hours of onset were reviewed.Data elements collected and analysed included:demographics,National Institutes of Health Stroke Scale(NIHSS)score at baseline and 2 hours,24 hours,7 days after thrombolysis and before discharge,the modified Rankin Scale(mRS)score at 3 months after discharge,imaging findings and any adverse event.results Forty-two patients with UTO and 62 in control group treated within 4.5 hours of onset were treated with intravenous tPA.The NIHSS scores after thrombolysis and/or before discharge in UTO group were significantly improved compared with the baseline(p<0.05).Between the two groups,no significant differences in NIHSS score were observed(p>0.05).Utilising the non-inferiority test,to compare mRS scores(0-2)at 3 months between the two groups,the difference was 5.2%(92%CI,OR 0.196).Patients in the UTO group had mRS scores of 0-2,which were non-inferior to the control group.Their incidence of adverse events was similar.Conclusions Utilising multimodal MRI to guide intravenous only thrombolysis for patients with AIS with UTO was safe and effective.In those patients with AIS between 6 and 24 hours of time of onset but without large arterial occlusion,intravenous thrombolysis could be considered an option.

Continuous-flow synthesis of nitriles from aldehydes via Schmidt reaction

A continuous-flow synthesis of nitriles by Schmidt reaction has been developed.Using this procedure,a variety of aldehydes could be smoothly transformed into the desired nitriles in good to excellent yields.The mild reaction conditions and the flowing reaction system greatly improved the safety and make the reaction easy to scale up.

Continuous-flow,one-pot synthesis of asymmetrical aromatic ureas from acids and amines via curtius rearrangement

In the present study,we described a continuous-flow,one-pot synthesis of asymmetrical ureas using nucleophilic addition reaction of amines to isocyanates derived from acids’Curtius rearrangement.The advantages of this method included broad substrate scope,high yields,rapid reaction,simplicity,extraordinary safety,and easy scale-up.

The spirocyclopiperazinium salt compound LXM-15 alleviates chronic inflammatory and neuropathic pain in mice and rats

In the present study,we aimed to evaluate the effect of the spirocyclopiperazinium salt compound LXM-15 on chronic inflammatory pain and chronic neuropathic pain induced by complete Freund’s adjuvant(CFA)or chronic constriction injury(CCI)in mice and rats.The results showed that administration with LXM-15 significantly reduced paw edema and ankle swelling and increased the mechanical withdrawal threshold and paw withdrawal latency after CFA injection in mice.LXM-15 significantly alleviated the mechanical allodynia and thermal hyperalgesia in CCI rats.The effect was abolished by pretreatment with hexamethonium(a peripheral nAChR antagonist)or methyllycaconitine citrate(anα7 nAChR antagonist).Furthermore,LXM-15 significantly inhibited the phosphorylation of JAK2 and STAT3,and suppressed the expressions of TNF-αand c-fos in dorsal root ganglia of CCI rats.Collectively,we reported that LXM-15 relieved chronic inflammatory pain in CFA mice and chronic neuropathic pain in CCI rats.The underlying mechanism might be related to the activation of peripheralα7 nicotinic receptor,further inhibiting JAK2/STAT3 signaling pathway,and eventually suppressing the expressions of TNF-αand c-fos.