Application and Research Progress of Crystal Forms of Dihydropyridine Antihypertensive Drugs / 医药导报

Dihydropyridine (DHP) calcium channel blockers drugs (dipine in drug names) are currently used in the treatment of hypertension clinically. In recent years, with the emergence of generic drugs, it has been found that the drug efficacy is quite different from that of the original drug, and the reason is closely related to the difference in the crystal forms of the oral preparations. This paper reviews the polymorphic phenomenon of some DHP calcium channel blockers in the domestic market, introduces the clinical application and research progress of the DHP drugs, analyzes the differences between different crystal forms of the same drugs. This work may provide references and ideas for the research and development of generic drugs or new crystalline drug of DHP drugs.

Vasorelaxant effect of novel Rho-kinase inhibitors on isolated thoracic aorta rings and underlying mechanisms / 中国药理学通报

Aim To evaluate the vasorelaxant effect of two new chemical entities, J35242 and J35243, on iso-lated rat thoracic aorta rings as Rho-kinase inhibitors, and further to explore the underlying mechanisms of these two compounds. Methods Isolated rat thoracic aorta rings pre-contracted by KCl or norepinephrine ( NE) were used to evaluate the vasodilatory effect of J35242 and J35243 . Through the interventions of sev-eral tool drugs, the mechanisms of compounds concern-ing endothelium, K+ channels and Ca2+ were studied. Results J35242 and J35243 showed potent relaxant effect on both KCl and NE pre-contracted vessels, and exhibited partial endothelium dependency. L-NAME and Methylene Blue( MB) could influence the relaxant effect of these compounds. Meanwhile, the compounds could inhibit intracellular Ca2+ release and extracellu-lar Ca2+ influx, which indicated that the compounds might block the calcium channels to relax the vessels. In addition, the two compounds probably did not dilate the aorta rings through opening potassium channels. Conclusions J35242 and J35243 have vasorelaxant effects on vessels in vitro and the potency of J35242 is stronger than that of J35243 . The underlying mecha-nisms might be endothelium-dependent. Also the com-pounds might block Ca2+ channels, lowering intracel-lular Ca2+ concentration to relax the vessels.

Use of Escitalopram for Treatment of Chronic Subjective Dizziness:A Report of 32 Cases / 医药导报

Objective To investigate the clinical efficacy and safety of escitalopram in the treatment of chronic subjec-tive dizziness ( CSD) . Methods A total of 90 CSD patients randomly divided into medication group ( n=32) ,vestibular reha-bilitation group (n=27) and psychological intervention group (n=31).Patients in the medication group treated with escitalopram (10-20 mg?d-1,PO),those in the vestibular rehabilitation group were underwent vestibular rehabilitation training and those in the psychological intervention group were given cognitive behavioral therapy. The treatment course lasted six weeks. All patients were evaluated by zDHI,HAMA and HAMD before and after the treatments. Results The total scores of HAMA,HAMD,DHI and the respective factor scores of DHI were significantly decreased in each group after 6-week treatment when compared with those before the treatment (P0.05),re-spectively.They were significantly lower in the two groups than in vestibular rehabilitation group [ (14.69±4.76),(14.96±4.77) and (14.88±4.65) for the emotional factor score,HAMA score and HAMD score,respectively,P<0.05 for all]. Conclusion Escitalopram can improve the symptoms of CSD involving the body,emotion and function.The vestibular rehabilitation training and cognitive behavioral therapy have their respective advantages.

Vestibular rehabilitation combined with cognitive behavioral therapy relieves chronic dizziness and the associ-ated anxiety / 中华物理医学与康复杂志

Objective To assess the efficacy of combining vestibular rehabilitation with cognitive behavioral therapy in treating chronic subjective dizziness ( CSD) and the associated anxiety. Methods A total of 98 anxious CSD patients were randomly divided into an experimental group ( n=50) and a control group ( n=48) . All of the pa-tients′scores on the Hamilton anxiety scale ( HAMA) were no less than 14 and their scores on the Hamilton depres-sion scale ( HAMD) were less than 18. Systematic vestibular rehabilitation was given to the patients in the control group, while this was combined with cognitive behavioral therapy for the patients in the experimental group. All pa-tients were evaluated using a dizziness handicap inventory ( DHI) and the HAMA before treatment and in the 4th and 8th week of the treatment. Results Before the treatment there was no significant difference between the 2 groups in any of the assessments. After 3 weeks of treatment, the average HAMA score, DHI total score and its factor scores had decreased significantly. Four weeks later, the average HAMA score, DHI total score and its factor scores for som-atization, emotion and function had improved significantly in both groups compared with before treatment and the scores after 3 weeks. After 3 and 7 weeks of treatment, the average HAMA score, DHI total score and its factor scores of the experimental group were significantly lower than those of the control group. Conclusion Cognitive behavioral therapy amplifies the effects of vestibular rehabilitation in treating persons with CSD, in part by significantly relieving their anxiety.

Vasorelaxant effect of Rho kinase inhibitor DL0805-0 on isolated rat aortic rings and its underlying mechanisms / 中国药理学通报

Aim To investigate the in vitro vasorelax-ant effect of DL0805-0, a Rho kinase inhibitor, on iso-lated rat thoracic aorta and explore its underlying mechanism. Methods Tension was measured to eval-uate the vasorelaxant effect of DL0805-0 on rat endo-thelium-intact and endothelium-denuded thoracic aorta rings. Rho kinase inhibitor fasudil, nitric oxide syn-thase inhibitor Nω-nitro-L-arginine methyl ester ( L-NAME), guanylate cyclase inhibitor methylene blue, cyclooxygenase inhibitor indomethacin, calcium-activa-ted potassium channel blocker tetraethyl ammonium ( TEA ) , ATP-sensitive potassium channel blocker glibenclamide and voltage-dependent potassium chan-nel blocker 4-aminopyridine ( 4-AP ) were used to il-lustrate the mechanisms of vasorelaxant effect of DL0805-0 . Results DL0805-0 exerted vasorelaxation in a dose-dependent manner in KCl (60 mmol·L-1 ) or NE ( 0. 1 μmol · L-1 ) -induced contraction. DL0805-0-induced vasorelaxation was significantly re-duced by L-NAME. However, methylene blue and in-domethacin did not significantly affect vasorelaxation of DL0805-0. In endothelium-denuded rings, TEA re-markably attenuated the vasorelaxant effect of DL0805-0 , while glibenclamide and 4-AP did not affect vasore laxation of DL0805-0 significantly. DL0805-0 also re-duced NE-induced transient contraction and inhibited contraction induced by increasing extracellular calci-um. Conclusion These results suggest that DL0805-0 induces vasorelaxation through an endothelium-depend-ent pathway. The opening of calcium-activated K+channels and blocking of Ca2+ channels in vascular smooth muscle cells may be one of the mechanisms of DL0805-0-induced vasorelaxation.

Preliminary study on pharmacokinetics of DL0805-1:a novel Rho kinase inhibitor in rats / 中国药理学通报

Aim ToestablishthemethodofHighper-formance liquid chromatography ( HPLC ) for detecting plasma concentration of indazole compound DL0805-1 , a Rho kinase inhibitor, and to investigate its pharma-cokinetics in rats with intravenous injection. Methods ThedetectingsystemwasAgilent1200-DAD;chro-matographic column was Agilent TC-C18 ( 4. 6 mm × 250 mm, 5 μm); the ultraviolet detection wavelength was 235 nm; the column temperature was 35 ℃; the flow rate was 1 ml·min-1;the mobile phase was ace-tonitrile-0. 05% H3 PO4 gradient elute. Rat blood sam-ples were collected at different intervals after intrave-nous injection of a single dose of DL0805-1 , and the concentration of DL0805-1 in rat plasma were deter-mined by HPLC method for estimating pharmacokinetic parameters.Results Afterintravenousinjectionof DL0805-1 in rats, prototype and its metabolite were detected in plasma. T1/2 of DL0805-1=(2. 34 ± 1. 42) h, Cmax=(3. 51 ± 0. 44) mg·L-1, T1/2 of metabolite of DL0805-1 = ( 1. 27 ± 0. 45 ) h, Cmax = ( 3. 55 ± 0.22)mg·L-1.Conclusion Theseresultssuggest that DL0805-1 may be metabolized into another sub-stance in vivo and play biological functions. The meth-od is sensitive, simple, and accurate, and can be used for the determination of DL0805-1 in rat plasma and pharmacokinetic studies.

Bulk-like endocytosis plays an important role in the recycling of insulin granules in pancreatic beta cells

Although bulk endocytosis has been found in a number of neuronal and endocrine cells, the molecular mechanism and physiological function of bulk endocytosis remain elusive. In pancreatic beta cells, we have observed bulk-like endocytosis evoked both by flash photolysis and trains of depolarization. Bulk-like endocytosis is a clathrin-independent process that is facilitated by enhanced extracellular Ca(2+) entry and suppressed by the inhibition of dynamin function. Moreover, defects in bulk-like endocytosis are accompanied by hyperinsulinemia in primary beta cells dissociated from diabetic KKAy mice, which suggests that bulk-like endocytosis plays an important role in maintaining the exo-endocytosis balance and beta cell secretory capability.