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Objective Desipramine is a tricyclic antidepressant with a negative side effect of dry mouth. The Na+/H+ exchanger was suggested to be a target of desipramine in salivary gland cells. However, it is unclear whether desipramine has other targets in the salivary secretion pathway. Here, we studied the effect of desipramine on salivary Ca2+ signaling. Materials and Methods Cytosolic free Ca2+ concentration ([Ca2+]i) was determined with the fluorescent Ca2+ indicator fura-2/AM. Aquaporin translocation was analyzed by Western blotting and immunocytochemistry of confocal microscopy. Results Desipramine inhibited the carbachol- and histamine-mediated increase in cytosolic Ca2+ ([Ca2+]i) in a concentration-dependent manner. However, desipramine did not affect increases in [Ca2+]i mediated by extracellular ATP, sphingosine-1-phosphate, or thapsigargin. The adrenergic receptor blockers prazosin and propranolol did not reverse the desipramine-mediated inhibition of carbachol- and histamine-induced increases in [Ca2+]i. We also found that desipramine inhibits the increase in membrane aquaporin-5 level triggered by carbachol and histamine treatments. Conclusions These results imply that desipramine blocks muscarinic and histamine receptor-mediated Ca2+ signaling and the subsequent translocation of aquaporin-5 in human salivary gland cells, suggesting a novel mechanism for the xerogenic effects of desipramine.

As a development strategy for backups of Fimasartan (1), a comparative molecular similarity indices analysis (CoMSIA) of a set of sixty-five 5-(biphenyl-2-yl)-1H-tetrazole derivatives has been performed to find out the pharmacophore elements for angiotensin II receptor type 1 (AT1) blockade. The most potent compound containing pyrimidin-4(3H)-one ring, Fimasartan (1) was used to align the molecules. As a result, we obtained 3D-QSAR model which provided good predictivity for both the training set (q2 = 0.846, r2 = 0.975) and the external test set ( r pred 2 = 0.980 ) . This model would guide the design of backups for Fimasartan (1), a launched oral antihypertensive agent.

The in-vitro activity of 12 antibacterial agents against 98 clinical isolates of Streptococcus pneumoniae, including 54 penicillin-resistant strains, was determined by a standardized broth microdilution method. CFC-222, vancomycin and imipenem were the most active agents, with an MIC90 of 0.5 mg/L for the test strains. CFC-222 was 16-fold more potent than ciprofloxacin and ofloxacin against all strains tested, including both penicillin-susceptible and -resistant strains. The anti-pneumococcal activity of fluoroquinolones was not affected by penicillin susceptibility. These results indicate that CFC-222 is potentially useful for treating infection caused by penicillin-resistant strains of S. pneumoniae.

CFC-222 is a novel fluoroquinolone with potent and broad-spectrum antibacterial activity. The in-vitro and in-vivo activities of CFC-222 were compared with those of ciprofloxacin, ofloxacin, lomefloxacin and sparfloxacin. Against gram-positive bacteria such as Staphylococcus aureus (quinolone-susceptible and quinolone-resistant), Staphylococcus epidermidis, Streptococcus pneumoniae and Enterococcus faecalis, CFC-222 was more active than ciprofloxacin and similar to sparfloxacin. Against gram-negative bacteria, including Enterobacteriaceae, the in-vitro activity of CFC-222 was similar to that of sparfloxacin, but less than that of ciprofloxacin. However, it was less active than ciprofloxacin and sparfloxacin against Pseudomonas aeruginosa. In mouse systemic infection caused by S. aureus Smith or S. aureus TMS 33, CFC-222 demonstrated an activity similar to that of ciprofloxacin and sparfloxacin, but better than that of ofloxacin. The compound was more effective than ciprofloxacin and sparfloxacin in murine infection caused by Streptococcus pyogenes ATCC 8668. Against Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae infections, the efficacy of CFC-222 was similar to those of ciprofloxacin, ofloxacin and sparfloxacin. The activity of CFC-222 was similar to those of ciprofloxacin and sparfloxacin against P. aeruginosa MB4-16 in the same infection model. These results suggest that CFC-222 may be a promising therapeutic agent for the treatment of various bacterial infections.

The pharmacological profile of BR-A-657, 2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-one, a new nonpeptide AT1-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, BR-A-657 displaced [(125)I][Sar(1)-Ile(8)]angiotensin II (Ang II) from its specific binding sites to AT1 subtype receptors in membrane fractions of HEK-293 cells with an IC50 of 0.16 nM. In a functional assay using isolated rabbit thoracic aorta, BR-A-657 inhibited the contractile response to Ang II (pD'2: 9.15) with a significant reduction in the maximum. In conscious rats, BR-A-657 (0.01, 0.1, 1 mg/kg; intravenously (i.v.)) dose-dependently antagonized Ang II-induced pressor responses. In addition, BR-A-657 dose-dependently decreased mean arterial pressure in furosemide-treated rats and renal hypertensive rats. Moreover, BR-A-657 given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats.

Since inhibition of angiotensin II type 1 (AT1) receptor reduces chronic inflammation associated with hypertension, we evaluated the anti-inflammatory potential and the underlying mechanism of fimasartan, a Korean Food and Drug Administration approved anti-hypertension drug, in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Fimasartan suppressed the expressions of inducible nitric oxide synthase (iNOS) by down-regulating its transcription, and subsequently inhibited the productions of nitric oxide (NO). In addition, fimasartan attenuated LPS-induced transcriptional and DNA-binding activities of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). These reductions were accompanied by parallel reductions in the nuclear translocation of NF-κB and AP-1. Taken together, our data suggest that fimasartan down-regulates the expression of the iNOS in macrophages via NF-κB and AP-1 inactivation.

Fimasartan (Kanarb®), an angiotensin II receptor antagonist with selectivity for the AT1 receptor subtype, is a pyrimidinone-related heterocyclic compound that was developed by Boryung Pharm. Co., Ltd. Among numerous synthetic derivatives, fimasartan was chosen as a new drug candidate through in vitro and in vivo screening studies. Pharmadynamic-pharmacokinetic properties and safety profiles were determined in a series of nonclinical and clinical studies. Fimasartan is a new angiotensin receptor blocker, and the first new molecular entity acting on cardiovascular system approved by Korean Food and Drug Administration for the treatment of essential hypertension in September 2010. Further development process for combination therapy and overseas registration is currently ongoing.

CFC-222 is a novel fluoroquinolone containing a C-7 bicyclic amine moiety with potent antibacterial activities against gram-positive, gram-negative, and anaerobic organisms. We compared the in vitro and in vivo activities of CFC-222 with those of ciprofloxacin, ofloxacin, and lomefloxacin. CFC-222 was more active than the other fluoroquinolones tested against gram-positive bacteria. CFC-222 was particularly active against Streptococcus pneumoniae (MIC at which 90% of isolates are inhibited [MIC90], 0.2 microg/ml), Staphylococcus aureus (MIC90, 0.2 microg/ml for ciprofloxacin-susceptible strains), and Enterococcus faecalis (MIC90, 0.39 microg/ml). Against Escherichia coli and other members of the family Enterobacteriaceae, CFC-222 was slightly less active than ciprofloxacin (MIC90s for E. coli, 0.1 and 0.025 microg/ml, respectively). The in vitro activity of CFC-222 was not influenced by inoculum size, medium composition, or the presence of horse serum. However, its activity was decreased significantly by a change in the pH of the medium from 7.0 to 6.0, as was the case for the other quinolones tested. The in vivo protective efficacy of CFC-222 by oral administration was greater than those of the other quinolones tested in a mouse model of intraperitoneally inoculated systemic infection caused by S. aureus. CFC-222 exhibited efficacy comparable to that of ciprofloxacin in the same model of infection caused by gram-negative organisms, such as E. coli and Klebsiella pneumoniae. In this infection model, CFC-222 was slightly less active than ciprofloxacin against Pseudomonas aeruginosa. These results suggest that CFC-222 may be a promising therapeutic agent in various bacterial infections.

One hundred thirty-one strains of Streptococcus pneumoniae isolated from clinical specimens between January 1991 and April 1993 were serotyped and tested for susceptibility to 10 antimicrobials by the agar dilution method. Five serotypes (6A, 6B, 14, 19F, and 23F) accounted for 67% of all isolates. Seventy percent of isolates were not susceptible to penicillin, exhibiting either intermediate resistance (37%) or high-level resistance (33%); 82% of isolates from children and 59% of those from normally sterile body fluids were resistant to penicillin. A significantly increased rate of penicillin resistance (P < .01, Fisher's exact or chi 2 test) was associated with hospitalization, an age of < or = 15 years, ongoing antimicrobial therapy at the time of isolation of the organism, nosocomial acquisition, and several specific serotypes (6, 14, 19F, and 23F). No penicillin-resistant strain showed beta-lactamase activity. Various proportions of the penicillin-resistant strains also displayed resistance to cefaclor (89%), cefotaxime (82%), chloramphenicol (65%), erythromycin (52%), and ciprofloxacin (15%), but none was resistant to teicoplanin or vancomycin. The prevalence of pneumococcal resistance documented in Korea in this study is among the highest figures published to date.