Drugs under experimental and clinical research最新文献

Stimulation of macrophages by lipopolysaccharide (LPS) leads to the synthesis of proinflammatory cytokines and nitric oxide (NO) and, as a consequence, to endotoxic shock. We provide evidence that LPS stimulates the activity of a membrane-associated neutral sphingomyelinase (nSMase) and that this activity is mandatory for the liberation of nuclear factor-kappa B (NF kappa B) and the induction of inducible NO-synthase (iNOS). With the aid of a newly developed, selective inhibitor of nSMase, C11AG, we could distinguish between nSMase-dependent and -independent LPS-induced signals. C11AG blocked LPS-stimulated sphingomyelin degradation and NF kappa B activation without interfering with p42 tyrosine phosphorylation. Concomitantly, the expression of iNOS was found to be reduced both in mononuclear cells and in murine endotoxemia. Therefore, specific inhibitors of nSMase may define a new class of antiinflammatory substances.

At present, the most effective drugs in treating hypercholesterolemia and atherosclerosis are the statins, which are potent inhibitors of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Serum triacylglycerol (TAG) levels associate positively with the risk for coronary heart disease (CHD). Triacylglycerols are mainly hydrolyzed by the enzyme lipase (glycerol ester hydrolase [GEH], EC 3.1.1.3) but can also be transformed by transacylation with cholesterol (glycerol ester:cholesterol acyltransferase [GECAT], EC 2.3.1.43). We evaluated the effect of a 3-month treatment with simvastatin (10 mg/day) on GEH and GECAT activity in the serum of 26 outpatients with CHD. The activity of both GEH and GECAT was reduced in the CHD group compared with that in the control group: 5.9 +/- 0.9 mU/mg vs. 7.5 +/- 1.8 mU/mg and 11.1 +/- 1.4 mU/mg vs. 19.3 +/- 3.3 mU/mg, respectively (p < or = 0.05). In addition to the well known effect of reducing total cholesterol and low-density lipoprotein cholesterol in patients with CHD, we observed two other results of simvastatin treatment. First, GEH activity increased to values similar to those found in healthy subjects and, simultaneously, GECAT activity decreased. Trioleylglycerol transacylation with cholesterol amounted to 72% and hydrolysis to 28% in the control group and to 65% and 35% in the CHD group, respectively. After simvastatin treatment, transacylation with cholesterol and hydrolysis amounted to 51% and 49%, respectively. In conclusion, by increasing GEH and reducing GECAT, simvastatin seems not only to affect cholesterol synthesis but also to alter triacylglycerol metabolism. Further studies are needed to determine the physiological significance of these changes and their relationship with the development of atherosclerosis.

The Japanese herbal medicine Hochu-ekki-to (Chinese name: Bu-Zhong-Yi-Qi-tang) is composed of ten species of medical plants and is used for many therapeutic purposes such as recovery from weakness, dysfunction of the digestive system and fatigue. In certain groups of patients with intractable atopic dermatitis this prescription has shown clinical effectiveness. We examined the ability of Hochu-ekki-to to inhibit dermatitis and IgE production in atopic NC/Nga mice. Oral administration of Hochu-ekki-to suppressed spontaneous dermatitis and serum IgE levels in NC/Nga mice. This finding provides evidence that Hochu-ekki-to may have immunological effects in atopic dermatitis.

A 12-week double-blind randomized study was performed to compare benzoyl peroxide 5% (BP) gel and chloroxylenol 0.5% plus salicylic acid 2% (PCMX + SA) cream (Nisal cream) for efficacy and adverse reactions. Thirty-seven volunteers participated in the study, 19 in the BP group and 18 in the PCMX + SA group. The patients applied the medication twice daily to the entire face. Clinical evaluation and lesion counts were obtained at 0, 3, 6, 9 and 12 weeks. At week 12 both groups showed a marked improvement in both inflammatory and noninflammatory lesions (60% and 54% for the BP group and 62% and 56% for and 56% for the PCMX + SA group, respectively). Although PCMX + SA showed a slightly stronger keratolytic effect throughout the study period, there was no statistically significant difference in the reduction of the papulopustules or comedones between the two groups. Adverse effects such as erythema and photosensitivity were significantly fewer in the PCMX + SA group at week 12 (p = 0.0002 and p = 0.05, respectively). These results suggest that PCMX + SA cream is as effective as BP gel in the treatment of papulopustular and comedonal acne and that it is better tolerated.

The aim of this study was to investigate the risk factors for adverse drug reactions (ADRs) to nimesulide in patients from Shanghai with osteoarthropathy. A retrospective epidemiological study was performed to obtain information (observational variables) on demographics, primary disease, family history of disease, quality of life, dietary habits, lifestyle, use of nonsteroidal anti-inflammatory drugs (NSAIDs) and ADR history of NSAIDs. Univariate and multivariate analyses were performed to establish the relationship between these observational variables and the occurrence of ADRs caused by nimesulide. Among the 726 variables, five risk factors for ADRs to nimesulide were identified. The study showed an increased risk for ADR occurrence with increased scoring of the following four factors: (i) "Concomitant drug therapy" (odds ratio [OR]: 4.66, 95% confidence intervals [CI]: 1.26-17.26, p < 0.05); (ii) "Compared with six months ago, how would you rate your health in general now?" (OR: 1.38, 95% CI: 1.03-1.84, p < 0.05); (iii) "General feeling of health status" (OR: 1.27, 95% CI: 1.03-1.56, p < 0.05) and (iv) "1 expect my health to get worse" (OR: 2.05, 95% CI: 1.22-3.44, p < 0.01). There was a decreased risk for ADR occurrence with increased scoring of the factor "Have you ever suffered from depression that impacted on your life?" (OR: 0.15, 95% CI: 0.03-0.66, p < 0.05). The predictive model for the overall incidence rate of ADRs caused by nimesulide was then established. In conclusion, the predictive model helps to indicate the risk of ADRs to nimesulide and provides clinicians with an alternative method for decision making when prescribing this drug.

Anaerobes isolated from skin specimens from 1999 to 2001 were examined. The most common type was Peptostreptococcus spp., especially P. magnus and P. assaccharolyticus and Bacteroides fragilis. Dominance was seen for P. magnus, P. acnes and P. prevotii. Peptostreptococcus spp. and P. acnes showed high susceptibility to four antimicrobial agents. Prevotella spp. and B. fragilis showed low or no susceptibility to ampicillin, while B. fragilis showed low susceptibility to ceftizoxime. Evaluation of anaerobes is important for the balance of skin flora as well as for the choice of antimicrobial agents, when the anaerobes are pathogenic.

In recent years many studies have focused on the well-known relationship between wine consumption and cardiovascular risk. Wine exerts its protective effects through various changes in lipoprotein profile, coagulation and fibrinolytic cascades, platelet aggregation, oxidative mechanisms and endothelial function. The last has earned more attention for its implications in atherogenesis. Endothelium regulates vascular tone by a delicate balancing among vasorelaxing (nitric oxide [NO]) and vasoconstrincting (endothelins) factors produced by endothelium in response to various stimuli. In rat models, wine and other grape derivatives exerted an endothelium-dependent vasorelaxing capacity especially associated with the NO-stimulating activity of their polyphenol components. In experimental conditions, reservatrol (a stilbene polyphenol) protected hearts and kidneys from ischemia-reperfusion injury through antioxidant activity and upregulation of NO production. Wine polyphenols are also able to induce the expression of genes involved in the NO pathway within the arterial wall. The effects of wine on endothelial function in humans are not yet clearly understood. A favorable action of red wine or dealcoholized wine extract or purple grape juice on endothelial function has been observed by several authors, but discrimination between ethanol and polyphenol effects is controversial. It is, however likely that regular and prolonged moderate wine drinking positively affects endothelial function. The beneficial effects of wine on cardiovascular health are greater if wine is associated with a healthy diet. The most recent nutritional and epidemiologic studies show that the ideal diet closely resembles the Mediterranean diet.

The antimicrobial activities of tobramycin and chloramphenicol were evaluated by determining minimum inhibitory and bactericidal concentrations against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, group A, group B and group G streptococci, Klebsiella spp., Stenotrophomonas maltophilia and ciprofloxacin-resistant and -susceptible Pseudomonas aeruginosa, as well as by evaluating interference on adhesion of slime producer strains of S. aureus and P. aeruginosa to intraocular lens from tobramycin and chloramphenicol pharmaceutical products by scanning electron microscopy. Chloramphenicol was more active against Gram-positive bacteria than was tobramycin, which instead showed higher activity against ciprofloxacin-susceptible P. aeruginosa. Treatment of lenses with the antimicrobial products eradicated the bacterial biofilm, which was already notably reduced after 5 min. This activity was more pronounced for chloramphenicol against S. aureus and for tobramycin against P. aeruginosa. Bacterial adhesion was also significantly reduced when lenses colonized by P. aeruginosa were treated with chloramphenicol, even if they were resistant to this drug. In conclusion, the tested drugs showed marked antibacterial activity, particularly by interfering with bacterial biofilms. The data obtained in this study suggest a specific use of chloramphenicol in topical prophylaxis aimed at avoiding bacterial contaminations. However, further specific in vivo studies are needed to confirm these data.

Impaired endothelial cell (EC) growth and function have been suggested to be an initial event that leads to the development of atherosclerosis. We have very recently found that nifedipine, one of the most popularly used dihydropyridine-based calcium antagonists, prevented EC monocyte chemoattractant protein-1 production elicited by tumor necrosis factor-alpha (TNF-alpha through its antioxidative properties. However, the effects of nifedipine on EC growth and apoptosis are not fully understood. In this study, we investigated whether nifedipine could inhibit tumor necrosis factor (TNF)-alpha-induced growth retardation and apoptotic cell death in human umbilical vein ECs (HUVECs). TNF-alpha inhibited EC proliferation, which was significantly blocked by nifedipine or antioxidant N-acetylcysteine (NAC). Nifedipine or NAC was also found to significantly inhibit apoptotic cell death of TNF-alpha-exposed HUVECs. Our present study suggests that nifedipine may play a protective role against the development and progression of atherosclerosis by promoting EC repair through its antioxidative properties.

We examined Propionibacterium acnes lipase in skin diseases and Unsei-in. Butyric acid production in axillary seborrheic dermatitis (ASD) was higher than in other dermatitis, and that in acne vulgaris (AV) was significantly higher than in controls. P. acnes lipase is the pathogenic factor in AV and fatty acids produced by lipase might be the pathogenic factor in ASD. Unsei-in suppressed P. acnes lipase probably because some ingredients have antimicrobial and anti-inflammatory activities.