Drugs online research references
J Clin Invest. 1995 Apr;95(4):1756-65.
Prevention of in vitro neutrophil-endothelial attachment through shedding of L-selectin by nonsteroidal antiinflammatory drugs.
Diaz-Gonzalez F, Gonzalez-Alvaro I, Campanero MR, Mollinedo F, del Pozo MA, Munoz C, Pivel JP, Sanchez-Madrid F.
Section of Rheumatology, Hospital de la Princesa, Universidad Autonoma de Madrid, Spain.
The activation of the endothelial cells by extravascular stimuli is the key event in the extravasation of circulating leukocytes to target tissues. L-selectin, a member of the selectin family, is constitutively expressed by white cells, and is the molecule involved in the initial binding of leukocytes to activated endothelium. After activation, leukocytes rapidly release L-selectin from the cell surface, suggesting that the functional activity of this molecule is controlled in large part by its appearance and disappearance from cell surface. We have studied in a neutrophil-activated endothelial cell binding assay, the effect of different antiinflammatory drugs (steroidal and nonsteroidal) in the L-selectin-mediated interaction of neutrophils with activated endothelial cells. Some nonsteroidal antiinflammatory drugs (NSAIDs), such as indomethacin, diclofenac, ketoprofen, and aspirin, but not steroids, strongly inhibited the neutrophil-endothelial cell attachment. Furthermore, we also investigated the underlying mechanism of this functional effect. The expression of L-selectin on the neutrophil surface rapidly decreased in the presence of different NSAIDs, in a dose- and time-dependent manner, whereas no changes in the expression of other adhesion molecules such as CD11a, CD11b, CD31, or ICAM-3 (CD50) were observed. Interestingly, studies in vivo on healthy volunteers treated with physiological doses of indomethacin showed a significant decrease of L-selectin neutrophil expression. Only diclofenac induced an upregulation of CD11b expression, suggesting an activating effect on neutrophils. No enzyme release was observed upon treatment of neutrophils with different NSAIDs, indicating a lack of degranulatory activity of NSAIDs, with the exception of diclofenac. The downregulation of L-selectin expression was due to the rapid cleavage and shedding of the membrane L-selectin, as determined by both immunoprecipitation from 125I-labeled neutrophils, and quantitative estimation in cell-free supernatants. These results suggest that NSAIDs exert a specific action on adhesion receptor expression in neutrophils, which might account, at least in part, for the antiinflammatory activities of NSAIDs.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7535797&dopt=Abstract
Drug Des Deliv. 1989 Jun;4(4):303-11.
The pharmacokinetics of a new sustained-release form of diclofenac sodium in humans.
Mascher H.
Pharm-Analyt Labor Gmbh, Traiskirchen, Austria.
In the present study, two sustained release diclofenac preparations were administered every 12 hours over 4 days to ten human volunteers. Diurnal profiles were recorded on the 1st and 4th days, from which pharmacokinetic parameters were calculated: particular attention was given to cumulation. One, a newly developed sustained release formulation, had a MRT of 5.5 hours, and showed surprisingly small variation coefficients [AUC ss (72-84 hrs) +/- 26%; Cmax ss (72-84 hrs) +/- 19%] after 7 administered doses; accordingly, the maximum concentrations were within a very narrow time window [tmax ss (72-84 hrs) range: 1.5-2.5 hours after administration]. Due to the selected release profiles with this formulation, there was no danger of cumulation in spite of administration every 12 hours [AUC 0-12 hrs, mean value = 1555 ng/ml x h; AUC ss 72-84 hrs, mean value = 1750 ng/ml x h].
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2775450&dopt=Abstract
Nippon Yakurigaku Zasshi. 1979 Nov;75(8):829-36.
[Irritative activity of a new anti-inflammatory agent 4-(p-chorophenyl)-2-phenyl-5-thiazoleacetic acid (CH-800) on the gastrointestinal tract in rats (author's transl)]
[Article in Japanese]
Tabata K, Ohtsuki H, Okabe S.
A single oral administration of CH-800 induced a dose-dependent irritation of the stomach and intestine. As determined from the UD50 value (the dose inducing ulceration by 50%), the potency of gastric irritation was as follows; indomethacin greater than diclofenac Na greater than ibuprofen greater than aspirin greater than CH-800 greater than phenylbutazone. Repeated administrations of CH-800 for 5 days induced a gastric irritation when given in doses from 3 to 100 mg/kg, however, the response was not dose-related. In contrast, the irritation of intestinal mucosa seen with CH-800 administration was dose-related. The degree of gastric or intestinal irritation seen with dosing of other drugs was as follows; indomethacin greater than diclofenac Na greater than ibuprofen greater than aspirin greater than phenylbutazone or indomethacin greater than CH-800 = diclofenac Na greater than ibuprofen greater than phenylbutazone, respectively. CH-800 given for 5 days significantly delayed the healing of active ulcers and the healed ulcers showed a tendency toward re-ulceration. However, the irritating activity of phenylbutazone, diclofenac Na and ibuprofen was more potent than that of CH-800. Thus, CH-800 appears to have a rather weak irritative activity on the gastrointestinal tract of rats without ulceration, in contrast to other commonly clinically prescribed drugs.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=544397&dopt=Abstract
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