Diflunisal, a lipophilic salicylate, is absorbed more slowly in healthy volunteers than aspirin. In this paper we report on attempts to influence diflunisal absorption by buffering the gastric milieu. Sodium bicarbonate given together and 30 min after diflunisal tablets significantly (p less than 0.05) shortened the time to reach peak plasma concentration (tmax greater than 15 per cent), raised maximum plasma concentration slightly (Cmax 6 per cent) and increased the area under the plasma concentration-time curve (AUC greater than 8 per cent). Other pharmacokinetic parameters, including terminal half-life and renal elimination of the compound, were not considerably influenced. These findings indicate that the absorption of diflunisal was enhanced by increased gastric pH, presumably a result of an increased solubility of diflunisal in the stomach together with faster transport into the small intestine. In one volunteer, after intravenous administration diflunisal plasma concentrations declined in a triphasic manner with a terminal half-life of 12.8 h. The volume of distribution was approximately 10 per cent of body weight. Based on the ratio of AUC after equivalent i.v. and oral diflunisal doses, the absolute bioavailability was 89.5 per cent.

Adult↗

PubMedDate not supplied

[Ambulatory diagnosis and therapy of gonarthrosis].

AIM OF STUDY: To develop recommendations for appropriate diagnostic procedures and conservative treatment of knee osteoarthritis in outpatients. MATERIAL AND METHODS: Following a consensus conference and expert reviews basic recommendations were developed. RESULTS: While standardized radiographic assessment is mandatory, MRI investigation should be restricted to problems apart from osteoarthritis. Indications for physical therapy, bracing and pharmaco-treatment depend on the severity of the disease. Guidelines for intraarticular injections are presented. CONCLUSION: Effective treatment of knee osteoarthritis must be based on available recommendations and guidelines.

Ambulatory Care↗

PubMedDate not supplied

Pharmacokinetic and pharmacodynamic aspects of the ideal COX-2 inhibitor: a pharmacologist's perspective.

Two classes of antipyretic analgesics were developed about 100 years ago, namely the acidic aspirin-like drugs and non-acidic acetaminophen-phenazone-like compounds. Since then, research has aimed at improving the side-effect profile of the acidic anti-inflammatory aspirin-like drugs and improving the anti-inflammatory efficacy of the non-acidic acetaminophen-phenazone-like compounds. Both drug classes inhibit the cyclooxygenase (COX)-1 and -2 enzymes non-selectively. The aspirin-like drugs achieve particularly high concentrations in inflamed tissue, which is assumed to account for their superior anti-inflammatory potency. These acidic drugs also reach comparatively high concentrations in the stomach wall, kidney cortex and blood, resulting in the well-known side effects that occur with acidic compounds but not with acetaminophen and phenazone. Following the discovery of the two differentially distributed and regulated COXs, two non-acidic COX-2-selective compounds--celecoxib and rofecoxib--were introduced. They proved to be less toxic to the gastrointestinal tract compared with, for example, diclofenac or naproxen. These non-acidic drugs distribute homogeneously throughout the body--a cause for concern since COX-2 has been found to be present constitutively in many organ systems, including brain, bone and the genito-urinary tract. It appears desirable to combine the tissue-targeted distribution of the highly protein-bound acidic aspirin-type drugs with the selectivity of the COX-2 inhibitors, in order to achieve improved anti-inflammatory activity and at the same time reduce the risk of side effects. Such agents should be devoid of COX-1-related side effects in, for example, the inhibition of blood coagulation and should only weakly affect COX-2 related functions of the central nervous system, due to slow blood-brain barrier penetration. We therefore propose that a drug combining the pharmacokinetic characteristics of, for example, ibuprofen with the COX-2 selectivity of rofecoxib is likely to be a superior anti-inflammatory analgesic.

Analgesics, Non-Narcotic↗

PubMedDate not supplied

Diflunisal disposition. Role of gastric absorption in the development of mucosal damage and anti-inflammatory potency in rodents.

Aspirin shows a high incidence of gastric side effects. These are thought to result from both systemic and local effects during drug absorption. In contrast, a lipophilic derivative of salicylic acid, diflunisal, causes significantly fewer adverse gastric effects. This is thought to be due to a lack of gastric absorption. To test this hypothesis, three types of experiments were performed with diflunisal: 1. Transgastric permeation was quantified under different pH conditions, using an isolated mouse stomach model. 2. Ulcerogenic potencies of buffered and unbuffered drug solutions were determined in rats. 3. The time course of its anti-inflammatory effect and the serum concentrations of diflunisal, given alone and with neutralizing buffer, were measured in rats with carrageenan-induced paw edema. Corresponding to the low gastric ulcerogenicity, absorption of diflunisal in the isolated stomach preparations was very small. However, absorption was pH-dependent and ranged between 0.69 and 8.73% with a maximum at pH 4.5. Gastric lesions were found to be more evident 24 hr after drug administration than after 5 hr. Comparing buffered vs. unbuffered diflunisal preparations, no difference in ulcerogenicity was detectable. However, using a buffered preparation, the anti-inflammatory effect of diflunisal was enhanced significantly (p less than 0.01), and elevated serum concentrations were found (p less than 0.05). The results show that raising the solubility of diflunisal does not influence gastric absorption or gastric toxicity considerably. However, its serum concentrations and systemic anti-inflammatory effects were significantly enhanced.

Absorption↗

PubMedDate not supplied

Effects of sodium salicylate on elimination kinetics of indomethacin and bile production in dogs.

We investigated the effects of sodium salicylate on the elimination kinetics of indomethacin in bile duct-cannulated beagles. Indomethacin and metabolites were quantified by HPLC in plasma, bile, and urine. Indomethacin was administered as iv bolus injection and iv infusion to yield a steady-state plasma concentration of approximately 1 microgram/ml. Following sodium salicylate, given either iv (25 mg/kg) or via duodenal fistula (50 mg/kg), the indomethacin plasma level dropped instantaneously by 60-70%. Concomitantly, total systemic clearance from the plasma and biliary clearance were increased significantly. In addition, a reduced plasma protein binding of indomethacin and a significant increase in the volume of distribution were observed. The amount of indomethacin, excreted as free and conjugated drug in bile, was significantly increased temporarily by sodium salicylate. The total amount eliminated in bile (approximately 70% of the dose), however, was not changed by sodium salicylate co-administration. The bile flow was significantly enhanced for at least 4 hr. Both phase 1 metabolism and renal excretion of indomethacin remained practically unaffected by sodium salicylate treatment.

Animals↗

PubMedDate not supplied

[Pharmacologic characteristics as the basis for differential therapy using non-steroidal anti-inflammatory agents].

An attempt is made to compile the pharmacological data on the leading non-steroidal anti-inflammatory drugs. They concern the pharmacodynamics, the pharmacokinetics and the unwanted effects of these compounds. From these data a few suggestions for rational use are made: Ibuprofen and diclofenac present as drugs with short and reliable elimination-halflife. The compound with the lower potency namely ibuprofen appears particularly suitable for use in patients suffering from mild inflammatory pain of probably short duration (hours, days). Diclofenac being more potent should be used in more serious painful conditions, the variable bioavailability and the sometimes delayed absorption of diclofenac should be kept in mind if success is not achieved. Ketoprofen may have similar characteristics as diclofenac. The quality of the available data is however limited. Indomethacin and piroxicam are highly potent and reliable in onset; the bioavailability amounts to 100%. Both compounds may owe their effectiveness and reliability to substantial enterohepatic recirculation which may also be responsible for the reported somewhat higher incidence of GI-tract problems in connection with their use. They should hence be used in serious conditions going along with intensive, long-lasting inflammatory pain. Naproxen being less potent than the later two may fall into the same category.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMedDate not supplied

[An experimental model of the microsurgical cannulation of the thoracic duct in the rat].

Explore the source record for details and available documents.

Anesthesia, Inhalation↗

PubMedDate not supplied

Lymph distribution of different non-steroidal anti-inflammatory drugs assessed by microsurgical cannulation of the thoracic duct in rat.

The motility of lymphatic vessels is regulated by arachidonate metabolites and, therefore, can be altered by cyclo-oxygenase blockers such as non-steroidal anti-inflammatory drugs (NSAIDs). In order to investigate the lymphotropic properties of different NSAIDs, pharmacokinetics in plasma and lymph following intragastric administration of three model compounds, namely racemic ibuprofen, tenoxicam and nabumetone, were investigated in rats. Microsurgical cannulation of the thoracic duct allowed cumulative sampling of lymph fluid up to 48 hrs (n = 16). Pharmacokinetic parameters in plasma were determined in a control group (n = 12). Concentrations of R-, S-ibuprofen, tenoxicam, nabumetone and the metabolites OH-ibuprofen, COOH-ibuprofen and 6-methoxy-2-naphthyl-acetic acid (6MNA, metabolite of nabumetone) were monitored in lymph and plasma by HPLC. To quantify the lymphotropic properties of the investigated compounds, a "lymphatic clearance" was defined by dividing the amount recovered in lymph fluid by the corresponding area under the plasma concentration-time curve (AUCP). The "lymphatic clearance" substantially differed between the investigated compounds (mean +/- SD: R-ibuprofen 6.71 +/- 3.15 microliters/min, S-ibuprofen 3.24 +/- 1.20 microliters/min, tenoxicam 8.74 +/- 8.11 microliters/min, nabumetone 46.05 +/- 26.08 microliters/min and 6MNA 6.32 +/- 2.96 microliters/min). The overall recovery of the investigated compounds in lymph did not exceed 5% of the doses given. The known fact that lymphatic drainage is regulated by arachidonate metabolites might suggest that NSAIDs differing in their lymphotropic properties could result in different responses of lymphatic vessels to an inflammatory fluid load.

Animals↗