非甾体抗炎药的肾毒性

肾毒性是传统抗炎药和特异性环氧合酶-2抑制剂最常见的不良反应,其发生率为3%～5%。肾毒性表现有末梢水肿、急性肾衰、间质性肾炎、肾病综合征及肾乳头坏死等,轻者停药可恢复,少数患者可致死。非甾体抗炎药所致肾毒性可见于肾功能正常者,及高危人群,如已有肾病变、心衰、肝病、服利尿剂或ACE抑制剂及老年患者。对接受非甾体抗炎药治疗的患者,在治疗前和治疗中都应密切监测尿常规和肾功能指标。     

Responses of neutrophils and lymphocytes in the cold stress: effects of nonsteroid anti-inflammatory drugs.

The cold stress induced in rabbits by lowering their body temperature by 3 degrees C resulted in neutrophilia and a decrease in number of phagocytes and phagocytized bacteria. The stress did not affect the number of lymphocytes and the ability of forming E rosettes by T lymphocytes, but depressed the formation of EAC rosettes by B lymphocytes. This inhibition of neutrophil activity was antagonized completely by acetylsalicylic acid, and substantially by mefenamic acid and indomethacin administered, in doses inhibiting pyrogen-induced fever, either 2.5 h before or 1.5 h after the hypothermia. The drugs did not antagonize the depression of the ability of formation of EAC rosettes.     

Inhibition of prostaglandin synthesis in vivo by nonsteroid anti-inflammatory drugs: evidence for the importance of pharmacokinetics.

A variety of acidic and non-acidic compounds are potent inhibitors of prostaglandin (PG) synthesis in vitro. However, only a few, namely the acidic nonsteroid anti-inflammatory drugs (NSAID) are useful anti-inflammatory analgesics in the clinic. Since inhibition of PG-synthesis is believed to be the main target of NSAID in inflammation this superiority of acidic compounds remains unexplained. We have considered that one explanation could be that only acidic NSAID appear in high concentrations in inflamed tissue to inhibit PG-synthesis sufficiently. To test this hypothesis the following experiments were carried out: (A) PG-synthesis and its inhibition by acidic and non-acidic NSAID was measured in vivo at the site of inflammation. It was found that in therapeutic doses only acidic NSAID were capable to reduce PG-synthesis significantly. (B) Measurement of drug concentration in inflamed tissue showed that only acidic NSAID were found in significantly higher concentrations in inflamed than in control tissue. From these observations it is concluded that a specific pharmacokinetic behaviour of acidic NSAID leading to high concentrations in inflamed tissue is a decisive aspect of their anti-inflammatory action.     

Relationships between biophasic disposition and pharmacokinetic behavior in nonsteroid antiinflammatory drugs

The time course of biophasic amounts of two nonsteroid antiinflammatory drugs (naproxen and oxyphenbutazone) after an intravenous dose of both drugs in rats (5 and 20 mg/kg, respectively) and their relationships with the drug amounts in central and peripheral compartments as defined through blood level data obtained after the same intravenous dose of the drug, are described. To assess the first point, the carrageenin-induced rat paw edema method is employed. Through previously established dose-response curves obtained after administration of different i.v. doses, the conversion of responses to biophasic amounts is achieved by means of the corresponding model equations. To calculate kinetic parameters through the fitting of the concentration-time data, a least-squares method based on the Marquardt algorithm is used on a computer. It can be concluded that the biophasic compartment cannot be identified as the "central" or the "peripheral" kinetic ones, being, however, the output biophasic rate constant not significantly different from the terminal disposition rate constant, beta or lambda 2.     

Gastrointestinal blood loss after non-steroidal anti-inflammatory drugs. Measurement by selective determination of faecal porphyrins.

1. A method for the detection of gastrointestinal blood loss based upon the selective measurement of faecal porphyrins was tested in two studies in healthy volunteers. 2. In the first study subjects (n = 6) received intragastric autologous blood (saline, 2 and 6 ml as a single dose) resulting in a dose dependent increase in faecal porphyrins. 3. In a subsequent placebo controlled cross over study in 12 subjects acetylsalicylic acid (ASA), nabumetone (a new NSAID) or placebo were administered for 5 days with a washout period of 9 days. They were no dietary restrictions. 4. All faeces were collected during the treatment period and both the full faecal homogenate and a random faecal sample were analyzed for deutero- and pemptoporphyrin content by h.p.l.c. Additionally a benzidine reaction was performed. 5. There was a highly significant correlation (r = 0.95) between the values obtained from random samples and the full homogenate. ASA increased the faecal porphyrin excretion (P less than 0.001) compared with placebo in contrast to nabumetone. Complaints of dyspepsia were most common after ASA. 6. Measurement of faecal porphyrins is useful for monitoring NSAID induced upper gastrointestinal blood loss and lacks some of the practical constraints of other methods.     

Pyrogenic immunomodulators increase the level of prostaglandin E2 in the blood simultaneously with the onset of fever

Blood prostaglandin E2 (PGE2) levels, estimated by radioimmunoassay, and body temperatures of conscious rabbits were measured simultaneously during fever in response to polyinosinic: polycytidylic acid, lipopolysaccharide and interleukin 1/endogenous pyrogen. The effects of the antipyretic agent ketoprofen on both parameters was also studied. Significant rises (in the order of 6- to 8-fold) in the PGE2 level were observed after injection of either of the three pyrogens and occurred simultaneously with the rise in temperature. Ketoprofen given after the onset of fever in response to the pyrogens produced an immediate defervescence and a simultaneous decrease in plasma PGE2. Ketoprofen given before the pyrogens prevented any rise in either body temperature or plasma PGE2 level. When animals were subjected to an environmental temperature of 34 degrees C a hyperthermia was observed without any change in the blood PGE2 level. These results suggest that an increase in the blood PGE2 level may contribute to the pathogenesis of fever.     

Protein binding of non-steroidal anti-inflammatory drugs in plasma and synovial fluid of arthritic patients

1 The protein binding of seven non-steroidal anti-inflammatory drugs (indomethacin, tolmetin, salicylic acid, ibuprofen, flurbiprofen, naproxen and GP53,633) and warfarin was investigated by equilibrium dialysis in simultaneous samples of synovial fluid and plasma from 12 arthritic patients. 2 The protein binding of all drugs studied except warfarin and flurbiprofen was significantly lower in synovial fluid than in plasma. 3 The decreased protein binding of these drugs is likely to explain the lower total drug concentrations found in synovial fluid in comparison to plasma. 4 The lower albumin concentration plays an important role in determination of reduced drug binding in synovial fluid compared to plasma and the fatty acid concentration in synovial fluid may also influence the protein binding of some of these drugs.