Comparative absorption of atropine from a metered-dose inhaler and an intramuscular injection.

The inhalation of atropine sulfate from a pressurized metered-dose inhaler was investigated in a nonrandomized four-period rising-dose study. Eight healthy, nonsmoking subjects received 1.7, 3.4, and 5.2 mg of atropine sulfate by inhalation and 1.67 mg of atropine free base (equivalent to 2 mg of atropine sulfate) by intramuscular (i.m.) injection. Serum atropine sulfate concentrations were measured over a 24-h period by gas chromatography/mass spectrometry. Mean serum concentrations increased nonproportionally as the inhaled dose increased. Mean peak concentrations were 4.9, 6.1, and 7.9 ng/ml for the inhaled doses and 8.4 ng/ml for the i.m. dose. Typical anticholinergic effects were seen after all doses.

Effect of food on salsalate absorption.

To assess the effect of food on salsalate absorption, single 1500-mg oral doses of salsalate were administered to 17 men under fasted and fed conditions according to a randomized open-label crossover design. A 7-day washout separated treatment periods. Blood samples were drawn throughout the 48-h period following dose administration and the resulting plasma samples assayed by high-performance liquid chromatography (HPLC) for unchanged drug, salsalate, and the major metabolite, salicylic acid. When results for the fasted and fed treatments were compared, no significant differences were observed in the pharmacokinetic parameters for the major metabolite salicylic acid or in the extent of absorption of unchanged drug; however, the rate of salsalate absorption was affected. Although the time-to-peak for salsalate was significantly delayed by approximately 1 h in the presence of food, the peak level was not significantly affected. The lack of difference between the two treatments for the therapeutic moiety, salicylic acid, indicates a lack of a significant food effect on single doses of salsalate.

Salsalate cross-sensitivity in aspirin-sensitive patients with asthma.

Ten aspirin (ASA)-sensitive patients with asthma underwent double-blind, placebo-controlled oral challenges with salsalate followed by ASA-sensitive confirmatory challenges. All 10 patients sustained asthmatic reactions to ASA, but only two developed respiratory reactions to 2 gm of salsalate. In these two patients, repeat confirmatory challenges with 2 gm of salsalate reproduced the same asthmatic reactions. Both patients were desensitized to ASA, and cross-desensitization with 2 gm of salsalate was then achieved. We conclude that salsalate, a weak inhibitor of cyclooxygenase in vitro, is less likely than ASA to induce asthma in known ASA-sensitive patients with asthma but may occasionally cross-react in these patients. Such reactions were mild and easily treated with beta 2-agonists.

Comparative absorption of inhaled and intramuscularly administered atropine.

The inhalation of atropine sulfate was investigated in a randomized, 4-period, rising-dose study. Atropine sulfate 2, 4, and 6 mg by inhalation, and atropine free base 1.67 mg (equivalent to 2.0 mg atropine sulfate) by intramuscular (IM) injection were given to 8 healthy, nonsmoking subjects. Serum atropine sulfate concentrations were monitored during an 8-h period by radioimmunoassay. Mean serum concentrations and area under the serum concentration-versus-time curves (AUC) increased as the inhaled dose increased. Peak concentrations (mean +/- SD) were 11.5 +/- 3.4, 16.4 +/- 6.2, and 18.0 +/- 3.1 ng/ml for the 2, 4, and 6 mg doses, and 11.7 +/- 2.5 ng/ml for the IM dose. The time to peak concentration for each dose was similar (mean, 0.8 to 1.9 h). The AUC ratio of the 2-mg inhaled and IM doses was 1.11 +/- 0.41. The observed bronchodilating, anticholinergic, and other pharmacologic effects were seen after all dose concentrations and were typical of atropine. This study showed that inhalation is an efficient way to administer atropine sulfate for systemic use.

Salsalate kinetics in patients with chronic renal failure undergoing hemodialysis.

A 1500 mg dose of salsalate (SSA) was given to five patients undergoing chronic hemodialysis on an interdialytic day and again before dialysis. Compared with control subjects, patients undergoing dialysis had a lower peak plasma SSA level (17 +/- 3 vs. 45 +/- 2 micrograms/ml; P less than 0.01) that occurred slightly later. In contrast, plasma salicylic acid (SA), the active SSA metabolite, had a similar but later peak level that remained substantially higher. Therefore, the AUC for SA was increased by 50% and the SA t1/2 was prolonged in the patients receiving dialysis (8.1 +/- 0.7 vs 3.8 +/- 0.2 hours; P less than 0.01). During a single treatment, dialysis clearance reduced plasma SA levels, removed 18% of total body SA, and returned the SA t1/2 to nearly normal. Because the elimination of SA is impaired in patients undergoing dialysis, the interdialytic SSA dosage should be reduced. Hemodialysis improves SA kinetics and may be followed by a normal SSA replacement dose. However, periodic monitoring of plasma SA levels is recommended when SSA dosing is begun in patients receiving dialysis.

Comparison of anti-inflammatory compounds in the carrageenan induced paw edema model and the reversed passive Arthus model utilizing the same animal.

In order to better define antiinflammatory activity in new agents, a test was devised utilizing both carrageenan induced paw edema and the reversed passive Arthus reaction in the same animal. The model of carrageenan induced rat paw edema is a standard laboratory assay used to predict classical "aspirin-like" antiinflammatory molecules. The reversed passive cutaneous Arthus reaction involves precipitating antigen-antibody complexes, complement and infiltrating polymorphonuclear leukocytes (PMN's) and can be used to identify agents that affect one or more of these factors specifically. Antiinflammatory compounds were given orally one hour prior to the administration of carrageenan and goat anti-rat serum. Comparisons were made between several non-steroidal compounds and the steroid hydrocortisone. All of the compounds tested gave good carrageenan activity, but only hydrocortisone produced significant Arthus lesion inhibition in this assay.

Effects of salsalate (nonacetylated salicylate) and aspirin on serum prostaglandins in humans.

Prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and salicylic acid were measured in blood samples from 10 healthy men after administration of antiinflammatory doses of aspirin (3.9 g/day) or salsalate (3.0 g/day). Each medication was given for 3 days, followed by an observation period of 13 days. Plasma salicylate concentrations were slightly, but generally insignificantly, higher during aspirin dosing, although both drugs produced salicylic acid levels in the antiinflammatory range. Serum levels of PGE2 and TXB2, which reflected synthesis of cyclo-oxygenase products by platelets, were minimally affected by salsalate but profoundly suppressed by aspirin. When medication was discontinued, the effects of salsalate on serum PGE2 and TXB2 were readily reversible within 36 h, whereas the recovery from aspirin was still incomplete after 13 days of observation. These results indicate that the two orally administered salicylates have differential effects on prostaglandin synthesis in platelets and may also differ in their therapeutic and adverse effects.

Salicylic acid plasma levels following multiple doses of Norgesic Forte and aspirin.

Plasma salicyclic acid levels from the recommended multiple dose regimen of Norgesic Forte (orphenadrine citrate, aspirin, and caffeine) were compared to those from an equivalent multiple dose regimen of aspirin alone in 24 volunteers. The drugs were administered double-blind so that side effects could also be compared. No statistically significant differences were found between Norgesic Forte and aspirin in peak or trough levels, time to peak level, area under the curve, or mean steady-state level of salicylic acid. Mean steady-state levels averaged 154 +/- 46 (+/- SD) and 152 +/- 49 micrograms/ml on days 5 and 10 following Norgesic Forte versus 161 +/- 49 and 154 +/- 47 micrograms/ml following aspirin. Thus, the aspirin in Norgesic Forte provides an anti-inflammatory amount of salicylic acid equivalent to that of plain aspirin. There was no evidence that the combination of orphenadrine citrate, caffeine, and aspirin in Norgesic Forte caused increased or unusual side effects compared with aspirin alone.

Chronic immune synovitis in rabbits. II. Modulation by anti-inflammatory and anti-rheumatic agents.

Synovitis was induced in rabbits sensitized to bovine serum albumin (BSA) by a modification of the method of Dumonde and Glynn. Agents were administered starting on the day of initial BSA joint challenge and every weekday (14-17 doses) for 17 to 21 day periods. Synovial tissues were then excised and evaluated either (1) histologically for inflammatory cell infiltration, or (2) both histologically and for total IgG, anti-BSA, and beta-glucuronidase levels in homogenates of portions of the same tissues. By the intraperitoneal and oral routes, methylprednisolone (1 mg/kg/day), azathioprine (25-40 mg/kg/day) and cyclophosphamide (10 mg/kg/day) produced significantly decreases of 40-100% in some or all of the parameters measured. Non-steroidal anti-inflammatory drugs, including phenylbutazone, ibuprofen and acetylsalicylic acid at oral doses of 75 or 100 mg/kg/day, were ineffective as were colchicine at 1 mg/kg/day and indomethacin at 5 mg/kg/day. Thus, as we have measured it, this model of rheumatoid arthritis is not affected by those agents considered to be of limited effectiveness in this chronic disease, but is ameliorated by corticoids and some slow acting agents.

Chronic immune synovitis in rabbits. I. Immunoglobulin and beta-glucuronidase analyses of synovial tissues and joint exudates.

Immunoglobulin and beta-glucuronidase levels in joint exudates and homogenates of synovial tissues were measured during the course of bovine serum albumin (BSA) antigen-induced synovitis in rabbits. After intra-articular BSA challenge, the anti BSA hemagglutinating antibody in tissue homogenates increased with time up to 14 days. Results obtained indicated relatively greater increases in specific anti-BSA activity compared with total IgG and are compatible with in vivo antibody synthesis by inflamed synovial tissue. beta-Glucuronidase was measured as a reflection of phagocytic cell activity. Tissue enzyme levels increased to a maximum at 1 day and this level persisted up to at least 7 days, despite the fact that exudate enzyme levels reached a maximum at 1 day and then declined significantly over the next 2-3 weeks. These observations reinforce the view that inflamed synovial tissue possesses a substantial potential for perpetuating joint destruction by producing increased levels of inflammatory mediators.

Rabbit synovial tissue in culture: influence of the inflammatory state in vivo on the secretion of collagenase.

Primary rabbit adherent synovial cell monolayer cultures were prepared from animals with antigen-induced synovitis. Primary cultures derived from chronically inflamed tissues released elevated levels of collagenase into the culture media compared to cultures derived from either normal or acute inflammatory tissues. No active of latent collagenase activity was detected in media of cultures derived from normal tissues grown under identical conditions. Cultures of acute inflammatory tissues secreted 1/4 to 1/10 the amount of collagenase when compared to cultures from chronically inflamed tissues. Collagenase secreted by cultures from inflammatory tissues was detected only in latent form. Fetal bovine serum enhanced the trypsin activation of latent collagenase produced by these cultures.

Immune synovitis in rabbits. Effects of differing schedules for intra-articular challenge with antigen.

The effects of varying intra-articular (ia) doses of bovine serum albumin (BSA) antigen on immune synovitis in rabbits have been investigated. Chronic synovitis, characterized by mononuclear cell infiltration in synovial tissues, was induced by a single ia challenge with BSA in sensitized rabbits. However, cartilage and bone erosions and pannus formation were rarely observed. By varying the number and magnitude of the BSA challenges, lesions with different characteristics were observed at different times of analysis of joint pathology. In 3- to 10-week studies, multiple ia challenges with BSA produced lesions characterized by severe cartilage and bone changes; polymorphonuclear leukocyte (PMN) exudates; and mononuclear cells and, sometimes, PMNs in synovial tissues. Substantial increases in knee widths and synovial tissue weights also observed. By increasing the frequency of ia injections, more severe changes were produced more rapidly, so that within a 3-week period, the animals also experienced pain and were unable to fully extend their antigen-challenged knees. Some of the lesions observed in immune synovis resembled those in rheumatoid arthritis (RA). However, the presence of large numbers of PMNs in synovial tissue under certain conditions suggests some possible differences between the pathogenesis of experimental synovitis and RA.

Effects of antiinflammatory agents on the acute response of immune synovitis in rabbits.

Immune synovitis in rabbits was investigated as a potential in vivo model for evaluating new antiinflammatory agents. Antigen-induced increases in knee width as well as beta-glucuronidase and acid phosphatase activities in exudates were observed. Histologically, polymorphonuclear leukocytes appeared within hours in synovial tissues and reached maximum infiltration at about 24 hours. Subsequently, mononuclear cells, including plasma cells, appeared. The 6-hour Arthus-like phase of synovitis can be depressed by some antiinflammatory agents, colchicine and steroids being particularly effective. It is suggested that this model can be utilized to define potentially more effective antiinflammatory drugs.

Evaluation of topical anti-inflammatory steroid formulations in an Arthus model of inflammation.

Formulations of a number of steroids were evaluated after topical application in a reversed passive Arthus test (RPA) in rabbits. Four 21-chlorosteroids in the same cream base were investigated. The preparations of SQ 18,566 (halcinonide) and SQ 20,811 showed anti-edema activity, but those of SQ 15,361 and SQ 20,589 were less active. Ointment formulations of halcinonide also reduced edema in the RPA. These results, coupled with previously reported clinical data, suggest that the RPA might be utilized to distinguish good from poor formulations of anti-inflammatory steroids prior to screening tests or clinical trials in humans.

Use of the reversed passive Arthus reaction as a test for anti-inflammatory agents.

The immune complex-induced reversed passive Arthus (RPA) reaction in the rabbit has been investigated as a screening test for detecting anti-inflammatory agents potentially more effective in the treatment of rheumatoid arthritis than those presently available. RPA lesions, characterized by edema, erythema, and hemorrhage, were elicited by intravenous injections of bovine serum albumin (BSA) followed by intradermal injections of rabbit anti-BSA antiserum. The anti-edema activities of compounds (mg quantities required for testing) were evaluated after their administration by the intradermal route (compounds admixed with antiserum) as well as by the intraperitoneal route. Of 14 reference anti-inflammatory agents tested by the intradermal screening procedure, only aurothioglucose and chloroquine were inactive. Other pharmacologically active compounds (e.g. antihistamines, anti-complement agents, cytotoxic-immunosuppressives) were also evaluated after their intradermal administration. Protoporphyrin, phloretin, and hexadimethrine bromide (Polybrene) were active. When whole antiserum, or the antibody fraction of the serum, was used to eliminate nonspecific edema, intraperitoneally administered reference agents were found to be effective in the RPA test.