Edward H. Wiseman

Anti-inflammatory drugs and renal papillary necrosis

The literature on renal papillary necrosis (RPN) associated with the administration of non-steroidal antiinflammatory drugs (NSAID) to rats and man, is reviewed. RPN is almost universally reported after long term administration of NSAID to rats, reports being cited for an indomethacin analog, phenylbutazone, fenamic acids, fenoprofen and sudoxicam. Aspirin will also induce RPN in rats, and is probably the cause of the ‘analgesic nephropathy’ linked to abuse of aspirin/phenacetin combinations in man. RPN is reported at autopsy in human arthritics, but whether this is a facet of the disease, or of long term salicylate ingestion, is not clear. NSAID are rarely implicated in RPN in humans.

A comparison of the carrageenan edema test and ultraviolet light-induced erythema test as predictors of the clinical dose in rheumatoid arthritis.

Twelve non-steroidal anti-inflammatory agents (NSAIs) and one steroidal anti-inflammatory agent, dexamethasone, were examined in the carrageenan edema test (CET) in the rat and in the ultraviolet light-induced erythema test (UVE) in the guinea pig to evaluate the correlation between those models of inflammation and the clinical dose of the NSAIs in the treatment of rheumatoid arthritis. The regression of the logarithm of the clinical dose with the logarithm of the ED50 for UVE gave a slope of 0.54 implying a non-parallelism of assays and a difference in mechanism. Dexamethasone failed to inhibit the UVE thereby corroborating this point. The parallelism of the logarithm of the clinical dose with the logarithm of the ED50 for the CET was substantially better (slope=0.86). Dexamethasone was active in CET and its dose would be predicted by the CET regression. When only one variable was used for a prediction, log(CET) was a better predictor of log (clinical dose) than log(UVE). Standard methods for best regression selection indicated that even when both predictor variables were considered, log(CET) alone gave the best regression equation for predicting clinical dose. The view that inhibition of prostaglandin biosynthesis is the primary anti-inflammatory mechanism of NSAIs in rheumatoid arthritis is discussed in terms of these findings.

Anti-inflammatory and pharmacokinetic properties of sudoxicam N-(2-thiazolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

Abstract Sudoxicam has demonstrated potent anti-inflammatory and antipyretic activity in several laboratory animal models of inflammation, in the range 0·5–3 times that of indomethacin. The plasma half-life ranged between 8 hr (monkey), 13 hr (rat), 60 hr (dog) and 24–96 hr (man). Sudoxicam, combining the high potency of indomethacin with the extended plasma half-life of phenylbutazone, has been well tolerated by animals and man, and evaluation in human inflammatory diseases is proceeding.

The distribution, excretion and metabolism of benzquinamide

Abstract Benzquinamide, a new benzoquinolizine psychotherapeutic agent, is rapidly absorbed after oral administration to man, dog, and rat. The drug is rapidly distributed throughout the tissues of experimental animals, but in spite of its high lipid:water partition ratio, it is not concentrated in adipose tissue. In the dog, benzquinamide is removed from plasma with a half-life of 30–40 min, chiefly by metabolism in the liver and, to a minor extent (2%–10%), by renal excretion. The principal metabolic reaction in the dog and man is N-dealkylation, the major urinary metabolite being N-deethylbenzquinamide (VI). Ten other metabolites, products of N-dealkylation, O-demethylation and, to a much lesser extent, deacetylation, have been identified. The metabolites are excreted, both in the urine and in the bile, from which the more polar metabolites are not reabsorbed and are excreted in the feces.

Interaction of sudoxicam and aspirin in animals and man.

In rats, both the plasma concentrations and the anti‐inflammatory activity of sudoxicam are depressed by concurrent administration of aspirin, being similar to that reported for other nonsteroidal agents, whereas, in man and monkey, plasma concentrations of sudoxicam are not affected by concurrent administration of aspirin. In this respect sudoxicam differs from such other nonsteroidal anti‐inflammatory agents as indomethacin and naproxen.

The Adjuvant Arthritic Rat Inflammatory Parameters during Development and Regression of Gross Lesions

Summary Inflammatory parameters were followed during the prearthritic stage of adjuvant-injected rats. Plasma inflammation units, erythrocyte sedimentation rates, and plasma sialic acid, glycoprotein and copper concentrations were raised 3 days post-dose and continued to increase up to 13 days, when gross lesions appeared. A prearthritic lymphoid hyperplasia occurred in the same manner. All these lesions regressed with dexamethasone treatment. It was concluded that none of the parameters investigated showed a unique sensitivity to the inflammatory state of the animal.SummaryInflammatory parameters were followed during the prearthritic stage of adjuvant-injected rats. Plasma inflammation units, erythrocyte sedimentation rates, and plasma sialic acid, glycoprotein and copper concentrations were raised 3 days post-dose and continued to increase up to 13 days, when gross lesions appeared. A prearthritic lymphoid hyperplasia occurred in the same manner. All these lesions regressed with dexamethasone treatment. It was concluded that none of the parameters investigated showed a unique sensitivity to the inflammatory state of the animal.

Studies of N-dealkylation of some aromatic sulfonamides.

Abstract The stability in vivo of N-methyl substituents on sulfonamide groups in a series of related benzothiadiazine-1,1-dioxides and disulfamylbenzenes has been studied. N-methyl substituents in the 2-position in benzothiadiazines and in the 3-position in disulfamylanilines were shown to be metabolically stable; a 7-methylsulfamyl substituent was smoothly and quantitatively demethylated in the benzothiadiazine studied, while the corresponding methyl group in the analogous disulfamylaniline was removed more slowly. The metabolically removed methyl groups were expired as carbon dioxide. Replacement of the amino function of the disulfamylaniline with a methyl group caused the methyl groups on both the 1- and 3-sulfamyl substituents to be liable to removal in vivo .

The purification of human chorionic gonadotropin on DEAE-Sephadex

Abstract A simple procedure for the purification of commercial human chorionic gonadotropin (HCG) by chromatography on DEAE-Sephadex is described. The method is reproducible and suitable for application on a preparative scale. The HCG thus purified had a specific immunological activity of 11,000 I.U./mg and was homogeneous by immunoelectrophoresis. The overall recovery of immunological activity was 19%. A simple, specific quantitative assay for HCG employing the technique of immunodiffusion is described. The precision, accuracy, and advantages of the method are discussed.

Renal Clearance of Polythiazide

Summary The renal clearance of C14 labeled polythiazide, a new and highly potent diuretic agent, was studied in anesthetized dogs. The ratio for polythiazide was found to be considerably lower than for other benzthiadiazines. The low clearance of polythiazide appears to be determined by the high degree of drug binding by plasma proteins, and by extensive reabsorption in the distal segment. The experimental data indicate that polythiazide is also secreted by the renal tubule.

PIROXICAM, A NOVEL ANTI-INFLAMMATORY AGENT

Piroxicam (CP-16 171) is a potent acidic anti-inflammatory agent structurally distinct from the current agents such as indometacin, phenylbutazone or naproxen. Pharmacokinetic studies indicate a longer plasma half-ife for piroxicam than for these agents. Potency in the range of indometacin is observed when piroxicam is tested in the carrageenan rat paw edema model. This activity is not dependent on an intact adrenocorticoid system. The high potency, long half-life and absence of cardiovascular or cental nervous system effects have encouraged clinical trial of piroxicam.