Peter F. Moore

TENIDAP, A STRUCTURALLY NOVEL DRUG FOR THE TREATMENT OF ARTHRITIS : ANTIINFLAMMATORY AND ANALGESIC PROPERTIES

Tenidap is a new anti-rheumatic agent which has clinical properties characteristic of a disease modifying drug combined with acute antiinflammatory and analgesic activity. This paper details tenidaps cyclooxygenase (COX) inhibitory activity and the resulting pharmacological properties in experimental animals. Tenidap inhibited calcium ionophore-stimulated prostaglandin D2 synthesis by rat basophilic leukemia cells (COX-1) with an IC50 of 20 nM. In two different in vitro human test systems, tenidap inhibited COX-1 activity more potently than COX-2, although the relative potency ratio (COX-1/COX-2) differed markedly between the two systems. Tenidap inhibited the COX pathway when added to human blood in vitro (IC50, 7.8 μM) and when administered orally to monkeys, rats and dogs (at 5, 2.5 and 10 mg/kg p.o., respectively) and COX activity measured ex vivo in blood collected 2 to 4 hours post dose. After oral administration to rats, tenidap inhibited carrageenan-induced paw edema with an ED50 of 14 mg/kg and inhibited the glucocorticoid-resistant UV erythema in guinea pigs with an ED50 of 1.4 mg/kg. It retained antiinflammatory activity in adrenalectomized rats indicating that this property is independent of adrenal stimulation. Oral administration of tenidap inhibited the development of adjuvant-induced polyarthritis in the rat and exhibited antinociceptive activity in the murine phenylbenzoquinone and rat acetic acid abdominal constriction tests. These data indicate that tenidap is an effective antiinflammatory and analgesic agent in animal models. These cyclooxygenase-dependent pharmacologic activities do not explain tenidaps disease modifying anti-arthritic properties but add a useful symptom modifying component to its clinical profile.

Ampiroxicam, an anti-inflammatory agent which is a prodrug of piroxicam

Ampiroxicam is a nonacidic ether carbonate prodrug of piroxicam. Our results demonstrate that, in contrast to piroxicam, ampiroxicam does not possess detectable prostaglandin synthesis inhibitory activityin vitro. Ampiroxicam, however, has similarin vivo potency to piroxicam in suppressing paw swelling in rat adjuvant arthritis. In an acute model of paw inflammation in rats, ampiroxicam is less potent than piroxicam itself: the ED50s of ampiroxicam are 9- and 3.5-fold higher than those of piroxicam following a single or multiple (5) daily oral doses, respectively. Using the phenylbenzoquinone stretching test as a method of evaluating acute analgetic activity, the ED50 for ampiroxicam is about 3-fold higher than that of piroxicam. These tests of activity share the property of being partially prostaglandin-dependent. Ampiroxicam itself is not observed in plasma after oral dosing to man [24], nor in the rat, dog, and monkey as reported here. Bioavailability studies show that conversion to piroxicam is about 100%, 90%, 70%, and 50% in these four species, respectively. These results indicate that ampiroxicams anti-inflammatory activity is producedin vivo by conversion to piroxicam and support its credentials as an efficacious prodrug of piroxicam.

Comparative pharmacology and clinical efficacy of newer agents in treatment of heart failure

The animal and human pharmacology of several new drugs (prazosin, trimazosin, pirbuterol, and carbazeran) useful in the treatment of congestive heart failure (CHF) is delineated in relation to the pharmacology of other agents employed for CHF management. Prazosin and trimazosin are selective alpha 1-blockers that cause a balanced increase in cardiac output (CO) and reduction in left ventricular filling pressure (LVFP); the reduction in diastolic blood pressure with these drugs is significantly related to increase in treadmill exercise, fall in LVFP, and increase in CO. Pirbuterol is a relatively selective beta 2-agonist with somewhat greater effects on CO than on LVFP. Early promise in CHF therapy is being shown by a novel series of cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitors with combined direct inotropic and vasodilator effects. Double-blind long-term studies demonstrate persistent efficacy of prazosin and trimazosin in CHF as measured by improvement in New York Heart Association functional class, treadmill exercise performance, and noninvasive measures of cardiac function; these data are supported by studies in which repeat cardiac catheterization has been performed after several months of therapy. Double-blind studies of other CHF drugs are in progress.

Tenidap inhibits 5-lipoxygenase product formation in vitro, but this activity is not observed in three animal models.

Abstract.Objective and Design: The effect of tenidap on the metabolism of arachidonic acid via the 5-lipoxygenase (5-LO) pathway was investigated in vitro and in vivo.¶Materials and Treatment: In vitro (cells). Arachidonic acid (AA) stimulated rat basophilic leukemia (RBL) cells; A23817 activated neutrophils (human rat, and rabbit), macrophages (rat), and blood (human). In vitro (enzyme activity). RBL-cell homogenate; purified human recombinant 5-LO. In vivo: Rat (Sprague-Dawley) models in which peritoneal leukotriene products were measured after challenge with zymosan (3 animals per group), A23187 (11 animals per group), and immune complexes (3-5 animals per group), respectively.¶Methods: 5-Hydroxyeicosatetraenoic acid (5-HETE) and dihydroxyeicosatetraenoic acids (diHETEs, including LTB4) were measured as radiolabeled products (derived from [14C]-AA) or by absorbance at 235 or 280 nm, respectively, after separation by HPLC. Radiolabeled 5-HPETE was measured by a radio-TLC analyser after separation by thin layer chromatography (TLC). Deacylation of membrane bound [14C]-AA was determined by measuring radiolabel released into the extracellular medium. 5-LO translocation from cytosol to membrane was assessed by western analysis. Rat peritoneal fluid was assayed for PGE, 6-keto-PGF1, LTE4 or LTB4 content by EIA and for TXB2 by RIA.¶Results: Tenidap suppressed 5-LO mediated product production in cultured rat basophilic leukemia (RBL-1) cells from exogenously supplied AA, and in human and rat neutrophils, and rat peritoneal macrophages stimulated with A23187 (IC50, 5–15 M). In addition, tenidap was less potent in inhibiting the release of radiolabeled AA from RBL-1 cells (IC50, 180 M), suggesting that the decrease in 5-LO derived products could not be explained by an effect on cellular mobilization of AA (i.e., phospholipase). Tenidap blocked 5-hydroxyeicosatetraenoic acid (5-HETE) production by dissociated RBL-1 cell preparations (IC50, 7 M), as well as by a 100,000 × g supernatant of 5-LO/hydroperoxidase activity, suggesting a direct effect on the 5-LO enzyme itself. In addition, tenidap impaired 5-LO translocation from cytosol to its membrane-bound docking protein (FLAP) which occurs when human neutrophils are stimulated with calcium ionophore, indicating a second mechanism for inhibiting the 5-LO pathway. Surprisingly, tenidap did not block the binding of radiolabeled MK-0591, an indole ligand of FLAP, to neutrophil membranes. Although its ability to inhibit the cyclooxygenase pathway was readily observed in whole blood and in vivo, tenidaps 5-LO blockade could not be demonstrated by ionophore stimulated human blood, nor after oral dosing in rat models in which peritoneal leukotriene products were measured after challenge with three different stimuli. The presence of extracellular proteins greatly reduced the potency of tenidap as a 5-LO inhibitor in vitro, suggesting that protein binding is responsible for loss of activity in animal models.¶Conclusions: Tenidap inhibits 5-lipoxygenase activity in vitro both directly and indirectly by interfering with its translocation from cytosol to the membrane compartment in neutrophils. A potential mechanism for the latter effect is discussed with reference to tenidaps ability to lower intracellular pH. Tenidap did not inhibit 5-LO pathway activity in three animal models.

Effects of dazmegrel, piroxicam and cyclophosphamide on the NZB(W model of SLE

To investigate the potential importance of prostaglandins and thromboxane in systemic lupus erythematosus (SLE), the effects of a nonsteroidal antiinflammatory drug (piroxicam) and a thromboxane synthetase inhibitor (dazmegrel) were examined on survival, proteinuria, food consumption, body weight, and peripheral lymphocyte subset distribution in the NZB/W model of autoimmune lupus disease. The effect of an immunosuppressant (cyclophosphamide) known to be effective in the treatment of murine lupus on these parameters was also examined. Cyclophosphamide at 25 mg/kg ip weekly prolonged survival, inhibited proteinuria and prevented the characteristic decline in peripheral T cells and the relative increase in B cells seen in NZB/W lupus disease while having no apparent effect on body weight or food consumption. Neither dazmegrel at 50 or 200 mg/kg/day in the diet nor piroxicam at 2 mg/kg/day in the diet had any significant effects on these parameters.