Pharmacologic and pharmacokinetic characteristics of norgestimate and its metabolites.

Biotransformation, pharmacologic, and pharmacokinetic studies of norgestimate and its metabolites indicate that 17-deacetyl norgestimate, along with the parent drug, contributes to the biologic response. The postulated metabolic pathway, which is based on the identification of urinary products had indicated that three metabolites of norgestimate, 17-deacetyl norgestimate, 3-keto norgestimate, and levonorgestrel, might participate in the response. The pharmacologic evaluation of these metabolites demonstrates that only 17-deacetyl norgestimate has a pharmacologic profile consistent with that of norgestimate, and significant concentrations of this metabolite have been measured in the serum of women after the administration of norgestimate. These studies indicate that 17-deacetyl norgestimate contributes to the pharmacologic response to norgestimate.

Selective inhibition of 14 alpha-desmethyl sterol synthesis in Candida albicans by terconazole, a new triazole antimycotic.

Terconazole, a new broad spectrum antimycotic triazole derivative, has been shown to have potent activity against Candida albicans in vitro and to be effective in animal models of yeast infections. The present study explored a possible mechanism of anticandidal activity of terconazole. The compound inhibited production of 14 alpha-desmethyl sterols (e.g. ergosterol) in C. albicans at concentrations (IC50 = 3-6 x 10(-9) M) lower than those inhibiting the in-vitro growth of the yeast. There was concomitant accumulation of methylated sterols, (e.g. lanosterol), which are considered detrimental to normal yeast cell membrane function. Terconazole stimulated incorporation of 14C-acetate into triglycerides, but had no other effect on C. albicans lipid metabolism. At concentrations greater than or equal to 10(-6)M terconazole inhibited the oxidation of 14C-acetate into 14CO2 in C. albicans although the mechanism for this effect remains unclear. These data indicate that terconazole is a specific inhibitor of yeast C-14 desmethyl sterol production in C. albicans. Furthermore, terconazole reduced cytochrome P-450 levels in yeast microsomes at concentrations 10,000-fold below those at which it showed effects on rabbit liver microsomes. These data indicate a species specificity for the biochemical actions of terconazole. The C-14 alpha-desmethylase system in yeast cell membranes is cytochrome P-450 associated. Thus, terconazole, was a potent inhibitor of C-14 desmethyl sterol synthesis. This effect could contribute to the anticandidal activity of the drug.

Altered susceptibility of arthritic rats to the gastric lesion-inducing effects of aspirin or ethanol and the antilesion effect of rioprostil.

It is well known that nonsteroidal antiinflammatory agents produce gastric mucosal lesions in both laboratory animals and man. However, the effect of an arthritic condition on their susceptibility to ulcerogenic agents and on the efficacy of antiulcer agents is less definitive. As a model to explore these questions, the effect of oral administration of aspirin or ethanol on gastric lesion formation was examined in rats with or without established adjuvant-induced polyarthritis. In addition, the antilesion efficacy of rioprostil, a primary alcohol prostaglandin E1 analog, was evaluated in both groups of rats. The results demonstrated that arthritic rats were more sensitive to the lesion-inducing effect of aspirin, but were more resistant to the lesion-inducing effect of ethanol when compared to normal rats. An increase in endogenous gastric prostaglandin production in arthritic rats may account for their relative resistance to ethanol. Aspirin inhibited the prostaglandin synthetic capacity of the stomach in both normal and arthritic rats, which may be responsible for eliminating the relative resistance of arthritic rats to gastric irritation. Rioprostil effectively prevented aspirin or ethanol-induced lesion formation in both arthritic and nonarthritic rats, but its potency against either irritant was decreased in arthritic rats.

Anticandidal activities of terconazole, a broad-spectrum antimycotic.

Terconazole is a new triazole ketal derivative with broad-spectrum in vitro and in vivo antifungal activities. This study further characterizes the effects of terconazole in vitro on yeast cell growth, viability, and morphology. Terconazole inhibited the growth of Candida albicans ATCC 44859 in a concentration-related manner, but with modest effects noted at levels from 10(-8) to 10(-5) M when the yeast was grown on media favoring the cell form. The inhibitory potency of terconazole on yeast cell viability varied with the strain and species of Candida tested. The susceptibility of C. albicans ATCC 44859 to terconazole was markedly enhanced when the yeast was grown on Eagle minimum essential medium, which favors mycelium formation. The effects of terconazole on the morphology of yeast cells (grown on Eagle minimum essential medium) were shown by phase-contrast and electron microscopy. There is a progression of changes, from loss of mycelia formation at 10(-8) M terconazole through complete necrosis at 10(-4) M.

Inhibition of rabbit platelet phosphodiesterase activity and aggregation by calcium channel blockers.

Rabbit platelet cyclic AMP phosphodiesterase is inhibited by the three calcium channel blockers nifedipine, diltiazem, and verapamil with IC50's of 100 microM, 100 microM and 420 microM, respectively. Also, platelet aggregation induced by 4 microM ADP is inhibited by those compounds. Verapamil is the most potent aggregation inhibitor with an IC50 of 260 microM while diltiazem and nifedipine have IC50's of 630 microM and 840 microM, respectively. All three compounds display a maximum inhibition of 80-85%. Diltiazem and PGD2 potentiate the antiaggregatory activity of each other in that the inhibitions occurring in the presence of the combination of the two (at varying concentrations) exceed the calculated sums of the inhibitions produced by each alone. On the other hand, the antiaggregatory activities of verapamil or nifedipine, are additive with that of PGD2 in that no significant differences exist between the observed inhibitions produced by the combinations and the calculated summed values of the individual inhibitions. Our data suggest, therefore, that in addition to lowering intracellular calcium ions, which are required for platelet aggregation, the three calcium channel blockers inhibit the breakdown of cyclic AMP thereby promoting antiaggregation.

Potent and selective effects of suprofen on uterine prostaglandin synthesis.

Suprofen is a non-narcotic, peripheral analgesic that exhibits potent prostaglandin (PG) synthesis inhibitory activities in a variety of subcellular tissue preparations and in vivo. The results of the present study show suprofen to be significantly more potent than either ibuprofen (6-fold) or aspirin (1000-fold) as an inhibitor of PG production by cell-free preparations of guinea pig uteri. It is selectively more potent against the production of PGF2 alpha and PGE2 than against the formation of 6-keto PGF1 alpha, the stable metabolite of prostacyclin. Suprofen is markedly more potent inhibiting the conversion of arachidonic acid to PGF2 alpha than is ibuprofen (30 times) or aspirin (1250 times). Taken together with the important role PGF2 alpha plays in the etiology of dysmenorrhea and the observation (Hahn et al., 1982) that suprofen is more potent and effective than a number of other PG synthesis inhibitors, including ibuprofen and aspirin, at reducing in vivo guinea pig uterine contractions induced by arachidonic acid, the results of the present study suggest a mechanism to support the clinical findings that suprofen is a very effective treatment for the signs and symptoms of dysmenorrhea.

Suprofen: the pharmacology and clinical efficacy of a new non-narcotic peripheral analgesic.

Suprofen is a potent, peripherally-acting, non-narcotic analgesic agent. The mechanism of action of the compound involves inhibition of prostaglandin biosynthesis and, perhaps, direct antagonism of the peripheral, pain inducing actions of prostaglandins, bradykinin and other pain mediators. Suprofen at a dose of 200 mg appears to be equal or greater in efficacy as an analgesic modality than those of ibuprofen, propoxyphene, naproxen and diflunisal or a combination of 650 mg aspirin plus 60 mg codeine. Its clinical utility has been amply demonstrated in the treatment of a number of types of pain including general and orthopedic surgery, episiotomy, post-partum pain, dysmenorrhea, dental pain and musculoskeletal disorders. Suprofen represents a new class of orally effective nonnarcotic analgesics with potential for effective clinical use in the treatment of pain.

Tissue selectivity and variability of effects of acetaminophen on arachidonic acid metabolism.

Acetaminophen has variable effects on prostaglandin synthesis depending on the tissue preparation used. The present study was designed to determine the effects of acetaminophen on arachidonic acid metabolism in different tissues simultaneously removed from the same animals treated with the compound. The ex vivo conversion of 14C-arachidonic acid into 14C-prostaglandins was monitored in homogenates or slices of tissues to which no exogenous cofactors were supplied. Administered orally at doses of 100-300 mg/kg to guinea pigs, acetaminophen stimulated prostaglandin production by cell-free preparations of stomach, but had no effect in lung or kidney medulla. At doses ranging from 25-300 mg/kg, p.o., to rats, acetaminophen stimulated stomach, but inhibited cerebral cortex prostaglandin production. These same effects were mimicked qualitatively when acetaminophen was added in vitro at 10(-4)M to 10(-2)M to similar preparations. In addition, at these same high concentrations, acetaminophen inhibited 5-lipoxygenase activity in cultured RBL-1 cells. It is speculated that the multiple and tissue variable effects that acetaminophen had on arachidonic acid metabolism depend on the inherent cofactors associated with each tissue type.

Enhanced insulin secretion and calcium uptake by Zucker "fatty" rat islets.

The relationship of the net uptake of calcium to insulin secretion by pancreatic islets isolated from Zucker "fatty" rats and their lean counterparts was studied. Islets from "fatty" rats secreted 1.5 to 3 times as much insulin as did the lean rat islets over a glucose concentration range of 0 to 27.7 mM. Over the same glucose concentration range, calcium accumulation was 2-fold greater in islets from the "fatty" rats than from the others. Both insulin secretion and calcium uptake were 2 to 3 fold greater for islets from the "fatty" rats than those from the lean animals over an extracellular calcium concentration range of up to 5 mEq/L. The data indicate that for islets isolated from Zucker "fatty" rats insulin hypersecretion in response to glucose and extra-cellular calcium is associated with enhanced calcium accumulation.

The pharmacological properties of fenbufen. A review.

gamma-Oxo(1,1'-biphenyl)-4-butanoic acid (fenbufen) was shown to be an orally and parenterally effective nonsteroidal antiinflammatory, analgesic and antipyretic agent in a variety of animal species. Like other clinically active antiinflammatory drugs such as acetylsalicylic acid (ASA), indometacin and phenylbutazone, fenbufen has demonstrated potent activity in a variety of laboratory test systems including carageenin edema (rats), UV erythema (guinea pigs), adjuvant arthritis (rats), urate synovitis (dogs), phenylquinone writhing (mice), and yeast-induced pyresis (rats). In general, fenbufen was less potent than indomethacin and more potent than ASA, and appeared of special interest because of its high analgetic efficacy and long duration of antiinflammatory and analgetic action. While shown to have ulcerogenic potential in rats at toxic doses, fenbufen was less potent than indometacin in this respect and had a superior margin of gastrointestinal safety in treatment of dogs with urate synovitis. One of fenbufen's major metabolites, 4-biphenylacetic acid (BPAA), was found to be potent inhibitor of prostaglandin (PG) synthesis both in vitro and in vivo with a variety of tissues tested. Fenbufen itself was devoid of this anti-PG-synthetase activity although it interacted with prostaglandins in other ways. These results, coupled with the fact that only BPAA showed pharmacological activities when applied locally, led to the conclusion that BPAA was the principle responsible for fenbufen's antiinflammatory action. Fenbufen thus appears to be a pro-drug capable of circumventing at least some of the gastric toxicity usually incurred when compounds, which are themselves capable of inhibiting PG synthesis, are introduced directly into the stomach. Fenbufen's relatively low gastric toxicity in dogs and humans seems to substantiate this hypothesis. The pharmacological evidence indicates that fenbufen should be a highly effective and clinically useful antiinflammatory, analgetic and antipyretic drug.

Prostaglandin E antagonist activity of 11-deoxy-16,16-trimethyleneprostaglandin E1.

11-Deoxy-16,16-trimethyleneprostaglandin E1 is a potent inhibitor of prostaglandin E-induced contractions of the gerbil colon. The antagonism is directed specifically against the prostaglandin E receptor and is not manifested when contractions are induced by either prostaglandin F2 alpha or acetylcholine.

Whole body surface electron irradiation in the treatment of mycosis fungoides. An evaluation of 200 patients.

The records of 200 patients with generalized cutaneous mycosis fungoides treated with whole body surface electron irradiation were reviewed. Type of skin lesion appeared to be the most important factor with respect to both survival and generalized skin disease-free interval. High-dose irradiation did not seem to influence prognosis significantly compared with a relatively conservative dose. The "cure" rate for the entire group was 7%. For a more homogeneous dose distribution, the eight-field technique is now used instead of the original four-field method. A new formula is proposed to standardize the reporting of doses.

Prostaglandin E antagonist activity of 11, 15-bisdeoxy prostaglandin E1 and congeners.

d,l-11, 15-bisdeoxy PGE1 and certain of its congeners were shown to inhibit gerbil colon contractions induced by l-PGE1. While some of these compounds were selectively antagonistic of PGE1-induced contractions, others additionally inhibited the gerbil colon agonist activities of l-PGE2alpha and acetylcholine. The PGE1 inhibitory activity was apparently competitive in nature. With relatively weak potencies, the bisdeoxy PGE congeners displaced 3H-PGE1 from a fat cell binding site, suggesting competition for a common, putative receptor. Structure-activity relationships and potential utility of these analogs are discussed.

Inhibition of prostaglandin-mediated ocular inflammatory responses by 4-biphenylacetic acid.

4-Biphenylacetic acid (BPAA),a prostaglandin-synthesis inhibitor, was tested for its effects on prostaglandin-related, laboratory models of ocular inflammation. Topically applied, BPAA inhibited arachidonic acid, but not prostaglandin E-induced increases in rabbit intraocular pressure (IOP). BPAA inhibited the IOP response to alkali burn and altered IOP changes following paracentesis. In vitro, BPAA inhibited prostaglandin production from arachidonic acid in cell-free preparations of rabbit uvea. It is suggested that BPAA may be useful for the therapy of ocular inflammatory disease.

Cyclic AMP-phosphodiesterase and epidermal mitosis.

The relationship between cyclic AMP-phosphodiesterase (cAMP-PDE) inhibition and inhibition of epidermal mitosis was examined for several compounds using a soluble, low Km PDE activity from hairless mouse skin and the G2 mouse ear mitosis assay. Orders of potency determined at IC50 levels (concentrations required for 50% inhibition) were SQ 20009 greater than RO 20-1724 greater than papaverine greater than bufexamac greater than indomethacin greater than theophylline greater than p-biphenylylacetic acid greater than or less than glycyrrhetinic acid for inhibition of both PDE and mitosis. The disproportionately high antimitotic potency of puromycin relative to PDE inhibition was believed to reflect effects on protein biosynthesis. Activity of the three nonsteroidal anti-inflammatory agents (bufexamac, indomethacin, and p-biphenylylacetic acid) was unrelated to their effect on prostaglandin synthesis in homogenates of hairless mouse skin. The results suggest that the epidermal antimitotic activity of the compounds tested is related to their inhibition of cAMP-PDE and provide additional support for cAMP as a regulator of the G2 stage of the epidermal cell cycle.