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R J Capetola

Publications and source records attributed to R J Capetola.

At least 37 records · Page 2Linked to original sources
PubMed1987

Anaphylactoid and anti-ovulatory activities of LHRH antagonists in rats.

Studies were conducted with LHRH antagonists examining the relationship of structure to anaphylactoid-like activity and the relationship of anaphylactoid-like activity to anti-ovulatory activity in rats. Substitution of basic amino acids appeared to enhance the anaphylactoid-like activity of these peptides but other complex structural characteristics may also be involved. Anaphylactoid and anti-ovulatory activities were clearly independent and potent LHRH antagonists with minimal anaphylactoid-like activity were identified.

Amino Acid Sequence↗
PubMed1987

The antialgesic drugs: human therapeutic correlates of their potency in laboratory animal models of hyperalgesia.

This survey discusses the correlation between the oral potency of antialgesic drugs in several pharmacology laboratories and their human oral dose in clinical practice. We also present a brief overview of a few biological assays that have been successfully used to direct the synthesis of newer antialgesic drugs. The laboratory assay that our analysis showed to be most predictive of the clinical analgesic dose is based upon the response of rats to flexion of an arthritic joint. Laboratory ED50 values from the ACh-induced abdominal constriction assay in mice are nearly as predictive while the predictive power of the yeast-induced hyperalgesia assay in rats is somewhat less. Probably because of the small number of experiments, the correlation between the efficacy of these agents in a canine model of synovitis and their clinical doses only reached borderline statistical significance (p = 0.0651). Regression equations are presented that permit calculations of single clinical analgesic doses from efficacy data in individual tests. Calculation of stepwise multiple regression showed that the clinical dose could be best predicted when efficacy data obtained in the joint flexion assay in rats and the ACh-induced constriction assay in mice are both taken into account. We have concluded that the effective doses are highly predictive of clinical efficacy because these animal assays have been designed to reflect the action of drugs upon prostanoid-induced hyperalgesia.

Acetylcholine↗
PubMed1987

Evaluation of 1-deamino-[D-Tyr(Oethyl)2, Thr4, Orn8] vasotocin, an oxytocin antagonist, in animal models of uterine contractility and preterm labor: a new tocolytic agent.

We attempted to characterize the ability of a new oxytocin derivative, 1-deamino[D-Tyr(Oethyl)2,Thr4,Orn8] vasotocin (ORF 22164), to antagonize the action of oxytocin in several in vitro and in vivo animal models of uterine hyperactivity. In these studies, the derivative was found to be a specific competitive inhibitor of oxytocin-induced contractions of pregnant guinea pig uterus in vitro. In addition, its intravenous administration induced a dose-dependent inhibition of oxytocin-induced uterine contractions in situ. Finally, like ritodrine, the drug induced a dose-dependent delay of ongoing labor in rats. These results suggest that 1-deamino-[D-Tyr(Oethyl)2,Thr4,Orn8] vasotocin, unlike ritodrine, is a potent and specific antagonist of oxytocin-induced uterine contractions and thus may have potential clinical utility in the treatment of preterm labor.

Animals↗
PubMed1986

Rioprostil prevents gastric bleeding induced by nonsteroidal antiinflammatory drugs in dogs and arthritic rats.

Gastrointestinal irritation is the most significant side effect in patients chronically taking nonsteroidal antiinflammatory drugs (NSAID) for treatment of arthritic conditions. Rioprostil, a primary alcohol prostaglandin E1 analog, prevents gastric bleeding induced by several NSAID in a rat model of arthritis that is similar in many aspects to human rheumatoid arthritis. Daily oral dosing of rioprostil (50 micrograms/kg BID for 15 days) did not influence the course of the adjuvant disease in rats or alter the antiinflammatory or analgesic effect of the NSAID. In a 13 week efficacy study in dogs, rioprostil (40-60 micrograms/kg, PO) completely prevented gastric hemorrhagic lesions induced by daily administration of aspirin.

Animals↗
PubMed1986

Humoral and cellular immunologic aspects of adjuvant and collagen arthritis in rats.

Systemic and local immunological responses of rats sensitized with either M. butyricum or native type II collagen have been evaluated. In rats exhibiting adjuvant-induced arthritis no antibodies to collagen could be detected. In animals exhibiting collagen-induced arthritis, high antibody titers developed by day 14, and could be correlated with the severity of the arthritis. Delayed type hypersensitivity (DTH) responses were measured by a 5-iodo-2'-deoxyuridine 125-I (125-IUdR) uptake assay. Arthritic scores in rats immunized with collagen were not accompanied by a positive DTH response, whereas adjuvant arthritic rats showed a positive response. T-lymphocyte cellular responses in both adjuvant- and collagen-induced arthritic rats were measured. In neither syndrome were major alterations observed in T-lymphocyte subpopulations. These results provide evidence that adjuvant-induced arthritis and type II collagen-induced arthritis are distinct entities, and that they may be discriminated by the nature of the humoral response.

Animals↗
PubMed1984

Topical and systemic effects of retinoids on horn-filled utriculus size in the rhino mouse. A model to quantify "antikeratinizing" effects of retinoids.

A method was developed to quantify the "antikeratinizing" effects of various retinoids (all-trans-retinoic acid, 13-cis-retinoic acid, motretinide, etretinate) in rhino mouse skin, which contains many keratinized pilosebaceous structures or horn-filled utriculi. Mean utriculus diameters in whole mount epidermis were determined and dose-response relationships were constructed after topical or oral administration of test retinoids. All-trans-retinoic acid was 3.7x, 12.5x, and 50x more potent than 13-cis-retinoic acid, etretinate, and motretinide, respectively, after topical administration. Administered orally, all-trans-retinoic acid was 2.3x more potent than 13-cis-retinoic acid. At 5 mg/kg, each retinoid produced a significant reduction in utriculus size. The rhino mouse model represents a novel and useful assay to quantify antikeratinizing activity and potency differences of biologically active retinoids.

Administration, Oral↗
PubMed1984

Evaluation of calcium entry blockers in several models of immediate hypersensitivity.

Several calcium-entry blockers, i.e., verapamil, nifedipine, flunarizine and diltiazem, were evaluated for their effects in models of immediate hypersensitivity disease. Verapamil, flunarizine and diltiazem were all effective in inhibiting antigen-induced bronchospasm in the guinea pig; however, the effects seen were at relatively high doses compared to the doses known to cause cardiovascular effects. Nifedipine caused no significant inhibition of resistance or compliance changes induced by antigen. Flunarizine, verapamil and diltiazem were ineffective in inhibiting antigen-induced histamine release from rat peritoneal mast cells in vitro. Although these compounds were active inhibitors of 5-D-[5,6,8,9,H,12,14,15-3H(N)]-hydroxy-6,8,11,14-eicosatetraenoic acid production in rat basophilic leukemia-1 cells, only flunarizine and verapamil showed effects on the 5-lipoxygenase enzyme when assayed directly. Also, these compounds were ineffective on SRS-A mediated bronchospasm in vivo. These data suggest that the currently available calcium entry blockers have little potential use in immediate hypersensitivity reactions.

Animals↗
PubMed1984

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.

Animals↗
PubMed1983

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.

Acetaminophen↗
PubMed1983

Introduction to the pharmacology of suprofen.

A number of peripherally acting analgesics have become available in the past two decades for the treatment of mild to moderate pain of diverse etiology. The action of these agents is based on their putative ability to inhibit prostaglandin biosynthesis and attenuate hyperalgesia. Suprofen is a new and potent peripherally acting analgesic with anti-inflammatory and antipyretic properties which appears to inhibit prostaglandin synthetase in a tissue-selective manner. In preclinical studies, suprofen was shown to possess a wide separation of analgesic activity from gastrointestinal irritation. Suprofen appears to exert its pharmacological effect by inhibiting synthesis of prostaglandins from precursor arachidonic acid, inhibiting the pain induced by bradykinin, and by raising the threshold to pain induced by prostaglandins. The onset of action is rapid with peak analgesic effect reached in 1-2 h. Preclinical data suggest that suprofen may be an extremely valuable and versatile analgesic for the clinical management of pain.

Animals↗
PubMed1982

Adjuvant arthritis: immunopathological and hyperalgesic features.

Adjuvant arthritis is an experimental immunopathy that is thought to share many features of human rheumatoid arthritis and, as such, is one of the most widely used models for studying the anti-inflammatory properties of compounds. Adjuvant arthritis can be induced in the rat by the injection of various bacterial cell walls or their components; however, the exact immunogen remains unknown. Recently, an autoantibody response to type II collagen was described not only in the collagen-induced arthritic model but in the adjuvant-induced disease as well. This response thus suggests that shared antigenic determinants exist between type II collagen and the responsible immunogen in the bacterial cell wall components. The contribution of the T lymphocyte to the pathogenesis of adjuvant arthritis is well known. It has now been shown that under specific conditions, adjuvant arthritis can be either enhanced or suppressed with pharmacologic or surgical manipulation, thus suggesting the heterogenicity of T lymphocytes capable of influencing the course of the disease. Levamisole was shown to reverse the augmentation of adjuvant disease seen after adult thymectomy, which suggests that levamisole can restore an aberrant immune response. Monoclonal antibodies are now being developed to evaluate T cell subsets in the rat. The use of these antibodies to study or selectively deplete lymphocyte subpopulations in this disease model promises to reveal immunologic characteristics that may lead to the development of new classes of immunoregulant drugs. Finally, the adjuvant rat has been found useful as a pain model capable of detecting the analgesic properties of both central and the newer peripheral analgesics. The above studies further corroborate the similarities between the immunopathological and hyperalgesic features of human rheumatoid arthritis and adjuvant disease. Recently developed immunologic technology may allow a new look at an old model and may result in the ability to evaluate new classes of immunoregulating agents.

Animals↗
PubMed1982

The pharmacologic profile of wy-41,195, a new orally effective antiallergic agent.

[2-Cyano-3-(methylamino)phenylamino]oxoacetic acid, sodium salt (Wy-41,195) was found to be a potent oral inhibitor (viz., ED50, 0.3 mg/kg) of IgE-mediated release in the rat passive cutaneous anaphylaxis (PCA) model and was very effective by the aerosol and oral route in the rat passive lung anaphylaxis model. High doses (25-50 mg/kg p.o.) were effective when administered up to 180 min before antigen challenge in the rat PCA model. The compound had minimal phosphodiesterase activity and demonstrated no bronchodilator or antihistamine activity. In the dog, Wy-41,195 inhibited histamine-induced reflex bronchoconstriction but had little effect on Ascaris-induced bronchoconstriction. No significant ancillary pharmacology was observed for Wy-41,195 except for inhibition of gastric secretion in the rat. The compound is relatively nontoxic and possesses a very high therapeutic index (greater than 10 000). Activity in these animal systems indicates that Wy-41,195 may hold promise in the treatment of bronchial asthma and other allergic diseases in man.

Amino Acids↗
PubMed1981

SRS-A mediated bronchospasm by pharmacologic modification of lung anaphylaxis in vivo.

Antigen challenge of actively sensitized guinea pigs results in the release of histamine eicosanoids (products of the cyclooxygenase pathway of arachidonic acid metabolism) and slow reducing substance of anaphylaxis (SRS-A). By antagonizing the effects of histamine, serotonin, and acetylcholine, inhibiting the cyclooxygenase pathway and supplying arachidonic acid as substrate, the contribution of SRS-A to anaphylactic bronchospasm can be enhanced, thus allowing suitable quantitation of antagonists. This SRS-A mediated bronchospasm can be inhibited in a dose dependent fashion by FPL55712, a selective antagonist of SRS-A. This system represents an in vivo method capable of detecting compounds which inhibit SRS-A synthesis/release of SRS-A action at the effector organ.

Anaphylaxis↗
PubMed1980

Suprofen, a new peripheral analgesic.

The antinociceptive properties of suprofen [alpha-methyl-4-(thienylcarbonyl)benzene acetic acid] are described in a pathologically induced hyperalgesic model, the rat adjuvant arthritis flexion test. By using this assay, suprofen was characterized as an orally effective, non-narcotic analgesic with a rapid onset and 4-hr duration of activity. Suprofen is 50 times more potent than acetaminophen, five times more potent than codeine and equipotent to the new peripheral analgesics, zomepirac and diflunisal. In combination experiments, suprofen potentiates the analgesic effects of acetaminophen and, unlike morphine, the analgesic effect of suprofen is not blocked by naloxone. In other hyperalgesic assays, suprofen is an extremely potent inhibitor of arachidonate-induced writhing and is equipotent to morphine in the yeast-induced paw edema (Randall-Selitto) assay. Additionally, suprofen is inactive on the normal paw in the Randall-Selitto test, the mouse Eddy hot-plate test and the tail withdrawal reflex assay induced by warm water in rats, all sensitive tests capable of detecting central (narcotic) but not peripheral analgesics. Activity on prostaglandin biosynthesis from several species and tissues suggests that suprofen is a tissue selective inhibitor of prostaglandin synthesis. These experiments suggest that suprofen represents a new class of potent, orally effective, peripheral (non-narcotic) analgesics with potential usefulness in a variety of clinical pain situations formerly reserved for narcotics.

Acetaminophen↗
PubMed1977

Interactions of narcotics and their antagonists with human serum esterase. VI: The behavior of 14-hydroxylated morphine derivatives.

Study of the interaction of 14-hydroxylated morphines and morphinans with human serum esterase revealed behavior similar to that of other morphine derivates as shown by similar acceleratory efficacies and affinity constants. However, 14-hydroxydihydro-6-morphinones showed anomalously low apparent affinities and anomalously high apparent efficacies, while at the same time seemingly interfering with the attachment of another drug to the enzyme. These anomalies are satisfactorily explained by assuming a second receptor site for which only the hydroxyketones have affinity and which interacts with the receptor site common to all opiates and opiate antagonists. Equations derived from this assumption allow to determine the parameters of the interactions of drugs with both receptor sites.

Esterases↗