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M P Finkel

Publications and source records attributed to M P Finkel.

At least 19 recordsLinked to original sources
PubMed1990

CI-949: a new, potential antiallergy compound inhibits antigen-induced allergic reactions in guinea-pigs in vitro and in vivo.

CI-949 (5-methoxy-3-(1-methyl-ethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H -indole-2-carboxamide) effectively inhibited the release of histamine and the synthesis or release of immunoreactive sulfidopeptide leukotrienes C4-D4 and thromboxane B2 from antigen-challenged lung fragments of of actively sensitized guinea-pigs. The IC50s were 26.7 +/- 2.8 microM for histamine, 2.7 +/- 2.4 microM for leukotriene, and 3.0 +/- 1.8 microM for thromboxane. Drugs including ketotifen, cromolyn and nedocromil did not inhibit histamine release or did so only at high concentrations, and only cromolyn inhibited the synthesis or releases of the 2 eicosanoids. A dose of 50 mg/kg i.p. of CI-949 protected conscious, aerosol-allergen challenged guinea-pigs for at least 1 h and 100 mg/kg i.p. or per os protected for at least 2 h. These results, the comparisons to standard antiallergic drugs, and other data from experiments with human lung fragments and isolated peripheral leukocytes 1,2,3,4 suggest that CI-949 should be evaluated for clinical activity against allergic and inflammatory conditions in which histamine, sulfidopeptide leukotrienes, and/or thromboxane mediate symptoms.

Anaphylaxis↗
PubMed1989

3-(aminoalkyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c] pyridin-5-ones as potential anticholinergic bronchodilators.

A series of 3-(aminoalkyl)benzopyrano[3,4-c]pyridin-5-ones was prepared and tested as potential orally active anticholinergic bronchodilators. Inhibition of methacholine-induced collapse in guinea pigs and inhibition of pilocarpine-induced bronchoconstriction in dogs served as in vivo models. Simultaneous measurement of salivary inhibition in the dog model allowed determination of a pulmonary selectivity ratio. The benzopyrano[3,4-c]pyridin-5-one parent ring system was prepared by Pechman condensation of phenols with a piperidine beta-keto ester. Alkylation with aminoalkyl halides, or with 1-chloro-2-propanone followed by reductive amination, yielded the 3-substituted target compounds. Bronchodilator potency was related to the extent of steric crowding surrounding the side-chain terminal amine function. Addition of a methyl substituent on the carbon alpha to the terminal amine often increased potency or pulmonary selectivity. After secondary pharmacological evaluation, compound 7a, designated CI-923, was selected for clinical trial as a bronchodilator.

Airway Resistance↗
PubMed1987

CI-922--a novel, potent antiallergic compound--II. Activity in animal models of allergy.

CI-922 (3,7-dimethoxy-4-phenyl-N-1H-tetrazol-5-yl-4H-furo [3,2-b]indole-2-carboxamide, L-arginine salt) is an effective antiallergic in guinea pig, rat, and canine models. This in vivo activity is attributed to its ability to inhibit inflammatory mediator release following antigen challenge in these species. Antigen-induced anaphylaxis in guinea pigs (collapse), which is mediated predominantly by histamine, was prevented by i.p. drug pretreatment. CI-922 (5 mg/kg, i.v.) reduced i.v. antigen-induced falls in pulmonary compliance in mepyramine-pretreated, anesthetized guinea pigs. By comparison, cromolyn sodium was inactive in both guinea pig models. In rats, CI-922 given immediately before antigen challenge (ID50 of 0.29 mg/kg, i.v.) was effective and twice as potent as cromolyn sodium and twenty times more potent than proxicromil in preventing i.v. antigen-induced pulmonary anaphylaxis. In addition, when the drugs were given 10 min before antigen challenge, only CI-922 caused a dose-related reduction of bronchoconstriction. CI-922 did not show direct antagonist activity when tested against a serotonin-induced bronchospasm, and exhibited only slight activity against a histamine-induced bronchospasm. CI-922 (0.3 mg/kg, i.v.) also reduced the bronchospasm caused by aerosol antigen (ascaris) challenge in spontaneously allergic dogs. In contrast, proxicromil was inactive in this dog model. The drug also inhibited passive cutaneous anaphylaxis in rats (ID50 of 0.2 to 0.3 mg/kg, i.v. and 0.7 to 6.4 mg/kg, p.o.). These data illustrate that CI-922 is active in several species in vivo, and has a spectrum of antiallergic activity significantly different from cromolyn-like drugs.

Anaphylaxis↗
PubMed1979

Odontomas in Peromyscus leucopus.

A colony of Peromyscus leucopus was established 15 years ago from animals trapped in the deciduous forest at Argonne National Laboratory, Argonne, Illinois. A roentgenographic survey of the skeletons of 189 of these untreated animals dying during a 13-month period disclosed 48 odontogenic growths in 21 of the mice. These growths were diagnosed on histopathologic examination as complex odontomas, the incidence of which was higher in males than in females. In this relatively small sample, these benign tumors appeared to be associated with youth rather than old age.

Age Factors↗
PubMed1978

FBJ osteosarcoma virus in tissue culture. III. Isolation and characterization of non-virus-producing FBJ-transformed cells.

Hamster and rat cell lines have been established that have been transformed by FBJ murine sarcoma virus (FBJ-MuSV) but that do not produce virus. The hamster cell line originated from an osteosarcoma that appeared in a hamster inoculated at birth with an extract of a CFNo1 mouse FBJ-osteosarcoma. The rat cell line was obtained by transferring the FBJ-MuSV genome to normal rat kidney cells in the absence of the FBJ type C virus (FBJ-MuLV), which, usually in high concentration, accompanies the FBJ-MuSV. Both transformed hamster and rat cell lines contain the FBJ-MuSV genome, which can be rescued by ecotropic and xenotropic murine type C viruses. This rescued genome produces characteristic FBJ-MuSV foci in tissue culture and, in appropriate animal hosts, induces osteosarcomas typical of those induced by FBJ-MuSV. FBJ-MuSV was isolated originally from a parosteal osteosarcoma that occurred naturally in a mouse. Since there was no previous history of passage of the agent through any other animal species, these non-virus-producing hamster and rat cells transformed by FBJ-MuSV should be very helpful in molecular studies examining the origin of spontaneous sarcoma genomes in mice.

Animals↗
PubMed1977

Pharmacologic studies on W10,294A, a new bronchodilator.

W10,294A (1,2,3,4-tetrahydro-8,9-dimethoxy-3(2-piperidinoethyl)-5H-[1] benzopyrano [3,4-c] pyridin-5-one dihydrochloride) is a potent antagonist of the bronchoconstriction induced by histamine, methacholine or acetylcholine. In vitro evaluation on guinea pig trachea indicated that W10,294A had both direct smooth muscle relaxant activity and modest antihistaminic properties. Resistance and dynamic compliance measurements in anesthetized dogs indicated that W10,294A prevented or reversed bronchoconstriction due to histamine or pilocapine. Bronchodilator activity of long duration was observed in dogs after oral administration. W10,294A was compared with aminophylline in several tests. W10,294A was 6 times more potent than aminophylline in relaxing isolated guinea-pig trachea. In the anesthetized dog W10,294A was more potent and longer acting than aminophylline in reversing pilocarpine-induced bronchospasm. The bronchodilator activity of W10,294A was not blocked by the beta adrenoceptor antagonist bunolol. Comparative studies in dogs and guinea pigs, using identical doses, showed that W10,294A had considerably less effect on the cardiovascular system than did aminophylline.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1976

Pathogenesis of radiation and virus-induced bone tumors.

Bone cancer can be induced by radionuclides that localize in the skeleton. Histologically, these experimentally induced tumors resemble those found naturally in man; they range from densely ossified osteogenic sarcomas to osteolytic tumors with giant cells and only a small osteoid component. Fibrosarcomas and hemangiosarcomas also can occur in some species. It has not been possible to determine the dose in terms of absorbed energy necessary for bone-tumor induction because radionuclides are not deposited uniformly, and they diminish in amount with time. Also, the precise time when irreversible noeplastic change occurs is not known. With X-rays, however, 500 rads delivered to the endosteal surface of a mouse femur has been shown to cause osteogenic sarcoma. Bone tumors can be induced in mice by viruses. FBJ osteosarcoma virus and RFB osteoma virus were obtained from spontaneous tumors; FBR osteosarcoma virus came from a radiation-induced tumor. All three are RNA viruses with C-type particle morphology, and they are propagated by injecting cell-free extracts of virus-induced tumor. All three are RNA viruses with C-type particle morphology, and they are propagated by injecting cell-free extracts of virus-induced tumor into newborn mice. Interaction studies with bone-seeking radionuclides and these viruses have led to the hypothesis that radiation produces cancer by inactivating a viral inhibitor. There is also evidence of a bone tumor virus in the human disease. The injection of cell-free extracts of human bone cancer into newborn Syrian hamsters has induced a variety of mesenchymal tumors at a rate significantly higher than in the control hamsters. Sixty tumors of this type, including 20 osteosarcomas, 11 fibrosarcomas, and 9 osteomas, have been diagnosed so far in experimental animals; in control hamsters there has been only one, a fibrosarcoma. Immunofluorescence assays and cytotoxicity studies indicated that these hamster tumors carried a human antigen.

Animals↗
PubMed1976

Plasma alkaline phosphatase in mice with experimentally-induced osteosarcomas.

No statistically significant difference in alkaline phosphatase levels was demonstrated in animals injected with the FBJ virus. However, there was a significant increase associated with the development of osteosarcomas in response to the iv injection of 1.0 uCi 90 Sr/g body weight into 11-18-mo-old Anl:CFl females. It was proposed that alkaline phosphatase determinations can be used as well as roentenographic analysis to detect 90Sr-induced tumors in mice.

Alkaline Phosphatase↗
PubMed1975

The etiology of osteosarcoma. A review of current considerations.

Various agents have caused osteosarcoma in several experimental animal systems. These agents or initiators may be classified as chemicals, radiation, viruses, and miscellaneous. Zinc beryllium silicate with beryllium oxide in rabbits and FBJ virus in mice are two such initiating agents. The relevance of these animal experiments to the human situation is not known, but recent reports regarding a transmissible agent obtained from human osteosarcoma tissue suggest that a virus may be implicated. There is a theoretic indication that the various etiologic agents, including viruses, may affect the DNA of normal cells in such a way that further evolution and differentiation through several cell divisions may result in the clinical appearance of cancer.

Animals↗