(+/-) 3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole: a conformationally restricted analogue of 5-carboxamidotryptamine with selectivity for the serotonin 5-HT1D receptor.
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Biomedical subjects
Publications and source records attributed to P Raval.
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The effects of 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), methysergide and sumatriptan were studied on endothelium-denuded rings of beagle dog large coronary arteries. Submicromolar concentrations of the compounds contracted the rings with the order of potency 5-CT > 5-HT > sumatriptan = methysergide. Concentrations greater than 2 microM of both 5-HT and 5-CT, and 60 mumol/l methysergide also caused concentration-dependent relaxation. Sumatriptan did not cause relaxation. Peak intrinsic activities relative to the plateau contraction to sumatriptan (1.00), were 5-CT 0.47, 5-HT 0.87 and methysergide 0.51. Ketanserin 1 mumol/l affected neither contractile responses nor relaxant responses to 5-CT, methysergide and sumatriptan and only caused marginal blockade of the contractile effects of 5-HT. Methiothepin 200 nM shifted the concentration-contractile response curves by around 2 log units, as expected from its affinity for 5-HT1-like receptors. The rank order of contractile potency of the agonists, the antagonism by methiothepin and the resistance to blockade by ketanserin are consistent with a nearly exclusive involvement of 5-HT1-like receptors. Isolated large coronary arteries from beagle dogs may be a suitable model for the study of human coronary artery 5-HT1-like receptors that are involved in the spasm observed with 5-HT and sumatriptan.
Two oligodeoxyribonucleotides were synthesized that were specific for the messenger RNAs for the polycyclic hydrocarbon-inducible cytochromes P450IA1 and P450IA2. The solution hybridization technique was modified for the use of these oligodeoxyribonucleotide probes so as to increase the sensitivity and specificity of this method. Using this technique, the steady-state levels of the mRNAs for cytochromes P450IA1 and P450IA2 in control rat liver were determined to be less than 3 and 6 molecules/cell, and 1.8 and 4.0 attomol/micrograms poly (A)+ RNA, respectively. At 15 hr after induction with 3-methylcholanthrene, the steady-state levels of the mRNAs for P450IA1 and P450IA2 were 68 and 200 molecules/cell, and 41.6 and 123 attomol/micrograms poly (A)+ RNA.
Giant cell tumor (GCT) of bone is a local, variably aggressive neoplasm with high local recurrence and occasional pulmonary metastases. Radiographically guided fine-needle aspiration (FNA) plays a large role in establishing a tissue diagnosis of lung metastases prior to therapeutic intervention. We present a patient with histologically proven pulmonary metastases from a femoral grade II GCT. These lesions were obliterated with combination HT-CT (hyperthermia and chemotherapy). The patient subsequently developed another pulmonary nodule at a site previously occupied by a GCT metastatic deposit. Radiographically guided FNA revealed that this new lesion was an adenocarcinoma, apparently of pulmonary origin. We suggest that this second neoplasm arose within a scar that developed after HT-CT ablation of one of the metastases. Additional intriguing features of this case are the effective HT-CT therapy of GCT metastatic to lung and the extended temporal course (some 16 yr from initial diagnosis to death).
Nine structurally dissimilar thromboxane antagonists (SQ 29548, ICI 185282, AH 23848, BM 13505 (Daltroban), BM 13177 (Sulotroban), SK&F 88046, L-636499, L-640035 and a Bayer compound SK&F 47821) were studied for activity as thromboxane A2 receptor antagonists. The assays used were inhibition of responses induced by the thromboxane mimetic, U46619, on human washed platelet aggregation, rabbit platelet aggregation, rabbit aortic strip contraction, anaesthetised guinea-pig bronchoconstriction, and a radio-labelled ligand (125I-PTA-OH) binding assay as a measure of affinity for the human platelet receptor. The results of the present study, with activities spanning at least four orders of magnitude along with statistically significant correlations (at least P less than 0.01), strongly suggests that between assays, antagonists and species a homogenous population of thromboxane A2 receptors exists. This finding is in contrast to those of a close series of 13-azapinane antagonists studied by other workers which have suggested receptor heterogeneity.
The biologic and clinical heterogeneity of the various subtypes of non-Hodgkin's lymphoma is related to differences in morphologic, immunologic, and kinetic properties. Comprehensive studies characterizing these features in lymphomatous effusion have yet to be reported. We recently studied 27 effusion specimens from 26 patients with clinically suspected or confirmed lymphoma. Wright-Giemsa- and Papanicolaou-stained cytologic preparations, acridine orange nucleic acid flow cytometry, and immunoperoxidase staining of cell suspensions using antibodies to a battery of T and B cell markers were evaluated and compared with prior histologic accessions. Specimens were classified by cytologic characteristics according to the International Working Formulation Scheme and by acridine orange nucleic acid flow cytometry using the parameters of DNA, RNA, and proliferative activity. Correlation of the cytometric and morphologic data demonstrated that with increasing cytologic grade of lymphoma, the proliferative activity increased progressively and distinguished between grades (P less than 0.01). Immunologic studies identified B cell phenotype in 16 specimens, T cell in three, and true histiocytic lymphoma in one; one lymphoma had no cell markers (null cell). Six effusions proved to be inflammatory and reactive according to surface marker studies. Classification by cytologic characteristics showed good correlation with histologic classification performed previously. Immunologic study of cytologic specimens gave results identical to those achieved by frozen-section immunohistologic examination. Thus, immunologic and cytometric parameters can be readily performed on effusion specimens and aid in the diagnosis and classification of lymphomas.
A simple, minimally invasive technique is described which allows assessment of histamine H1-receptor antagonist activity in conscious dogs. The technique is based on the inhibition of the tachycardia caused by intravenous administration of the H1-receptor agonist, 2-pyridylethylamine. The response to 2-pyridylethylamine is dose dependent and is inhibited, in a dose-dependent manner by H1-receptor antagonists, such as temelastine, terfenadine, and chlorpheniramine. In contrast, cimetidine does not inhibit this response. This technique allows comparison of antagonist activity after either oral or intravenous administration of antagonists and also permits an assessment of the time course of antagonism.
Various procedures which achieve the local separation of the lipid bilayer portion of the plasma membrane from the membrane skeleton cause a destabilisation of the lamellar form of the bilayer and release of bilayer microvesicles containing encapsulated cytosol. These procedures can give us information concerning the composition of the bilayer, the nature of its interaction with the membrane skeleton and the mechanism of the membrane fusion events which are involved in vesiculation. Bilayer microvesicles appear to retain the phospholipid orientation of the original cells, suggesting that spectrin is not essential for the maintenance of lipid asymmetry.
The role of histamine H1- and H2-receptors in mediating the vascular events associated with carrageenin-induced inflammation has been investigated in the guinea-pig ear. Increased vascular permeability, oedema formation and vasodilatation, a parameter known to be reduced by cimetidine in inflammatory responses where histamine is widely accepted as an important mediator, were quantitatively measured. Cimetidine and mepyramine, alone and in combination, failed to modify the vascular changes produced by carrageenin; conventional doses of steroidal and non-steroidal anti-inflammatory agents were also found to be ineffective. Furthermore, combinations of cimetidine, mepyramine and indomethacin had only minor effects on the inflammation. These findings suggest that histamine and cyclo-oxygenase derived metabolites of arachidonic acid do not play a significant role in carrageenin-induced inflammation in the guinea-pig.
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The effect of non-steroidal anti-inflammatory agents on u.v. radiation-induced cutaneous inflammation has been re-evaluated using a model which permits simultaneous and quantitative measurement of vasodilatation, vascular permeability and oedema formation throughout the entire time course of the inflammatory reaction. Indomethacin and phenylbutazone produced a substantial reduction in u.v. erythema during the initial stages but subsequently were far less effective, although small, significant reductions were obtained. Attempts to reverse an established inflammatory response to u.v. injury also yielded small, significant reductions in erythema but vascular permeability remained unaffected. In addition, it was found that arachidonic acid and prostaglandin E2 selectively produced vasodilatation: the vasodilator response to arachidonic acid, but not prostaglandin E2, was greatly reduced by indomethacin. It is suggested that cyclo-oxygenase derived arachidonic acid metabolites play an important role in mediating u.v. erythema only during the initial period.
Forty-five silicone rubber implants fabricated over a 13-year period for tissue augmentation in 44 patients were reviewed. All implants were custom-made with perforations using 382 RTV silicone elastomer. High rates of success and patient compatibility have been recorded.
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The efficacy of immunocytochemical staining for prostate-specific antigen (PSA) and prostate-specific acid phosphatase (PSAP) was studied in aspiration biopsy specimens from 19 patients. Eighteen patients had prostatic carcinoma and one had hyperplasia of prostate. Specimens were obtained from both the primary tumors and metastatic sites. Immunoperoxidase staining was performed on alcohol-fixed cytology smears (some prepared up to 9 years previously) using appropriate antisera followed by an avidin-biotinylated horseradish peroxidase complex. Results were scored according to the percentage and intensity of positively stained malignant cells. Corresponding histologic specimens were stained and scored in a similar fashion. Correlations were made between the staining characteristics of the tumor markers and grade of tumor, using the University of Texas M.D. Anderson Hospital classification of prostate carcinoma. Overall there was good correlation between cytologic and histologic specimens for the presence of PSA and PSAP, although metastases tended to show fewer positively stained cells than the primary tumor. There was no relationship between tumor grade and percentage of positively stained cells. Ninety-three percent of aspirated primary and secondary prostatic tumors stained positively for PSAP compared with 81% for PSA. In one of 3 patients, negative staining of neoplastic cells by both PSAP and PSA was helpful in confirming the existence of a second primary tumor.
A case is presented of lymphoepithelioma (undifferentiated nasopharyngeal carcinoma) metastatic to the cervical lymph nodes in a 12-year-old boy for whom material was obtained by fine needle aspiration (FNA) for the primary diagnosis as well as for ancillary studies. Papanicolaou-stained smears demonstrated the characteristic cytopathologic features of Regaud-type lymphoepithelioma; the diagnosis was substantiated by immunocytochemical and electron microscopic studies. This report discusses the reliability and rapidity of FNA in definitively diagnosing undifferentiated metastatic malignancies as well as providing superior material for ancillary studies demanded by lesions with complicated and difficult differential diagnoses.
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