Biomedical subjects
W A Murphy
Publications and source records attributed to W A Murphy.
Differences in composition and function of iodinated substances in stimulated thyroid glands.
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Somatostatin antagonist analog increases GH, insulin, and glucagon release in the rat.
We have utilized the relative structural simplicity of several short, cyclic, highly active somatostatin analogs in the search for competitive antagonists of somatostatin. During an attempted synthesis of cyclo(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr), catalytic hydrogenation of the protected peptide intermediate unexpectedly gave cyclo [7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)] in which the benzyl protecting group on Thr could not be removed even upon prolonged treatment under standard conditions. Injection of this new peptide into the rat completely blocked the inhibitory effects of exogenous somatostatin on GH, insulin, and glucagon release. Indeed, in fasted rats, basal hepatic portal insulin and glucagon levels were significantly increased after analog treatment. Plasma GH levels in Nembutal-anesthetized and stimulated rats were also increased after injection of the analog. These results provide strong evidence that endogenous somatostatin exerts local tonic control of pituitary and pancreatic secretions. The availability of a somatostatin anatagonist should be of considerable value in elucidating the roles of somatostatin in these and many other physiological processes.
Diagnosis of joint effusion on lateral and axial projections of the knee.
Lateral and axial scout radiographs of 100 patients undergoing knee arthrography were evaluated for the presence of joint effusion by multiple observers. Specific observations were characterized. Knee joint effusions were diagnosed with comparable overall accuracy on lateral and axial projections. The combination of both projections increased sensitivity from 75% to 91% and decreased specificity from 87% to 27%.
CT observation of rib abnormalities: spectrum of findings.
The CT studies in 63 patients in which rib abnormality was identified or excluded were retrospectively analyzed. The CT features were detailed and correlated with other available radiographic findings as well as clinical data. Contiguous spread of tumor to rib or metastasis to rib characteristically showed subtle or complete segmental lytic rib destruction. An accompanying extrapleural soft tissue mass was frequently seen with metastatic disease and myeloma. In nine patients CT showed rib destruction that had been obscured on chest radiography by heart, diaphragm, mass, or pleural effusion. Other imaging studies prompted consideration of neoplasm in seven patients in whom CT clearly showed benign post-traumatic or developmental lesions. Six patients had a clinically suspected chest wall mass excluded, leading to the diagnosis of Tietze syndrome. The ribs should be carefully inspected on all CT studies of the thorax and upper abdomen. Computed tomography is helpful when other imaging techniques, such as rib films or isotopic bone scans, have not resolved the question of clinically or radiographically suspected rib abnormality.
Utilization characteristics of a superconductive MR system undergoing initial clinical trial.
The authors describe their initial 7 month experience with magnetic resonance (MR) imaging using a superconductive MR system. Factors affecting system utilization were scheduled and unscheduled downtime, specific system characteristics, and physician experience with the new technology. Technical improvements that reduced the duty cycle and radiologist experience in tailoring examinations have improved patient throughput by reducing the average patient study time by approximately 40% during the 7 month survey. These considerations have important economic consequences for patients and operators of MR equipment.
Introduction to wavelet-based compression of medical images.
Medical image compression can significantly enhance the performance of picture archiving and communication systems and may be considered an enabling technology for telemedicine. The wavelet transform is a powerful mathematical tool with many unique qualities that are useful for image compression and processing applications. Although wavelet concepts can be traced back to 1910, the mathematics of wavelets have only recently been formalized. By exploiting spatial and spectral information redundancy in images, wavelet-based methods offer significantly better results for compressing medical images than do compression algorithms based on Fourier methods, such as the discrete cosine transform used by the Joint Photographic Experts Group. Furthermore, wavelet-based compression does not suffer from blocking artifacts, and the restored image quality is generally superior at higher compression rates.
The new pharmacology of somatostatin and its multiple receptors.
A large number of somatostatin analogs taken from several major families of peptides has been examined for binding to three newly discovered somatostatin receptors (SSTR1, 2 and 3) transfected and expressed in various cell membrane preparations. Extremely potent octapeptide analogs related to and including octreotide (SMS 201-995) were found to bind with high affinity to SSTR2 receptors, which appear to be primarily of a pituitary type, and indeed affinities correlated extremely well with inhibitory potencies for inhibition of GH release from rat pituitary cells. Several new octapeptides were discovered with affinities and in vitro potencies greater than previously reported analogs. Whereas all of the octapeptides had much lower affinity for SSTR1 and SSTR3 receptors, which appear to be primarily present in the CNS, high affinity and highly specific ligands for the latter were found within a series of linear somatostatin analogs. No analogs were found which had high affinity for SSTR1 receptors. These studies confirm the feasibility of designing ligands which are specific for the various somatostatin receptors. These should provide useful tools for delineating the physiological roles of these receptors, specifically labeling certain receptors, and developing therapeutically interesting compounds targeted towards specific physiological events.
Structure-activity relationships of adrenomedullin in the adrenal gland.
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Novel heptapeptide somatostatin analog displays anti-tumor activity independent of effects on growth hormone secretion.
A series of heptapeptide somatostatin (SRIF) analogs containing mercaptopropionic acid (Mpa) and based on the parent structure Mpa-Tyr-[D]Trp-Lys-Val-Cys-Thr-NH2 were synthesized by solid-phase methodologies and assayed for their effects on rat growth hormone (GH) secretion and their ability to displace [125I]Tyr11-SRIF bound to various tissues in vitro. Structural modifications consisted primarily of aromatic substitutions for Thr. All analogs were less potent than SRIF in inhibiting GH secretion in vitro from 4-day primary cultures of rat pituitary cells (0.04-21% that of SRIF). Higher GH inhibitory potencies were observed in an acute 15 min in vivo potency assay probably reflecting increases in plasma half-life of the analogs as compared to native SRIF. All analogs had extremely low binding affinity for rat cerebral cortex (0.05-4% that of SRIF), while binding potency for rat pancreas ranged from 3-130% of SRIF. Several analogs exhibited enhanced binding to human small cell lung carcinoma cells (SCLC; NCI-H69) as compared to SRIF. One of these, containing Phe at the C-terminus, exhibited an affinity 3.5 X greater than SRIF itself and was further tested for possible effects on the proliferation of SCLC and rat pancreatic tumor cells (AR42J) in vitro. The proliferation of both tumor types was inhibited 32 and 60%, respectively (p less than 0.01). The data suggest that SRIF and certain analogs may have a direct action on proliferating tumors independent of endocrine effects and that the anti-tumor activity of SRIF analogs can be further dissociated from the other actions of native SRIF, thereby providing for potentially more selective therapeutic analogs.
Potent long-acting alkylated analogs of growth hormone-releasing factor.
Analogs of growth hormone-releasing factor-(1-29)-NH2 (GRF-29) involving derivatization with alkyl substituents at the N-terminus, with or without concomitant alkylation of basic amino acids within the peptide chain (lysine in positions 12 and 21), were synthesized using solid-phase methodology and tested for their ability to stimulate growth hormone release in pentobarbital and urethane-anesthetized rats and in 4-day primary cultures of rat anterior pituitary cells. N alpha-MeTyr1-GRF-29 was 40% as potent as GRF-29 15 min after injection of peptide into pentobarbital-anesthetized rats; N alpha-EtTyr1, Nle27-GRF-29 was 5 times more potent and N alpha-iPrTyr1-GRF-29 was 35 times more potent. Combining this latter modification with our previously reported superactive analog modification, D-Ala2, did not appreciably change potency. Analogs with larger alkyl groups, N alpha-cyclohexyl-Tyr1-GRF-29 were not superactive. However, N alpha-benzyl-Tyr1-GRF-29 was 73 times more potent than GRF-29. Most strikingly, the triisopropylated analog N alpha-iPrTyr1, N epsilon-iPr-Lys12,21-GRF-29 was 106 times more active. Several analogs were tested in time course assays. All were long-acting as compared to GRF-29, with the triisopropylated analog having the longest duration of activity. In vitro potencies among the analogs with the higher in vivo activities were only slightly increased (2-4 X) with respect to GRF-29. The observed increases in in vivo potencies presumably occur due to enhanced resistance to enzymatic degradation following alkylation or through some other pharmacokinetic effect due to the increased lipophilicity of these analogs.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparison of responses to adrenomedullin and calcitonin gene-related peptide in the feline erection model.
The purpose of the present study was to investigate the effects of intracavernosal injections of adrenomedullin (ADM) and calcitonin gene-related peptide (CGRP), two structurally similar peptides, on penile erection in the anesthetized cat. Erectile responses to ADM and CGRP were compared with responses to a standard drug combination (1.65 mg papaverine, 25 microg phentolamine, and 0.5 microg prostaglandin E1 [PGE1]). Intracavernosal injections of ADM (0.1-3 nmol) and CGRP (0.01-0.3 nmol) induced erection in a dose-dependent manner. The maximal increase in intracavernosal pressure in response to ADM was a 75% increase, while the maximal response to CGRP was comparable to that induced by the reference combination, and the maximal increase in penile length was comparable with ADM, CGRP, and the standard drug combination. The duration of the maximal pressure increase and the total duration of the response to ADM and CGRP were more abbreviated than with the control combination, and systemic blood pressure was reduced significantly after administration of CGRP, the control combination, and the higher doses of ADM. The nitric oxide synthase inhibitor, L-NAME, and the K+(ATP)-channel antagonist, glybenclamide, had no effect on the erectile response to CGRP or ADM. The CGRP receptor antagonist CGRP(8-37) attenuated the erectile response to CGRP but not to ADM. These data suggest that the erectile responses to ADM and CGRP are not mediated by nitric oxide release or the opening of K+(ATP) channels, two mechanisms reported to be involved in penile erection, and that CGRP and ADM induce penile erection by activating different receptors.