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Biomedical subjects

C M Winslow

Publications and source records attributed to C M Winslow.

17 recordsLinked to original sources
PubMed1997

Low dose clemastine inhibits sneezing and rhinorrhea during the early nasal allergic reaction.

BACKGROUND: Clemastine (1 mg) is currently available over-the-counter for the treatment of allergic rhinitis. OBJECTIVE: To evaluate the efficacy of half the standard dose of clemastine (0.5 mg) in inhibiting the nasal response to allergen and the cutaneous response to histamine. METHODS: Double-blind, placebo-controlled, crossover study of 20 allergic subjects out of season. The subjects received placebo or clemastine administered one, four, and six hours before the challenges. Filter paper discs were used both to challenge the nasal mucosa with diluent and allergen and collect generated secretions. Sneezes, secretion weights, nasal and ocular symptoms, and albumin levels in nasal secretions were monitored for the nasal challenge. Intradermal skin testing was performed with diluent followed by histamine and the wheal and flare reactions were measured. RESULTS: There was a significant reduction in the number of sneezes after clemastine administered one, four, and six hours prior to challenge compared with placebo (P < .01). Clemastine administered four and six hours before challenge reduced sneezing significantly more than clemastine administered one hour before challenge (P < .05). Antigen-induced increases in secretion weights and symptoms of rhinorrhea were significantly reduced compared with placebo only when clemastine was administered four and six hours prior to challenge (P < .05). Pretreatment with clemastine had no significant inhibitory effects on other nasal symptoms or on albumin levels in nasal secretions, an objective index of increased vascular permeability. Pretreatment with clemastine did not inhibit the histamine-induced wheal skin reaction but showed a tendency, when administered six hours prior to the intradermal challenge, to reduce the flare reaction induced by the lowest dose of histamine (P = .05). CONCLUSIONS: The data show that clemastine, given at half the usual dose four and six hours prior to allergen challenge, provides relief for sneezing and rhinorrhea and suggests that this dose might be useful in the treatment of allergic rhinitis.

Adult↗
PubMed1993

The mechanisms of action of cyclosporin A in the treatment of psoriasis.

This article describes the effects of cyclosporin A (CsA) on the immunopathological mechanisms operative in psoriasis, a human skin disease. The main focus is the effect of CsA on keratinocytes, T cells and antigen-presenting cells, the key players in lesional psoriatic skin. The effect of CsA on other cells, such as neutrophils and endothelial cells, which are important in the maintenance of psoriasis, are also discussed.

Antigen-Presenting Cells↗
PubMed1991

Designing a guideline-based utilization management program.

Many public and private organizations are developing and publishing clinical guidelines to assist health care providers and patients in making appropriate medical decisions. Unless clinical guidelines are part of a well-designed managed care program, they have little effect on physician practice styles. This article explores integral components of an effective guideline-based utilization management program. Initial evaluation of this program suggests that, as part of a well-designed utilization management program, clinical guidelines can inform patients and physicians, and create appropriate incentives for effective health care delivery.

Clinical Protocols↗
PubMed1988

Diagnosis and treatment of coronary disease: comparison of doctors' attitudes in the USA and the UK.

Two panels of doctors, one in the USA and one in the UK, were asked to indicate how appropriate they judged a series of possible indications for coronary angiography and coronary artery bypass graft (CABG) operations. "Appropriateness" was defined with respect to possible benefit to the patient and excluded considerations of cost. The indications were presented as a series of detailed clinical situations in which the procedure might be used, and for each indication individual panel members rated appropriateness on a scale of 1 to 9. The US panel judged more indications appropriate than did the UK panel, and there was more agreement among the members of the US panel than among those of the UK panel. Although the two panels tended to rate the appropriateness of the indications in the same order, the UK panel placed more emphasis than did the US panel on the importance of symptoms and the amount of medical treatment. Application of the panels' ratings to two groups of patients who had had coronary angiography showed that 17% and 27% of the investigations had been inappropriate by the standards of the US panel, whereas 42% and 60% were inappropriate by the UK panel ratings. 13% of the CABG operations studied were inappropriate by the US and 35% by the UK panel ratings.

Aged↗
PubMed1988

The appropriateness of carotid endarterectomy.

Carotid endarterectomy is a commonly performed but controversial procedure. We developed from the literature a list of 864 possible reasons for performing carotid endarterectomy, and asked a panel of nationally known experts to rate the appropriateness of each indication using a modified Delphi technique. On the basis of the panel's ratings, we determined the appropriateness of carotid endarterectomy in a random sample of 1302 Medicare patients in three geographic areas who had had the procedure in 1981. Thirty-five percent of the patients in our sample had carotid endarterectomy for appropriate reasons, 32 percent for equivocal reasons, and 32 percent for inappropriate reasons. Of the patients having inappropriate surgery, 48 percent had less than 50 percent stenosis of the carotid artery that was operated on. Fifty-four percent of all the procedures were performed in patients without transient ischemic attacks in the carotid distribution. Of these procedures, 18 percent were judged appropriate, as compared with 55 percent judged appropriate in patients with transient ischemic attacks in the carotid distribution. After carotid endarterectomy, 9.8 percent of patients had a major complication (stroke with residual deficit at the time of hospital discharge or death within 30 days of surgery). We conclude that carotid endarterectomy was substantially overused in the three geographic areas we studied. Furthermore, in situations in which the complication rate is equal to or above the study's aggregate rate, carotid endarterectomy would not be warranted, even in cases with an appropriate indication, because the risks would almost certainly outweigh the benefits.

Aged↗
PubMed1987

Effects of the National Institutes of Health Consensus Development Program on physician practice.

The effects of the National Institutes of Health Consensus Development Program on physician behavior were investigated. The medical records of 2770 patients treated in ten hospitals throughout the state of Washington were reviewed to determine if quality of care improved with respect to 12 recommendations put forth by four consensus panels concerning surgical management of primary breast cancer, the use of steroid receptors in breast cancer, cesarean childbirth, and coronary artery bypass surgery. Care was studied during 24 months before and 13 to 24 months after each consensus conference. Results showed that the conferences mostly failed to stimulate change in physician practice, despite moderate success in reaching the appropriate target audience. It was concluded that the consensus development conference is an important educational tool whose effects might be enhanced by focusing on areas of practice that need improvement and by encouraging follow-up programs at the state and local level.

Breast Neoplasms↗
PubMed1987

Does inappropriate use explain geographic variations in the use of health care services? A study of three procedures.

We studied the appropriateness of use of coronary angiography, carotid endarterectomy, and upper gastrointestinal tract endoscopy and its relationship to geographic variations in the rates of use of these procedures. We selected geographic areas of high, average, and low use of these procedures and randomly sampled Medicare beneficiaries who had received one of the procedures in 1981. We determined the indications for the procedures using a detailed review of medical records and used previously developed ratings of appropriateness to assign an appropriateness score to each case. Differences among sites in levels of appropriateness were small. For example, in the high-use site for coronary angiography, 72% of the procedures were appropriate, compared with 81% in the low-use site. Coronary angiography was performed 2.3 times as frequently in the high-use site compared with the low-use site. Under the conditions of this study, we did find significantly levels of inappropriate use: 17% of cases for coronary angiography, 32% for carotid endarterectomy, and 17% for upper gastrointestinal tract endoscopy. We conclude that differences in appropriateness cannot explain geographic variations in the use of these procedures.

Carotid Arteries↗
PubMed1987

In vitro and in vivo pharmacological profiles of the PAF receptor antagonist SRI 63-675.

We have examined a recently developed PAF antagonist SRI 63-675 (dimethyl-tetrahydrofuran-methoxyphosphinyloxy-ethylquinolinium ) for its ability to inhibit several major PAF-induced physiological responses. The compound was a potent inhibitor of PAF-induced platelet aggregation in platelet rich plasma obtained from humans, guinea pigs, and rabbits, with IC50 values of 3.43, 0.25, and 0.97 microM, respectively. SRI 63-675 did not inhibit ADP, collagen nor epinephrine-induced human platelet aggregation. The IC50 for inhibition of PAF receptor binding to human platelets was 0.37 microM. In the rat SRI 63-675 inhibited 0.1 microgram kg-1 i.v. PAF-induced hypotension, with an ED50 of 32 micrograms kg-1 i.v. Using the same PAF challenge in the guinea pig, SRI 63-675 inhibited the hemoconcentration (ED50 = 17 micrograms kg-1 i.v.) and bronchoconstriction (ED50 = 24 micrograms kg-1 i.v.) responses. In the primate, the ED50 was 28 micrograms kg-1 i.v. against 3.5 micrograms kg-1 PAF-induced hemoconcentration. The ratio (1:6) in the primate of PAF used (6.3 nmol kg-1) to antagonist at the ED50 (40.7 nmol kg-1) indicates exceptional potency of SRI 63-675 in this species. The inhibition by SRI 63-675 of the major PAF-induced effects in the rat, guinea pig and primate suggests a common receptor may be involved in the expression of these PAF responses.

Animals↗
PubMed1987

Antitumor activity of SRI 62-834, a cyclic ether analog of ET-18-OCH3.

SRI 62-834, an analog of the antitumor agent ET-18-OCH3 in which the oxygen atom at carbon atom 2 has been incorporated into a five-membered heterocycle, has been prepared and evaluated as an antitumor agent. The compound exhibited good cytotoxicity in vitro against a variety of tumor cell lines and was as effective as ET-18-OCH3 given orally in the mouse Meth A sarcoma model. SRI 62-834 was shown to be an inhibitor of platelet-derived growth factor (PDGF), possibly at the receptor level, and platelet-activating factor (PAF) at the receptor level.

Animals↗
PubMed1982

Enzymatic regulation of mast cell activation and secretion by adenylate cyclase and cyclic AMP-dependent protein kinases.

This review details the biochemical events that follow IgE dimerization by antigen and cross-linking of receptors and are linked with the early rise in cyclic AMP. That the monophasic rise in cyclic AMP at 15 s is essential to the degranulation process is evident by pharmacological manipulation of adenylate cyclase, using specific activators and inhibitors to achieve potentiation and inhibition of immunologic release, respectively. Although only a small percentage of membrane adenylate cyclase is transmembrane linked to IgE-Fc perturbation, its product, cyclic AMP, is elevated during activation and is responsible for the activation of two protein kinase isoenzymes at 30-60 s. This sequence appears to be essential for secretion to occur, as evidenced by dose-related inhibition of both beta-hexosaminidase release and protein kinase activation by adenylate cyclase inhibitors. Competitive activation of cyclic AMP-dependent protein kinase activity by a phosphodiesterase inhibitor leads to inhibition of mediator release by diverting an essential enzyme or recruiting an inhibitory sequence. The precise functional role of the mast cell cyclic AMP-dependent protein kinases has not yet been identified, but there is much evidence in other cell types that protein phosphorylation is an essential accompaniment to cellular regulation. Although other apparently essential biochemical steps are noted, such as uncovering a serine esterase, methylation of membrane phospholipid, and increased Ca2+ influx, only a portion of the activation-secretion response is presented here as a sequence, namely, the IgE-Fc receptor-initiated, transmembrane-coupled activation of adenylate cyclase and the subsequent cytoplasmic cyclic AMP-dependent activation of types I and II protein kinases.

Adenylyl Cyclases↗
PubMed1981

Mast cell mediator release as a function of cyclic AMP-dependent protein kinase activation.

Stereo-specific perturbation of the IgE-receptor (shown in previous studies) produces a monophasic rise in cyclic AMP that peaks at 15 s and a depletion of cyclic AMP-dependent protein kinase that plateaus at 30-60 s. The previously observed linear relationship between the attenuation in the monophasic rise in cyclic AMP and the quantity of mediator release in the presence of incremental concentrations of the adenosine analogue 2',5',-dideoxyadenosine, DDA, which is known to inhibit adenylate cyclase, indicated a direct relationship between receptor perturbation, transmembrane activation of adenylate cyclase, and granule secretion. The role of cyclic AMP as a second messenger in this sequence is now apparent from the linear relationship between net percent mediator release and net percent activation of cyclic AMP-dependent protein kinase isoenzyme when IgE-dependent activation of adenylate cyclase is suppressed by incremental quantities of DDA. There was a comparable percent activation of both types I and II mast cell cyclic AMP-dependent protein kinase isoenzymes with anti-IgE-induced activation and secretion, and there was a parallel suppression of the activation of both isoenzymes in the presence of DDA. Although these studies firmly link the activation of cytoplasmic cyclic AMP-dependent protein kinase to the IgE receptor-initiated transmembrane activation of adenylate cyclase. they do not discriminate among the functions of the two isoenzymes.

Animals↗
PubMed1981

Effects of prostaglandin D2 and theophylline on rat serosal mast cells: discordance between increased cellular levels of cyclic AMP and activation of cyclic AMP-dependent protein kinase.

Previous studies have shown that perturbation of the mast cell IgE-Fc receptor activates adenylate cyclase so as to raise cellular levels of cyclic AMP and to activate cyclic AMP-dependent protein kinase. Theophylline, an inhibitor of cytoplasmic cyclic nucleotide phosphodiesterase, raises cellular cyclic AMP levels, activates Type I and Type II cytoplasmic cyclic AMP-dependent protein kinase isoenzymes, and inhibits immunologic mediator release in a dose-dependent fashion. Since the EC50 values for each of these effects are similar (8 to 9.5 mM), it seems likely that a relationship exists between the activation of cyclic AMP-dependent protein kinase and the inhibition of mediator release. Such inhibition could be due to either to the uncovering of an inhibitory protein by phosphorylation or to the depletion of cyclic AMP-dependent protein kinase holoenzyme, which is essential for productive IgE-Fc receptor-induced activation-secretion coupling. PGD2, which also raises mast cell cyclic AMP levels in a dose-dependent fashion and interacts synergistically with theophylline in this regard, fails to suppress mediator release alone or to add to the inhibitory effect of theophylline. The finding that PGD2 also fails to activate cyclic AMP-dependent protein kinase suggests that the adenylate cyclase stimulated by this agonist is not linked to the mast cell activation-secretion response.

Animals↗
PubMedDate not supplied

Cyclic oxygen analogues of alkyl-lysophospholipids. Synthesis and neoplastic cell growth inhibitory properties.

Ether phospholipids have demonstrated both in vitro and in vivo activity against a wide variety of tumor cell lines. The known cyclic ether phospholipid, SRI 62-834, was used as the model to prepare eight novel phospholipids containing a cyclic ether. All of the compounds were as effective as ET-18-OCH3 in their ability to activate macrophage-induced cytotoxicity against the Abelson-8.1 tumor cell line but varied in their direct cytotoxic effects. One of the new compounds, SDZ 62-406, was selected for in vivo studies and showed oral and i.v. activity in the mouse MethA fibrosarcoma model in the same range as ET-18-OCH3. No correlation was found between the direct or macrophage-activated cytotoxicity and the ability of the compounds to inhibit or promote platelet-activating factor (PAF)-induced aggregation of human platelets.

Animals↗
PubMedDate not supplied

The appropriateness of performing coronary artery bypass surgery.

Information about how appropriately procedures are performed is vital to the understanding of the impact of technology and to the success of efforts to channel its use appropriately. While the efficacy of coronary artery bypass surgery has been addressed in several large-scale, randomized trials, there is little information about how appropriately the procedure is actually being used in the community. We determined the appropriateness of coronary artery bypass surgeries performed in three randomly chosen hospitals in a western state. We determined appropriateness by comparing data obtained from a detailed medical record review with a list of 488 indications. This list, developed by a national panel of physicians, covered all possible reasons for performing the procedure. Three hundred eighty-six cases from the years 1979, 1980, and 1982 were examined. Fifty-six percent of the surgeries were performed for appropriate reasons, 30% for equivocal reasons, and 14% for inappropriate reasons. The percentage of appropriate surgeries varied by hospital, from 37% to 78%, but did not vary by patient age. Eliminating the performance of inappropriate procedures may lead to reductions in health care expenditures or to improved patient outcomes.

Age Factors↗