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Biomedical subjects

J L McGuire

Publications and source records attributed to J L McGuire.

At least 19 recordsLinked to original sources
PubMed2000

Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes.

Adenosine (ADO) exerts potent anti-inflammatory and immunosuppressive effects. In this paper we address the possibility that these effects are partly mediated by inhibition of the secretion of IL-12, a proinflammatory cytokine and a major inducer of Th1 responses. We demonstrate that 5'-N-ethylcarboxamidoadenosine (NECA), a nonspecific ADO analogue, and 2-p-(2-carbonyl-ethyl)phenylethylamino-5'-N-ethylcarboxamidoadenos ine (CGS-21680), a specific A2a receptor agonist, dose-dependently inhibited, in whole blood ex vivo and monocyte cultures, the production of human IL-12 induced by LPS and Stapholococcus aureus Cowan strain 1. However, the A1 receptor agonist 2-Chloro-N6-cyclopentyladenosine and the A3 receptor agonists N6-Benzyl-NECA and 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-be ta-d -ribofuranuronamide expressed only weak inhibitory effects. On the other hand, NECA and CGS-21680 dose-dependently potentiated the production of IL-10. The differential effect of these drugs on monocyte IL-12 and IL-10 production implies that these effects are mediated by A2a receptor signaling rather than by intracellular toxicity of ADO analogue's metabolites. Moreover, CGS-21680 inhibited IL-12 production independently of endogenous IL-10 induction, because anti-IL-10 Abs failed to prevent its effect. The selective A2a antagonist 8-(3-Chlorostyryl) caffeine prevented the inhibitory effect of CGS-21680 on IL-12 production. The phosphodiesterase inhibitor Ro 20-1724 dose-dependently potentiated the inhibitory effect of CGS-21680 and, furthermore, Rp-cAMPS, a protein kinase A inhibitor, reversed the inhibitory effect of CGS-21680, implicating a cAMP/protein kinase A pathway in its action. Thus, ligand activation of A2a receptors simultaneously inhibits IL-12 and stimulates IL-10 production by human monocytes. Through this mechanism, ADO released in excess during inflammatory and ischemic conditions, or tissue injury, may contribute to selective suppression of Th1 responses and cellular immunity.

Adenosine↗
PubMed1999

A double-blind, placebo-controlled, clinical trial of dehydroepiandrosterone in severe systemic lupus erythematosus.

OBJECTIVE: To determine if dehydroepiandrosterone (DHEA) is beneficial in severe systemic lupus erythematosus (SLE). METHODS: A double-blinded, placebo-controlled, randomized clinical trial in 21 patients with severe and active SLE, manifestated primarily by nephritis, serositis or hematological abnormalities. In addition to conventional treatment with corticosteroids +/- immunosuppressives, patients received DHEA 200 mg/d vs. placebo for 6 months, followed by a 6-month open label period. The primary outcome was a prospectively defined responder analysis, based on a quantitatively specified improvement of the principal severe lupus manifestation at 6 months. RESULTS: Nineteen patients were available for evaluation at 6 months. Baseline imbalance between the groups was noted, with the DHEA group having greater disease activity at baseline (P<0.05 by physician's global assessment). Eleven patients were responders: 7/9 patients on DHEA vs. 4/10 patients on placebo (P<0.10). Of the secondary outcomes, mean improvement in SLE disease activity index (SLE-DAI) score was greater in the DHEA group (-10.3+/-3.1 vs. -3.9+/-1.4. P<0.07). Bone mineral density at the lumbo-sacral spine showed significant reduction in the placebo group, but was maintained in the DHEA group. CONCLUSION: DHEA therapy, when added to conventional treatment for severe SLE, may at most have a small added benefit with respect to lupus outcomes, but baseline imbalances in the study population limit the generalizability of the results. DHEA appears to have a protective effect with respect to corticosteroid-induced osteopenia in such patients.

Adrenal Cortex Hormones↗
PubMed1998

Treatment of systemic lupus erythematosus with dehydroepiandrosterone: 50 patients treated up to 12 months.

OBJECTIVE: To determine whether longterm therapy (up to 1 year) with the weakly androgenic adrenal steroid dehydroepiandrosterone (DHEA) is feasible and beneficial in patients with mild to moderate systemic lupus erythematosus (SLE). METHODS: In a prospective, open label, uncontrolled longitudinal study 50 female patients (37 premenopausal, 13 postmenopausal) with mild to moderate SLE were treated with oral DHEA 50-200 mg/day. RESULTS: DHEA therapy was associated with increases in the serum levels of DHEA, DHEA sulfate, and testosterone and, for those patients who continued DHEA, with decreasing disease activity measured by SLE Disease Activity Index score (p < 0.01), patient global assessment (p < 0.01), and physician global assessment (p < 0.05), compared to baseline. Concurrent prednisone doses were reduced (p < 0.05). These improvements were sustained over the entire treatment period. Thirty-four patients (68%) completed 6 months of treatment and 21 patients (42%) completed 12 months. Mild acneiform dermatitis was the most common adverse event (54%). Pre and postmenopausal women experienced similar efficacy and adverse effects from DHEA. CONCLUSION: DHEA was well tolerated and appeared clinically beneficial, with the benefits sustained for at least one year in those patients who maintained therapy.

Adult↗
PubMed1998

Dehydroepiandrosterone in systemic lupus erythematosus: relationship between dosage, serum levels, and clinical response.

OBJECTIVE: To examine in women with systemic lupus erythematosus (SLE) who participated in a clinical trial the relationship between daily dose of dehydroepiandrosterone (DHEA), serum levels of DHEA and DHEA sulfate (DHEAS), clinical effectiveness, and side effects. METHODS: Twenty-three women with mild to moderate SLE were treated with DHEA for a 6 month period. The starting dose was 50 mg/day, and monthly stepwise increases were allowed. Subjects were assessed monthly by the Systemic Lupus Erythematosus Disease Activity Index, Systemic Lupus Activity Measure (SLAM), Health Assessment Questionnaire, and other outcomes. Serum testosterone, DHEA, and DHEAS levels were obtained and side effects noted monthly. RESULTS: Statistically significant improvements were found in all lupus outcomes over 6 months. Serum DHEA and DHEAS levels correlated with the dose of DHEA. Serum DHEA and DHEAS correlated negatively with SLAM score. A second order regression analysis of serum DHEAS level versus SLAM score suggested that the optimal serum level of DHEAS was 1000 microg/dl. The most common side effect was acne. CONCLUSION: The clinical response to DHEA was not clearly dose dependent. Serum levels of DHEA and DHEAS correlated only weakly with lupus outcomes, but suggested an optimum serum DHEAS of 1000 microg/dl. Monitoring these serum levels appears to have limited clinical utility.

Acne Vulgaris↗
PubMed1997

Skeletal status of men with early and late ankylosing spondylitis.

PURPOSE: To assess the influence of extent of disease on the skeletal status of men with ankylosing spondylitis (AS). PATIENTS AND METHODS: Fourteen men with AS were studied at entry and again after 15 months. Bone mineral density (BMD) was assessed by single photon absorptiometry (SPA), dual energy x-ray absorptiometry (DXA), and quantitative computed tomography (QCT). Calciotropic hormones and bone turnover were also assessed, and biopsies of iliac crest and skin were taken after tetracycline double-labeling from 10 subjects. Clinical evaluation and Health Assessment Questionnaires were used to assess functional status. RESULTS: Of the 14 participants, 7 had sacroiliitis alone without radiologic evidence of spinal involvement (early disease) and 7 had sacroiliitis with extensive vertebral calcifications and immobilization (late disease). QCT baseline lumbar spine BMD was very low in both groups compared with normative standards (Z score = -3.08 +/- 1.83, P < 0.0001) and did not change significantly over 15 months. This low BMD was more marked in late disease than in early disease subjects (P < 0.01). DXA BMD at the lumbar spine was lower than predicted in early disease subjects (Z score = -1.08 +/- 0.67, P = 0.005) but not in the late disease group. DXA BMD was also low at the all three hip sites (Z score = -0.96 +/- 0.86, P < 0.01). Significant differences between late disease group and normative values were apparent at all hip sites. Values in early disease subjects, however, did not differ from age-predicted norms. Bone mineral status did not change significantly over the 15-month period of observation. Circulating parathyroid hormone (PTH) and vitamin D metabolites were normal in both groups as were creatinine clearance and urinary excretion of calcium and hydroxyproline. Osteocalcin levels were normal in all but the two youngest subjects in the early disease group. Histomorphometry of the iliac crest showed no consistent change in bone turnover. Bone volume and trabecular width were low in many cases. Cancellous bone volume correlated with lumbar spine BMD by QCT (r = 0.69, P = 0.026) but not with DXA. Although beneficial changes occurred in exercise tolerance and pain over time, anthropometric measurements did not improve. CONCLUSION: BMD is low in both the axial and peripheral skeleton in men with AS and is independent of spinal immobilization. Anterioposterior lumbar spine DXA in late AS is less useful than QCT in determining the degree of osteopenia in late AS. Bone mineral deficits in AS do not reflect measurable metabolic derangement or hypogonadism. Although bone histomorphometry suggests both trabecular thinning and loss of structural elements as mechanisms involved in low bone volume, the exact cause of osteopenia in AS remains to be determined.

Absorptiometry, Photon↗
PubMed1996

Overuse syndromes in adult athletes.

Approximately 50% of all sports participants will be injured at some point, and at least half of these injuries will be attributed to overuse. This article provides an in-depth review of the presentation, diagnosis, and treatment of the most common overuse injuries encountered in the adult population: epicondylitis, shoulder impingement/rotator cuff tears, patello-femoral dysfunction, and Achilles tendinitis. Stress fractures, the "ultimate" overuse injuries, are also discussed.

Achilles Tendon↗
PubMed1996

Acute injuries and specific problems in adult athletes.

Special considerations need to be given to specific groups of adult athletes. The most common problems and needs of female and older athletes are discussed in the first section of this article. The second section reviews the diagnosis and management of certain acute injuries most frequently encountered in adult athletes. The last section discusses the differentiation between tarsal tunnel syndrome and plantar fasciitis, chronic compartmental pressure syndrome and medial tibial stress syndrome ("shin splints"), and pelvic stress fractures and osteitis pubis, some commonly encountered difficult diagnoses.

Aging↗
PubMed1996

Studies of dehydroepiandrosterone (DHEA) as a therapeutic agent in systemic lupus erythematosus.

Several lines of investigation led to the consideration of dehydroepiandrosterone (DHEA) as a candidate for hormonal therapy in systemic lupus erythematosus, including DHEA deficiency in patients with SLE, the effects of sex steroids on SLE, the immunomodulatory effects of DHEA, and the results of DHEA in animal models of SLE. Uncontrolled observations in 50 patients suggested that DHEA has overall benefits for lupus activity, alleviating specific lupus symptoms as well the systemic manifestations of lupus, with incremental benefits over 3 to 12 months of treatment. DHEA, which was very well tolerated and safe, appeared to decrease the number of lupus flares and to have a steroid sparing effect. These results were confirmed in a small placebo-controlled trial, although the results were of borderline statistical significance. Currently, a number of additional trials with DHEA are underway, and it is anticipated that DHEA will find its place as a useful agent in the treatment of SLE.

Dehydroepiandrosterone↗
PubMed1995

Dehydroepiandrosterone in systemic lupus erythematosus. Results of a double-blind, placebo-controlled, randomized clinical trial.

OBJECTIVE: To determine if dehydroepiandrosterone (DHEA) is beneficial in the treatment of systemic lupus erythematosus (SLE). METHODS: In a double-blind, placebo-controlled, randomized trial, 28 female patients with mild to moderate SLE were given DHEA 200 mg/day or placebo for 3 months. Outcomes included the SLE Disease Activity Index (SLEDAI) score, patient's and physician's overall assessments of disease activity, and concurrent corticosteroid dosages (which were adjusted as clinically indicated). RESULTS: In the patients who were receiving DHEA, the SLEDAI score, patient's and physician's overall assessment of disease activity, and concurrent prednisone dosage decreased, while in the patients taking placebo, small increases were seen. The difference in patient's assessment between the groups was statistically significant (P = 0.022, adjusted). Lupus flares occurred more frequently in the placebo group (P = 0.053). Mild acne was a frequent side effect of DHEA. CONCLUSION: DHEA may be useful as a therapeutic agent for the treatment of mild to moderate SLE. Further studies of DHEA in the treatment of SLE are warranted.

Adult↗
PubMed1994

An open study of dehydroepiandrosterone in systemic lupus erythematosus.

OBJECTIVE: To determine if dehydroepiandrosterone (DHEA) has clinical benefits in patients with systemic lupus erythematosus (SLE). METHODS: Ten female patients with mild to moderate SLE and various disease manifestations were given DHEA (200 mg/day orally) for 3-6 months. The patients were given other medications as clinically indicated, and followed with respect to overall disease activity and specific outcome parameters. RESULTS: After 3-6 months of DHEA treatment, indices for overall SLE activity including the SLEDAI (SLE Disease Activity Index) score and physician's overall assessment were improved, and corticosteroid requirements were decreased. Of 3 patients with significant proteinuria, 2 showed marked and 1 modest reductions in protein excretion. DHEA was well tolerated, the only frequently noted side effect being mild acneiform dermatitis. CONCLUSION: DHEA shows promise as a new therapeutic agent for the treatment of mild to moderate SLE. Further studies of DHEA in the treatment of SLE are warranted.

Adrenal Cortex Hormones↗
PubMed1993

Aggressive drug therapy for rheumatoid arthritis.

Recent data indicate that rheumatoid arthritis is more often systemic, progressive, and disabling than benign, and that it reduces life expectancy. The new evidence argues for a dramatic alteration in pharmacologic management. If several months of rest, exercise, and anti-inflammatory therapy are ineffectual, aggressive treatment with disease-modifying antirheumatic and immunosuppressive agents may be in order.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity.

Norgestimate is a novel progestin with highly selective progestational activity and minimal androgenicity. In rabbits, norgestimate binds to uterine progestin receptors, stimulates the endometrium, and inhibits ovulation. Norgestimate acts directly on target organs, stimulating rabbit endometrium when injected into the uterine cavity and inhibiting luteinizing hormone-releasing hormone-stimulated luteinizing hormone release in dispersed rat pituitary cells in culture. Norgestimate has no estrogenic activity, and like other progestins, it suppresses the action of estrogen. Unlike some other progestins, it is relatively free of androgenic activity. Norgestimate and its 17-deacetylated metabolite demonstrate very poor affinity for androgen receptors compared with levonorgestrel and gestodene and do not exhibit androgenic activity when measured as the stimulation of prostatic growth in immature rats. Norgestimate's lack of affinity for human sex hormone-binding globulin is further evidence of its minimal androgenicity.

Androgens↗
PubMed1991

Pneumocystis carinii pneumonia complicating low dose methotrexate treatment for rheumatoid arthritis.

Low dose methotrexate has been used effectively for various rheumatic and non-rheumatic diseases. Three cases of Pneumocystis carinii pneumonia occurring during treatment of rheumatoid arthritis with low dose methotrexate are presented. Several mechanisms might contribute to impaired immunity and the rare development of opportunist lung infection with methotrexate. A high degree of suspicion may result in earlier diagnosis and treatment.

Adolescent↗
PubMed1991

Effects of a sustained release formulation of the gonadotrophin-releasing hormone agonist histrelin on serum concentrations of gonadotrophins and oestradiol, and ovarian LH/human chorionic gonadotrophin receptor content in the rat.

Pituitary and ovarian function were studied during the loss and recovery of oestrous cyclical activity in rats following treatment with a sustained release formulation of the gonadotrophin-releasing hormone (GnRH) agonist [imidazole benzyl-D-His6,Pro9-ethylamide]-GnRH (histrelin). A single s.c. injection of microencapsulated histrelin (10-300 micrograms peptide/kg) induced a dose-dependent disruption of normal oestrous cyclical activity with a persistent dioestrous-like vaginal cytology. In preliminary studies, pituitary gland stimulation and desensitization were demonstrated when serum LH and FSH levels were greater 1 week after administration of 10 micrograms microencapsulated histrelin/kg compared with 300 micrograms microencapsulated histrelin/kg. Changes in pituitary and ovarian function were assessed over time following injection of microencapsulated histrelin (100 micrograms peptide/kg). LH secretion was maximal within 8 h and then gradually declined, remaining at dioestrous levels from days 7 to 28. Serum oestradiol concentrations remained low and rose above dioestrous levels only on day 28. In contrast, ovarian LH/human chorionic gonadotrophin (LH/hCG) receptor content fell within 8 h and, after a nadir on day 7, slowly returned to dioestrous levels by day 28. The increase in ovarian LH/hCG receptor content preceded any significant change in pituitary gonadotrophin secretion, indicating a differential pattern of recovery for pituitary and ovarian function. Subsequent studies tested the possibility that these temporal differences in pituitary and ovarian function may result from histrelin acting directly on these tissues. Treatment with histrelin microcapsules (300 micrograms peptide/kg) prevented any increase in LH secretion in response to a GnRH challenge 3 days later, indicating a direct action of histrelin on the pituitary gland.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Pharmacologic and pharmacokinetic characteristics of norgestimate and its metabolites.

Biotransformation, pharmacologic, and pharmacokinetic studies of norgestimate and its metabolites indicate that 17-deacetyl norgestimate, along with the parent drug, contributes to the biologic response. The postulated metabolic pathway, which is based on the identification of urinary products had indicated that three metabolites of norgestimate, 17-deacetyl norgestimate, 3-keto norgestimate, and levonorgestrel, might participate in the response. The pharmacologic evaluation of these metabolites demonstrates that only 17-deacetyl norgestimate has a pharmacologic profile consistent with that of norgestimate, and significant concentrations of this metabolite have been measured in the serum of women after the administration of norgestimate. These studies indicate that 17-deacetyl norgestimate contributes to the pharmacologic response to norgestimate.

Animals↗
PubMed1990

Progestational and androgenic receptor binding affinities and in vivo activities of norgestimate and other progestins.

The progestational and androgenic in vitro receptor binding affinity and the in vivo activity of norgestimate was compared with that of its metabolites and other progestins. The relative binding affinities (RBAs) of norgestimate and its 17-deacetylated metabolite for rabbit uterine progestin receptors were similar to that of progesterone (P); those of 3-keto norgestimate and levonorgestrel were about five times that of P; those of gestodene and 3-keto desogestrel were about nine times that of P. The RBAs of norgestimate, P, and 3-keto norgestimate for rat prostatic androgen receptors were from 0.003 to 0.025 times that of dihydrotestosterone (DHT); those of 3-keto desogestrel, gestodene, and levonorgestrel were from 0.118 to 0.220 times that of DHT. The order of receptor level selectivity represented by the ratio of androgen:progestin IC50 values (with a greater ratio value reflecting a better selectivity) was norgestimate greater than P = 3-keto norgestimate greater than 17-deacetylated norgestimate greater than 3-keto desogestrel greater than gestodene greater than levonorgestrel. In vivo studies demonstrated similar profiles for norgestimate and its 17-deacetylated metabolite. These latter two steroids were equally potent as progestins in stimulating rabbit endometrium, and compared with the other progestins, both steroids exhibited minimal androgenicity as measured by the stimulation of rat prostate growth. In conclusion, these studies, as well as previous preclinical and clinical studies, provide evidence of the selectivity of norgestimate based on minimal androgenicity, indicating an improvement over other progestins used in oral contraceptives.

Animals↗