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Biomedical subjects

J W Jacobs

Publications and source records attributed to J W Jacobs.

At least 55 records · Page 3Linked to original sources
PubMed1996

AF12198, a novel low molecular weight antagonist, selectively binds the human type I interleukin (IL)-1 receptor and blocks in vivo responses to IL-1.

Interleukin-1 (IL-1) -alpha and -beta are potent regulators of inflammatory responses. The naturally occurring interleukin-1 receptor antagonist (IL-1ra) is effective in vitro and in vivo in modulating biological responses to IL-1. We have previously reported the discovery of IL-1 antagonist peptides from the search of phage display libraries. Further characterization of this group of peptides has led to a 15-mer, AF12198, Ac-FEWTPGWYQJYALPL-NH2 (J represents the unnatural amino acid, 2-azetidine-1-carboxylic acid), with both in vitro and in vivo IL-1 antagonist activity. AF12198 selectively binds the human type I IL-1 receptor but not the human type II receptor or the murine type I receptor. In vitro, AF12198 inhibits IL-1-induced IL-8 production by human dermal fibroblasts with a half-maximal inhibition concentration or IC50 of 25 nM and IL-1-induced intercellular adhesion molecule-1 (ICAM-1) expression by endothelial cells with an IC50 of 9 nM. When given as an intravenous infusion to cynomolgus monkeys, AF12198 blocks ex vivo IL-1 induction of IL-6 and down modulates in vivo induction of IL-6. This is the first small molecule to show IL-1 receptor antagonist activity in vivo.

Amino Acid Sequence↗
PubMed1996

High affinity type I interleukin 1 receptor antagonists discovered by screening recombinant peptide libraries.

Two families of peptides that specifically bind the extracellular domain of the human type I interleukin I (IL-1) receptor were identified from recombinant peptide display libraries. Peptides from one of these families blocked binding of IL-lalpha to the type I IL-1 receptor with IC50 values of 45-140 microM. Affinity-selective screening of variants of these peptides produced ligands of much higher affinity (IC50 approximately 2 nM). These peptides block IL-1-driven responses in human and monkey cells; they do not bind the human type II IL-1 receptor or the murine type I IL-1 receptor. This is the first example (that we know of) of a high affinity peptide that binds to a cytokine receptor and acts as a cytokine antagonist.

Animals↗
PubMed1996

The effectiveness of early treatment with "second-line" antirheumatic drugs. A randomized, controlled trial.

OBJECTIVE: To compare two therapeutic strategies for patients with recent-onset rheumatoid arthritis. DESIGN: Open, randomized clinical trial. SETTING: Outpatient clinics of six clinical centers. PATIENTS: 238 consecutive patients with recently diagnosed rheumatoid arthritis. INTERVENTIONS: Delayed or immediate introduction of treatment with slow-acting antirheumatic drugs (SAARDs). MEASUREMENTS: Primary end points were functional disability, pain, joint score, and erythrocyte sedimentation rate at 6 and 12 months and progression of radiologic abnormalities at 12 months. RESULTS: Statistically significant advantages at 12 months for patients receiving the SAARD strategy (immediate treatment with SAARDs) with regard to all primary end points that may be clinically important are indicated by the differences in improvements from baseline and their 95% CIs. These differences were 0.3 (95% CI, 0.2 to 0.6) for disability (range, 0 to 3), 10 mm (CI, 1 to 19 mm) for pain (range, 0 to 100 mm), 39 (CI, 4 to 74) for joint score (range, 0 to 534), and 11 mm/h (CI, 3 to 19 mm/h) for erythrocyte sedimentation rate (range, 1 to 140 mm/h), all in favor of SAARD treatment. The SAARD strategy also appears to be advantageous at 6 months. Radiologic abnormalities progressed at an equal rate in the SAARD and the non-SAARD groups; the difference in progression (range, 0 to 448) was 1 (CI, -3 to 5). Analyses were based on the intention-to-treat principle and thus included 29% of patients in the non-SAARD group who discontinued the non-SAARD treatment strategy; treatment was usually discontinued because of insufficient effectiveness. The SAARD strategy including two alternative SAARDs could not be continued by 8% of patients, usually because of adverse reactions. CONCLUSIONS: Early introduction of SAARDs may be more beneficial than delayed introduction for patients with recently diagnosed rheumatoid arthritis.

Adrenal Cortex Hormones↗
PubMed1996

Versatile approach to encoding combinatorial organic syntheses using chemically robust secondary amine tags.

Encoded combinatorial organic synthesis has recently emerged as a powerful tool for the discovery of biologically active compounds from complex chemical libraries. This report describes a new encoding methodology that uses chemically robust secondary amines as tags. These amines are incorporated into an N-[(dialkylcarbamoyl)methyl]glycine-coding oligomer through simple chemistry that is compatible with a wide range of polymer-supported transformations useful in combinatorial synthesis. In the decoding process acidic hydrolysis of the tagging polymer regenerates the secondary amines, which after dansylation are resolved and detected at sub-picomole levels by reversed-phase HPLC. The versatility of this strategy is demonstrated here by encoded syntheses of members of several representative heterocyclic compound classes, including beta-lactams, 4-thiazolidinones, and pyrrolidines.

Anti-Bacterial Agents↗
PubMed1996

Lack of correlation between the mean tender point score and self-reported pain in fibromyalgia.

OBJECTIVES: To study the validity and nature of self-assessed symptoms among patients with fibromyalgia syndrome (FMS) and to compare our data with findings reported in the US. To determine whether tender point scores correlate with self-reported pain and other symptoms and to study the influence of disease duration. METHODS: Tender point scores were assessed in 113 consecutive patients with FMS. All patients completed 2 self-assessment questionnaires (an extended Campbell list, the Enschede Fibromyalgia Questionnaire, and the Dutch Arthritis Impact Measurement Scales). RESULTS: The self-assessed symptoms of the Dutch FMS patients seem to be valid and are comparable with those of American patients. No association between disease duration and number of self-reported symptoms was found. An association between self-reported pain and mean tender point score was lacking for patients with disease of shorter duration and was weak for patients with disease of longer duration. CONCLUSIONS: The use of a self-report questionnaire for patients with FMS is feasible and appears to be valid. Tender point scores and self-reported pain represent very different aspects of pain in FMS.

Adult↗
PubMed1996

Combinatorial modification of natural products: preparation of unencoded and encoded libraries of Rauwolfia alkaloids.

We report the preparation of combinatorial libraries which consist of derivatives of the stereoisomeric alkaloids yohimbine and rauwolscine-members of the Rauwolfia genus. The chemistry was performed on solid support using the divide-and-pool method, and involved the derivatization of the E-ring carboxylates and hydroxyls of these alkaloids with 36 amino acids and 22 carboxylic acids, respectively, to afford 792 bifunctionalized derivatives. The rauwolscine library was prepared using an encoding strategy in which the identity of each incorporated amino acid was recorded by cosynthesizing chemically inert tags prior to the pooling step. The general strategy for library synthesis exploits existing functionality present on the natural products, and should be applicable to other families of secondary metabolites.

Chromatography, High Pressure Liquid↗
PubMed1996

Androgens as adjuvant treatment in postmenopausal female patients with rheumatoid arthritis.

OBJECTIVE: To examine the possible beneficial effect of androgens in postmenopausal women with active rheumatoid arthritis. METHODS: 107 women participated in a double blind placebo controlled trial to evaluate the effect of 50 mg testosterone propionate intramuscularly every two weeks for one year. RESULTS: An improvement in ESR, Dutch health assessment questionnaire, and pain was noted. In addition, 21% of patients treated with testosterone fulfilled the ACR improvement criteria after one year, versus only 4% of the placebo group. The treatment was well tolerated. CONCLUSIONS: Testosterone may improve the general wellbeing of postmenopausal women with active rheumatoid arthritis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Changes in (markers of) bone metabolism during high dose corticosteroid pulse treatment in patients with rheumatoid arthritis.

OBJECTIVE: To examine the effect of high dose corticosteroid pulse treatment (three times 200 mg dexamethasone intravenously in eight days) on calcium and bone metabolism in 17 consecutive patients with active rheumatoid arthritis (RA). METHODS: Bone formation was quantified by measurement of serum alkaline phosphatase, osteocalcin, and carboxyterminal propeptide of type I procollagen (pro-I-CPP) concentrations. Bone resorption was measured by urinary excretion of calcium, hydroxyproline, (free and total) deoxypyridinoline (Dpyr), (free and total) pyridinoline (Pyr), and serum concentrations of the carboxyterminal cross linked telopeptide of type I collagen (I-CTP). Disease activity of RA was measured by erythrocyte sedimentation rate, C reactive protein, and Ritchie and Thompson joint scores. RESULTS: Disease activity was initially high, and decreased during corticosteroid pulse treatment and the following five weeks. Osteocalcin, alkaline phosphatase, and pro-I-CPP concentrations were initially within normal limits, while I-CTP, Dpyr, and Pyr were increased. Osteocalcin and pro-I-CPP concentrations decreased (p < 0.01) during corticosteroid pulse treatment, but rapidly returned to baseline after the treatment. No changes were observed in alkaline phosphatase and urinary excretion of calcium and hydroxyproline. Bone resorption measured by serum I-CTP and urinary excretion of Pyr and Dpyr was unchanged or decreased (p < 0.05-0.01), depending on the time of measurement and the parameter measured. CONCLUSIONS: In these patients with active RA, bone resorption was increased, while bone formation was within normal limits. During high dose corticosteroid pulse treatment, bone formation was only transiently decreased, while markers of bone resorption were unchanged or decreased. Because corticosteroid pulse treatment has only a short term negative effect on bone formation, and because it probably reduces bone resorption, at least partly as a result of the decreased disease activity, the effect of corticosteroid pulse treatment on bone may be assumed to be relatively mild.

Acute Disease↗
PubMed1996

Diminished autonomic nervous system responsiveness in rheumatoid arthritis of recent onset.

OBJECTIVE: To investigate responsiveness of the autonomic nervous system in rheumatoid arthritis (RA) of recent onset. METHODS: 21 patients (17 women, mean age 55.7 years) and 20 healthy controls (16 women, mean age 52.7 years) were subjected to 4 tasks eliciting divergent autonomic reactions: film watching, mild physical exercise, cognitive discrimination, and the Stroop color-word interference test. Changes in heart rate, diastolic (DBP) and systolic (SBP) blood pressure, and skin conductance relative to pretask baseline values were computed and related to erythrocyte sedimentation rate, pain, mobility, and dexterity. RESULTS: Mean autonomic levels of patients were normal, as well as autonomic responses to film watching and mild physical exercise. Diminished autonomic responses were observed during cognitive discrimination and during the Stroop test. Blood pressure responses were negatively related to pain severity, but positively to impaired dexterity. CONCLUSION: Diminished autonomic nervous system response is observed in RA of recent onset, most clearly in patients with more severe pain. This suggests that it is associated with primary pathophysiological mechanisms.

Adult↗
PubMed1995

Prediction of progression of radiologic damage in newly diagnosed rheumatoid arthritis.

OBJECTIVE: To investigate the extent to which early radiologic damage is predicted by joint inflammation in patients with newly diagnosed rheumatoid arthritis (RA). METHODS: Regression analysis was performed on 1-year progression of total radiologic damage for baseline characteristics and cumulative disease activity measures, and the effects of continued joint inflammation on the progression of damage in separate joint groups were investigated. RESULTS: Odds ratios for progression of total damage were 12 for the presence of rheumatoid factor, 5 for the presence of damage at baseline, and 2 for cumulative joint inflammation. A positive association between continued joint inflammation and progression of damage was found to be statistically significant for most joint groups. CONCLUSION: Progression of radiologic damage in patients with newly diagnosed RA is independently associated with the presence of rheumatoid factor and damage at baseline and with cumulative joint inflammation.

Adult↗
PubMed1995

Changes in calcium and bone metabolism during treatment with low dose prednisone in young, healthy, male volunteers.

The effect of low dose prednisone on calcium and bone metabolism was evaluated in 8 healthy, young, male volunteers. Sodium and calcium intake were kept stable during the whole study period of 7 weeks. Week 0 was the baseline period; during week 1, 3 and 5 prednisone (10 mg/day) was given, during week 3 together with 500 mg elementary calcium and during week 5 with 4000 IU vitamin D on alternate days. During week 2, 4 and 6 no medication was given. No changes occurred in fasting urinary excretion of calcium or hydroxyproline, nor in serum levels of alkaline phosphatase, 25-Vitamin D, PTH, creatinine and inorganic phosphorus. A rapid decrease of serum osteocalcin during prednisone intake was found (p<0.01). This dip also occurred during prednisone and vitamin D treatment, but did not occur when calcium was added to prednisone, although the baseline value was lower at the start of combined treatment with prednisone and calcium. Serum calcium decreased during prednisone (p<0.05), but when prednisone was given together with calcium, an increase of serum calcium was found (p< 0.05). It is concluded that 10 mg prednisone/day decreases bone formation, as shown by its effect on osteocalcin, while no influence is seen on bone resorption. Thus, prednisone, even when used in low doses, influences bone metabolism by uncoupling bone formation (decreased) and bone resorption (unchanged). These data suggest that the Cs-associated decrease in serum osteocalcin and in serum calcium does not occur during calcium suppletion.

Adult↗