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J Caldwell

Publications and source records attributed to J Caldwell.

At least 19 recordsLinked to original sources
PubMed2000

Safety and efficacy of meloxicam in the treatment of osteoarthritis: a 12-week, double-blind, multiple-dose, placebo-controlled trial. The Meloxicam Osteoarthritis Investigators.

BACKGROUND: Meloxicam (Mobic; Boehringer Ingelheim, Ridgefield, Conn) is an enolic acid derivative of the oxicam group of nonsteroidal anti-inflammatory drugs (NSAIDs) whose mechanism of action may be related to prostaglandin (cyclooxygenase) synthetase inhibition. In previous studies, meloxicam has been found to be safe and effective in the treatment of osteoarthritis (OA) at doses of 7.5 to 15 mg daily. To evaluate a lower dose and a different patient population, we evaluated the efficacy and safety of 3 doses of meloxicam vs placebo and diclofenac for the treatment of OA among patients with symptom exacerbations. METHODS: In this double-blind, double-dummy, parallel-group, multicenter study, 774 patients with confirmed OA of the hip or knee and a flare were randomized and treated with daily oral administration of meloxicam tablets (at dosages of 3.75, 7.5, or 15 mg/d), diclofenac (100 mg [50 mg twice daily]), or placebo. Treatment was for 12 weeks, with regular assessments for drug safety and efficacy. Safety was assessed by evaluation of adverse events, vital signs, and laboratory data. Primary efficacy variables included the Western Ontario and McMaster University Osteoarthritis (WOMAC) index, the patient's overall assessment of pain, and the patient's and investigator's overall assessment of disease activity. RESULTS: The incidence of all adverse events was lower at each dosage of meloxicam than for diclofenac but greater than for placebo. However, the incidence of gastrointestinal adverse events and dropout rates because of such events was the same for meloxicam as for placebo and lower than for diclofenac. Meloxicam, at 7.5 and 15 mg/d, and diclofenac were statistically significantly more effective than placebo for all end points, while the 3.75-mg/d dosage of meloxicam did not always reach statistical significance for all end points. Efficacy was evident after 2 weeks of treatment, improved with increasing doses, and was maintained until the end of the trial. CONCLUSIONS: Meloxicam is a safe and effective medication for the symptomatic treatment of OA. The data support consideration of 7.5 to 15 mg of meloxicam once daily to treat the pain and stiffness of OA, with gastrointestinal tolerability comparable to that of placebo. Arch Intern Med. 2000;160:2947-2954

Adult↗
PubMed2000

Association of SWAP-70 with the B cell antigen receptor complex.

SWAP-70 is a component of an enzyme complex that recombines Ig switch regions in vitro. We report here the cloning of the human cDNA and its B lymphocyte-specific expression. Although its sequence contains three nuclear localization signals, in small resting B cells, SWAP-70 is mainly found in the cytoplasm. On stimulation, SWAP-70 translocates to the nucleus. In activated, class-switching B cell cultures, it is associated with membrane IgG, but not IgM. The membrane Ig association requires a functional pleckstrin homology domain and is controlled by the C terminus. We suggest that SWAP-70 is involved not only in nuclear events but also in signaling in B cell activation.

Amino Acid Sequence↗
PubMed2000

Estimating cancer risk from outdoor concentrations of hazardous air pollutants in 1990.

A public health concern regarding hazardous air pollutants (HAPs) is their potential to cause cancer. It has been difficult to assess potential cancer risks from HAPs, due primarily to lack of ambient concentration data for the general population. The Environmental Protection Agency's Cumulative Exposure Project modeled 1990 outdoor concentrations of HAPs across the United States, which were combined with inhalation unit risk estimates to estimate the potential increase in excess cancer risk for individual carcinogenic HAPs. These were summed to provide an estimate of cancer risk from multiple HAPs. The analysis estimates a median excess cancer risk of 18 lifetime cancer cases per 100,000 people for all HAP concentrations. About 75% of estimated cancer risk was attributable to exposure to polycyclic organic matter, 1,3-butadiene, formaldehyde, benzene, and chromium. Consideration of some specific uncertainties, including underestimation of ambient concentrations, combining upper 95% confidence bound potency estimates, and changes to potency estimates, found that cancer risk may be underestimated by 15% or overestimated by 40-50%. Other unanalyzed uncertainties could make these under- or overestimates larger. This analysis used 1990 estimates of concentrations and can be used to track progress toward reducing cancer risk to the general population.

Adolescent↗
PubMed2000

Melanomas with concordant loss of multiple melanocytic differentiation proteins: immune escape that may be overcome by targeting unique or undefined antigens.

Melanoma-reactive HLA-A x 0201-restricted cytotoxic T lymphocyte (CTL) lines generated in vitro lyse autologous and HLA-matched allogeneic melanoma cells and recognize multiple shared peptide antigens from tyrosinase, MART-1, and Pme117/gp100. However, a subset of melanomas fail to be lysed by these T cells. In the present report, four different HLA-A x 0201+ melanoma cell lines not lysed by melanoma-reactive allogeneic CTL have been evaluated in detail. All four are deficient in expression of the melanocytic differentiation proteins (MDP) tyrosinase, Pme117/gp100, gp75/ trp-1, and MART-1/Melan-A. This concordant loss of multiple MDP explains their resistance to lysis by melanoma-reactive allogeneic CTL and confirms that a subset of melanomas may be resistant to tumor vaccines directed against multiple MDP-derived epitopes. All four melanoma lines expressed normal levels of HLAA x 0201, and all were susceptible to lysis by xenoreactive-peptide-dependent HLA-A x 0201-specific CTL clones, indicating that none had identifiable defects in antigen-processing pathways. Despite the lack of shared MDP-derived antigens, one of these MDP-negative melanomas, DM331, stimulated an effective autologous CTL response in vitro, which was restricted to autologous tumor reactivity. MHC-associated peptides isolated by immunoaffinity chromatography from HLA-A1 and HLA-A2 molecules of DM331 tumor cells included at least three peptide epitopes recognized by DM331 CTL and restricted by HLA-A1 or by HLA-A x 0201. Recognition of these CTL epitopes cannot be explained by defined, shared melanoma antigens; instead, unique or undefined antigens must be responsible for the autologous-cell-specific anti-melanoma response. These findings suggest that immunotherapy directed against shared melanoma antigens should be supplemented with immunotherapy directed against unique antigens or other undefined antigens, especially in patients whose tumors do not express MDP.

Antigen Presentation↗
PubMed1999

Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group.

CONTEXT: Leflunomide is a reversible inhibitor of de novo pyrimidine synthesis shown to be effective in a phase 2 trial in 402 patients with active rheumatoid arthritis (RA). OBJECTIVE: To compare the efficacy and safety of leflunomide treatment with placebo and methotrexate treatment in patients with active RA. DESIGN: Randomized, double-blind, placebo, and active-controlled 12-month study. SETTING: Forty-seven university and private rheumatology practices in the United States and Canada. PATIENTS: Diagnosis of RA by the American College of Rheumatology (ACR) criteria for duration of 6 months or longer and no previous methotrexate treatment. INTERVENTION: Leflunomide treatment (20 mg/d), placebo, or methotrexate treatment (7.5-15 mg/wk). MAIN OUTCOME MEASURES: American College of Rheumatology success rate (completed 52 weeks of treatment and met the ACR > or = 20% response criteria), disease progression as assessed by x-ray films, and improvement in function and health-related quality of life using the intent-to-treat population. RESULTS: The 482 patients studied were predominantly women (mean age, 54 years; mean disease duration, 6.7 years) for whom a mean of 0.8 disease-modifying antirheumatic drugs had failed. The ACR response and success rates for patients receiving leflunomide treatment (52% and 41%, respectively) and methotrexate treatment (46% and 35%, respectively) were significantly higher than those for patients receiving placebo (26% and 19%, respectively) (P<.001), and they were statistically equivalent, with mean time to initial response at 8.4 weeks for patients receiving leflunomide vs 9.5 weeks for patients receiving methotrexate therapy. X-ray analyses demonstrated less disease progression with leflunomide (P=.001) and methotrexate (P = .02) therapy than with placebo. Leflunomide and methotrexate treatment improved measures of physical function and health-related quality of life significantly more than placebo (P<.001 and P<.05, respectively). Common adverse events for patients receiving leflunomide treatment included gastrointestinal complaints, skin rash, and reversible alopecia. Asymptomatic transaminase elevations resulted in treatment discontinuations for 7.1% of patients receiving leflunomide therapy, 1.7% of patients receiving placebo, and 3.3% of patients receiving methotrexate therapy. CONCLUSIONS: Clinical responses following administration of leflunomide, a new therapeutic agent for the treatment of RA, were statistically superior to those with placebo and equivalent to those with methotrexate treatment. Both active treatments improved signs and symptoms of active RA, delayed disease progression as demonstrated by x-ray films, and improved function and health-related quality of life.

Adult↗
PubMed1999

Corrections

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Journal Article↗
PubMed1999

Dose-loading with hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: a randomized, double-blind six-week trial with eighteen-week extension.

OBJECTIVE: To investigate the usefulness of hydroxychloroquine (HCQ) dose-loading to increase the percentage of responders or rate of response in treating rheumatoid arthritis (RA). METHODS: Two hundred twelve patients with early RA (mean duration 1.5 years) were enrolled in a 24-week trial. Patients were stabilized with 1,000 mg naproxen/day and then began a 6-week, double-blind trial comparing treatment with HCQ at 400 mg/day (n = 71), 800 mg/day (n = 71), and 1,200 mg/day (n = 66), followed by 18 weeks of open-label HCQ treatment at 400 mg/day. RESULTS: All patients had mild, active disease at the time of initiation of HCQ treatment (31-43% rheumatoid factor positive; no previous disease-modifying antirheumatic drugs; mean swollen joint count 8.6-10.4). Based on the Paulus criteria, response during the 6-week double-blind portion of the study was 47.97%, 57.7%, and 63.6% in the 400 mg/day, 800 mg/day, and 1,200 mg/day groups, respectively (P = 0.052). Discontinuations for adverse events were dose related (3 in the 400 mg/day group, 5 in the 800 mg/day group, 6 in the 1,200 mg/day group). Most involved the gastrointestinal (GI) system, with the background naproxen treatment possibly contributing. Ocular abnormalities occurred in 17 of 212 patients (8%) but were not dose related. CONCLUSION: Dose-loading with HCQ increased the degree of response at 6 weeks in this group of patients with early, predominantly seronegative RA. Adverse GI events were dose related, while adverse ocular events were not.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Comparison of the upper gastrointestinal safety of Arthrotec 75 and nabumetone in osteoarthritis patients at high risk for developing nonsteroidal anti-inflammatory drug-induced gastrointestinal ulcers.

A 6-week, multicenter, double-masked, placebo-controlled, parallel-group study compared the upper gastrointestinal (UGI) safety of Arthrotec 75 (diclofenac sodium 75 mg-misoprostol 200 microg; G.D. Searle & Co., Skokie, Illinois) administered twice daily with that of nabumetone 1500 mg administered once daily in 1203 patients with symptomatic osteoarthritis (OA) of the hip or knee. All patients had a documented clinical history of endoscopically confirmed gastric, pyloric-channel, or duodenal ulcer or > or = 10 erosions in the stomach or duodenum. UGI endoscopy was performed at baseline and again at week 6 or early withdrawal. Treatment with Arthrotec 75 resulted in a significantly lower combined incidence of endoscopically confirmed gastric and duodenal ulcers compared with nabumetone (4% vs 11%), and its rate of endoscopically confirmed ulceration was equivalent to that of placebo. The incidence of gastric ulcers alone was also significantly lower with Arthrotec 75 than with nabumetone (1% vs 9%). The incidence of duodenal ulcer with Arthrotec 75 was not significantly different from that with nabumetone (4% vs 3%). Types of adverse events were similar for all treatment groups, with GI adverse events predominating. Arthrotec 75 was well tolerated by the majority of patients. The results of this study demonstrate that Arthrotec 75 has a superior UGI safety profile, causing significantly fewer UGI ulcers, in comparison with nabumetone in patients with symptomatic OA and a documented history of ulcers or > or = 10 erosions.

Adult↗
PubMed1999

Sexual regimes and sexual networking: the risk of an HIV/AIDS epidemic in Bangladesh.

Bangladesh adjoins the Asian region with the severest AIDS epidemic and has common borders with two of the most affected areas, the Indian Hill States and northern Burma. There has been disagreement about the danger to Bangladesh, one view citing the likelihood of transmission from neighbouring infected populations and the other claiming that the country's predominantly Muslim culture protects it. This paper reports on a 1995-1997 research project. Preliminary research was carried out in Dhaka in 1995-1996 which suggested that the poor squatter areas might well sustain an epidemic. The experience also showed that more accurate measures of sexual networking could be obtained from males than females. The 1997 field research reported here investigated 983 males, 52% single and 48% married in Chittagong city and two more rural areas of Chittagong Division in southeast Bangladesh. It was found that around half of all males and probably a somewhat lower proportion of females, experience premarital sexual relations, with males having a lower level of extramarital than premarital relations. The factor heightening Bangladesh's risk of an epidemic is that one-quarter of single males and a significant but lower level of married males have had relations with prostitutes. This is one explanation for quite high levels of STDs in Bangladesh. The factors restricting the chances of a major national epidemic are the small number of premarital sexual episodes per person and the low level of intravenous drug use.

Acquired Immunodeficiency Syndrome↗
PubMed1999

A pilot study using a staph protein A column (Prosorba) to treat refractory rheumatoid arthritis.

OBJECTIVE: To assess the safety and effectiveness of extracorporeal treatments with protein A (Prosorba) columns in the treatment of patients with severe refractory rheumatoid arthritis (RA) in an open label pilot study. METHODS: Fifteen patients with RA who had failed to respond to 2 or more disease modifying antirheumatic drugs were "washed out" for 1-3 months before enrollment into this 6 month pilot study. The treatment schedule called for patients to receive apheresis treatments across staphylococcal protein A columns once a week for 12 weeks. Clinical evaluations of RA activity, defined by Paulus criteria, were conducted at study enrollment (baseline) and monthly throughout the treatment phase. In addition, examinations were conducted at 2, 4, 8, and 12 weeks after the last treatment. Fourteen patients received all 12 scheduled treatments, while one patient received only 10 treatments due to complications secondary to pneumonia. RESULTS: Using Paulus 50% criteria, 9 of 15 (60%) patients were improved at the 4th month, and one more fulfilled >20% Paulus criteria (7%) in the 5th month after starting therapy. The study group reported an average of 2.47 adverse effects per treatment, of which the most common were joint pain and swelling and fatigue of short duration (arthritic flare). CONCLUSION: The adverse effects associated with this apheresis based treatment proved to be manageable and of short duration and resolved without sequelae. The results suggest that extracorporeal protein A therapy may have a role in the management of refractory RA, and encouraged the initiation of a larger, blinded, controlled clinical trial.

Adult↗
PubMed1998

Preoperative risk models for minimally invasive coronary bypass: a preliminary study.

OBJECTIVE: Available risk assessment models are designed for standard coronary artery bypass grafting. We hypothesized that minimally invasive coronary bypass could improve on predicted outcome in extremely high-risk patients (Parsonnet score > 20%) by the current risk models. METHODS: From September 1996 to September 1997, 27 consecutive extremely high-risk patients underwent minimally invasive coronary bypass. Seventeen patients were male; age was 73 +/- 12 years, and 63% of patients were older than 75 years. Left ventricular ejection fraction was 33.7% +/- 15% and 63% had an ejection fraction of less than 35%. The predicted 30-day mortality according to the System 97 model was 25.6% +/- 11.3%. The Parsonnet risk score was 36.2% +/- 11%; the predicted length of stay in the hospital was 15.3 +/- 3 days. The predicted risk of stroke according to the Multicenter Perioperative Stroke Risk Index was 22.3% +/- 11.7%. RESULTS: Minimally invasive coronary bypass was isolated in 20 patients and integrated with angioplasty and stenting in 7 patients. The observed 30-day mortality was 0% (P < .01 vs predicted): at an average follow-up of 10.8 +/- 4.1 months, 26 patients (96.3%) are alive without angina; one patient with acquired immunodeficiency syndrome died on postoperative day 40 of acute pancreatitis. No patient had a stroke or neurologic deficit (P < .01 vs predicted). Patency of internal thoracic artery anastomosis was confirmed by angiography in all 27 patients. No patient required reoperation. Eighteen patients (67%) were extubated in the operating room. The observed length of hospital stay after minimally invasive coronary bypass was 3.8 +/- 2.6 days (P < .01 vs predicted). CONCLUSION: On the basis of our results on a relatively small series of patients, we suggest that risk models geared for standard coronary bypass grafting may not be appropriate for minimally invasive coronary bypass.

Aged↗
PubMed1998

Immunochemical identification of hepatic protein adducts derived from estragole.

Hepatic protein adducts derived from the allylbenzene food flavor estragole, which is hepatocarcinogenic when given to rodents at high doses, have been identified using immunochemical approaches. Male Fischer 344 rats were given estragole orally and hepatic protein adducts were detected by immunoblotting, using antisera raised by immunizing rabbits with 4-methoxycinnamic acid-modified rabbit serum albumin. A major 155-kDa adduct was expressed in livers of animals that had been treated with estragole at 100, 300, or 500 mg/kg. Levels of expression of the adduct increased disproportionately with respect to dose, and other adducts (170, 100, 44, and 35 kDa) were detected also in the high-dose group. Rats given estragole for 5 days, at 300 mg/kg/day, expressed predominantly 155- and 44-kDa adducts. The 155-, 100-, 44-, and 35-kDa adducts were detected in greatest abundance in liver microsomal fractions, while the 170-kDa adduct was most abundant in the nuclear fraction. Interestingly, whereas the 170-, 155-, 100-, and 35-kDa adducts were detected in cytosolic fractions, relatively low levels of the 44-kDa adduct were detected in nuclear fractions but not in cytosolic fractions. The various adducts were solubilized when microsomal fractions were extracted with sodium carbonate and were digested by trypsin. This implies that the target proteins are peripheral membrane proteins bound to the outer surface of microsomal membranes. Experiments undertaken with isolated rat hepatocytes and with V79 cells transfected with human monoamine phenol sulfotransferase cDNA revealed that adduct formation required 1'-hydroxylation of estragole, followed by sulfation. The pattern of adducts expressed when the transfected V79 cells were incubated with 1'-hydroxyestragole was very similar to that expressed in livers of estragole-treated rats. These cells should constitute a valuable in vitro model system for investigation of toxicological consequences arising from estragole-induced protein adduct formation.

Allylbenzene Derivatives↗
PubMed1998

Neurotoxicity risk assessment of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) as a synthetic impurity of drugs.

1-Methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) induces symptoms indistinguishable from those of Parkinson's disease. It selectively destroys dopaminergic neurons in the substantia nigra and the globus pallidus. Death of these same neurons is apparently the cause of idiopathic Parkinson's disease. As phenyl-1,2,3,6 tetrahydropyridine is a commonly encountered subunit in heterocyclic drugs and because MPTP was found as a minor impurity in early batches of a candidate drug at Merck KGaA, it may be assumed that MPTP will also be present as an as yet undiscovered minor impurity in various existing drugs. A neurotoxicity risk assessment on MPTP has been conducted to define the risk of MPTP as an impurity in drugs that are used orally. This risk assessment has shown that compounds containing less than 5.0 p.p.m. MPTP administered orally will not cause a neurotoxicological health risk to patients treated with such a drug.

Animals↗