Post-traumatic stress disorder and serum cytokine and chemokine concentrations in patients with rheumatoid arthritis✰.

OBJECTIVE: Although post-traumatic stress disorder (PTSD) is identified as a risk factor in the development of rheumatoid arthritis (RA), associations of PTSD with disease progression are less clear. To explore whether PTSD might influence disease-related measures of systemic inflammation in RA, we compared serum cytokine/chemokine (cytokine) concentrations in RA patients with and without PTSD. METHODS: Participants were U.S. Veterans with RA and were categorized as having PTSD, other forms of depression/anxiety, or neither based on administrative diagnostic codes. Multiplex cytokines were measured using banked serum. Associations of PTSD with cytokine parameters (including a weighted cytokine score) were assessed using multivariable regression, stratified by anti-CCP status and adjusted for age, sex, race, and smoking status. RESULTS: Among 1,460 RA subjects with mean (SD) age of 64 (11) years and disease duration of 11 (11) years, 91% were male, 77% anti-CCP positive, and 80% ever smokers. Of these, 11.6% had PTSD, 23.7% other depression/anxiety, and 64.7% had neither. PTSD, but not depression/anxiety, was associated with a higher cytokine score and number of high-concentration analytes in adjusted models, though this was limited to anti-CCP positive subjects. PTSD was associated with heightened expression of several individual cytokines including IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-17, IFN-γ, GM-CSF, MCP-1, and TNF-α. CONCLUSION: Anti-CCP positive RA patients with PTSD have higher serum cytokine concentrations than those without PTSD, demonstrating that systemic inflammation characteristic of RA is heightened in the context of this relatively common psychiatric comorbidity.

Population pharmacokinetics of glyburide in patients with well-controlled diabetes.

STUDY OBJECTIVES: To investigate glyburide pharmacokinetics in patients with well-controlled noninsulin-dependent diabetes mellitus (NIDDM), and test the hypothesis that intersubject variability in the glyburide dose is due to patient differences in the drug's pharmacokinetics. METHODS: Prospective, open-label study. SETTING: University-affiliated, internal medicine outpatient clinic. PATIENTS: Fifty-one patients with NIDDM (11 women, 40 men, mean age 56.7 +/- 15.3 yrs) receiving oral glyburide and with well-controlled glycohemoglobin levels 10.0% or below. INTERVENTION: After fasting overnight, patients ingested their regular morning dose of glyburide and then ate breakfast. Blood samples were drawn before dosing and between 0.5-2 hours, 2-5 hours, and 5-10 hours after dosing. MEASUREMENTS AND MAIN RESULTS: Serum glyburide was assayed by high-performance liquid chromatography and pharmacokinetics by NONMEM. Glyburide clearance was proportional to weight and greater in older patients (> 60 yrs). CONCLUSION: Variability in the glyburide dose was not primarily due to intersubject differences in the drug's pharmacokinetics.

Effect of two aspirin pretreatment regimens on niacin-induced cutaneous reactions.

OBJECTIVE: To compare the effects of pretreatment with two aspirin regimens and placebo on niacin-induced cutaneous reactions. DESIGN: Randomized, double-blind, placebo-controlled, crossover study. SETTING: Internal medicine clinic in an academic health center. PARTICIPANTS: Forty-two healthy subjects (22 males and 20 females) between the ages of 35 and 65 (mean age 44.2 years) were recruited and completed the study. Subjects received aspirin 325 mg, aspirin 650 mg, and placebo for 4 consecutive days, and on the fourth day also ingested 500 mg of immediate-release niacin 30 minutes after taking aspirin or placebo. They reported the intensity of flushing, headache, pruritus, tingling, and warmth on a 10-cm visual analogue scale. Reactions were evaluated at time 0 (before the niacin dose), and at 15, 30, 60, and 120 minutes following the niacin dose. Cutaneous reactions were compared at each evaluation time and scored by two other methods. The peak intensity was the highest score recorded at any of the four evaluation times after niacin administration. An intensity-time factor was calculated by totaling the scores of each of the four evaluation times. MEASUREMENT AND MAIN RESULTS: The symptom scores for flushing, itching, tingling, and warmth were all significantly reduced by both aspirin regimens (p < .05 in all cases), although there were no significant differences between the 325-mg and 650-mg doses. The results were similar for each scoring method. CONCLUSIONS: An aspirin regimen of 325 mg is effective in suppressing niacin-induced cutaneous reactions. Increasing the dose to 650 mg does not provide additional benefit.

Possible association of a reduction in cardiovascular events with blood donation.

BACKGROUND: The iron hypothesis suggests that females are protected from atherosclerosis by having lower iron stores than men, thus limiting oxidation of lipids. OBJECTIVE: To test the iron hypothesis by comparing cardiovascular event rates in whole blood donors compared with nondonors. DESIGN: Prospective cohort with telephone survey follow up. SETTING: The State of Nebraska, USA. PARTICIPANTS: A sample was selected from the Nebraska Diet Heart Survey (NDHS) restricting for age > or = 40 years and absence of clinically apparent vascular diseases at time of enrollment in to NDHS (1985-87). MAIN OUTCOME MEASURES: The occurrence of cardiovascular events (myocardial infarction, angina, stroke), procedures (angioplasty, bypass surgery, claudication, endarterectomy), nitroglycerin use, or death (all cause mortality), and level of blood donation. RESULTS: Participants were 655 blood donors and 3200 non-donors who differed in education, physical activity, diabetes, and frequency of antihypertensive treatment; 889 were lost to follow up. Sixty four donors and 567 non-donors reported cardiovascular events (crude odds ratio = 0.50, 95% confidence interval (CI) 0.38-0.66). The benefit of donation was confined to non-smoking males (adjusted odds ratio 0.67, 95% CI 0.45-0.99). Benefit was limited to current donors (the most recent three years). No additional benefit resulted from donating more than once or twice over three years. CONCLUSION: In support of the iron hypothesis, blood donation in non-smoking men in this cohort was associated with reduced risk of cardiovascular events. A randomised clinical trial is warranted to confirm these findings as the observed personal health benefit of donation has public policy ramifications.

Treatment of early rheumatoid arthritis with minocycline or placebo: results of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To determine if minocycline is an effective therapy for seropositive rheumatoid arthritis (RA) when used within the first year of disease. METHODS: The Rheumatoid Arthritis Investigational Network enrolled 46 patients with RA of <1 year duration into a 6-month study of minocycline (100 mg twice daily) versus placebo. All patients were rheumatoid factor positive. The primary end point of the study was successful completion of 6 months of treatment with no drug toxicity while maintaining 50% improvement in composite symptoms of arthritis. RESULTS: Eighteen of the 46 patients who were enrolled met 50% improvement criteria at 3 months, and maintained at least a 50% improvement for 6 months with no significant drug toxicity. Among them were 15 of the 23 patients (65%) treated with minocycline and 3 of 23 patients (13%) treated with placebo (P < 0.001). CONCLUSION: In patients with early seropositive RA, therapy with minocycline is superior to placebo.

Safety of antioxidant vitamins.

As a result of the many scientific and popular press reports of the benefits of antioxidant vitamins (vitamin A, beta-carotene, vitamin E, and ascorbic acid), it is estimated that 40% of the US population is consuming vitamin supplements. The efficacy of these supplements is not yet proved, and some have questioned their safety. Approximately 10 to 15 cases of vitamin A toxic reactions are reported per year in the United States, usually at doses greater than 100,000 IU/d. No adverse effects have been reported for beta-carotene. The frequency of vitamin E toxic reactions is not well delineated, but case reports are few at dosages less than 3200 mg/d. Ascorbic acid toxic reactions are rare at dosages less than 4 g/d. Despite a lack of clinical trial data, it seems that antioxidant vitamins are safe, although prudence might dictate their avoidance by women of childbearing potential, persons with liver disease or renal dysfunction, and those taking certain medications or undergoing specific laboratory tests.

Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications.

BACKGROUND: Rheumatoid arthritis is a common disease that causes substantial morbidity and mortality. The responses of patients with rheumatoid arthritis to treatment with a single so-called disease-modifying drug, such as methotrexate, are often suboptimal. Despite limited data, many patients are treated with combinations of these drugs. METHODS: We enrolled 102 patients with rheumatoid arthritis and poor responses to at least one disease-modifying drug in a two-year, double-blind, randomized study of treatment with methotrexate alone (7.5 to 17.5 mg per week), the combination of sulfasalazine (500 mg twice daily) and hydroxychloroquine (200 mg twice daily), or all three drugs. The dose of methotrexate was adjusted in an attempt to achieve remission in all patients. The primary and point of the study was the successful completion of two years of treatment with 50 percent improvement in composite symptoms of arthritis and no evidence of drug toxicity. RESULTS: Fifty of the 102 patients had 50 percent improvement at nine months and maintained at least that degree of improvement for two years without evidence of major drug toxicity. Among them were 24 of 31 patients treated with all three drugs (77 percent), 12 of 36 patients treated with methotrexate alone (33 percent, P < 0.001 for the comparison with the three-drug group), and 14 of 35 patients treated with sulfasalazine and hydroxychloroquine (40 percent), P = 0.003 for the comparison with the three-drug group). Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity. CONCLUSIONS: In patients with rheumatoid arthritis, combination therapy with methotrexate, sulfasalazine, and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine, and hydroxychloroquine.

Efficacy of triple DMARD therapy in patients with RA with suboptimal response to methotrexate.

Rheumatoid arthritis (RA) has a profound effect on patients, producing significant morbidity and in some cases mortality. Because of this, most rheumatologists are moving to disease modifying antirheumatic drug (DMARD) therapy earlier in the course of RA. Methotrexate (MTX) has become the initial DMARD of choice for most rheumatologists. Unfortunately, treatment of RA with a single DMARD, including MTX, often results in a suboptimal response. Therefore, most rheumatologists are now using combinations of DMARD to treat patients with RA who have had incomplete responses to single DMARD therapy. The Rheumatoid Arthritis Investigational Network (RAIN) reported the results of a double blind, controlled comparison of triple drug therapy (MTX-sulfasalazine-hydroxychloroquine) against MTX alone, and against the combination of hydroxychloroquine and sulfasalazine. Twenty-eight patients who had suboptimal responses to MTX or the combination of sulfasalazine and hydroxychloroquine were then treated with triple therapy in an open label study. Fourteen had previously failed MTX therapy, and 14 had previously failed combination therapy with sulfasalazine and hydroxychloroquine. Both groups had statistically significant improvements in sedimentation rates, morning stiffness, swollen joint scores, tender joint scores, patient global status assessment, and physician global status assessment. Statistical significance was reached for all these variables for patients in both groups, but improvement was greater for the patients in the sulfasalazine-hydroxychloroquine group. Patients with RA who have had suboptimal responses to MTX, or to the combination of sulfasalazine-hydroxychloroquine, show both statistical and clinically significant improvement in multiple clinical variables when treated with the combination of MTX 17.5 mg/week, sulfasalazine 500 mg bid, and hydroxychloroquine 200 mg bid.

The antioxidant vitamins: impact on atherosclerosis.

Atherosclerosis, the great killer of Western society, probably is initiated when the balance of subendothelial lipoproteins and oxidation potential is upset. Oxidation products, especially oxidized low-density lipoprotein, set into motion the cascading of numerous pathways, culminating in the fibrous atherosclerotic plaque. The natural antioxidant system includes enzymes and vitamins A, E, and C. The lipophilic vitamins A and E protect the fatty acid components of lipoproteins and membranes, and vitamin C functions in the aqueous phase both directly and by regenerating oxidized vitamin E. In animal models, the antioxidant vitamins protect lipids and prevent atherosclerosis. Population studies suggest an inverse relationship between atherosclerosis and vitamin levels. Several observational studies and some clinical trials have demonstrated that antioxidant vitamin supplements may prevent atherosclerosis. Although approximately 20% of the United States population regularly consumes vitamin supplements, often in high doses, the antiatherogenic benefits of antioxidant vitamins remain unproved by clinical trials, and the long-term effects of mega-dose vitamins are yet undefined.

Blind comparison of patient preference for Flavored Colestid Granules and Questran Light.

OBJECTIVE: To compare the sensory and mixability characteristics of Flavored Colestid Granules (a new colestipol formulation) with Questran Light (the most recent cholestyramine formulation). METHODOLOGY: Seventy-two nonsmoking adults between the ages of 25 and 64 years were enrolled in the study. Subjects assessed the sensory and mixability characteristics of each product in chilled bottled water and orange juice after at least a one-hour fast. Products were administered in a double-blind, randomized fashion. The sensory characteristics that were rated included overall rating, aftertaste, appearance, aroma, color, consistency, flavor, sweetness, mouthfeel, and thickness. Each characteristic was rated with a nine-point hedonic scale. Mixability of the products was assessed on a five-point scale. Subjects also were asked to choose which product they preferred as to sensory and mixability characteristics in each vehicle. RESULTS: Fifty-three of the 72 subjects preferred the sensory characteristics of Flavored Colestid Granules in water (p < 0.001). Questran Light was preferred by 61 subjects when mixed in orange juice (p < 0.001). The sensory characteristic rating scores also supported subject preferences for Flavored Colestid Granules in water and Questran Light in orange juice. Mixability of Flavored Colestid Granules was rated significantly better (p < 0.001) than Questran Light in water. There was no significant difference for mixability between the products in orange juice. CONCLUSIONS: Questran Light was significantly preferred on a sensory basis when mixed in orange juice. Flavored Colestid Granules was significantly preferred over Questran Light for both sensory and mixability characteristics with water as the vehicle.

Pravastatin: a new drug for the treatment of hypercholesterolemia.

The chemistry, pharmacology, pharmacokinetics, clinical trials, adverse effects, role in lipid-lowering therapy, and dosage and administration of pravastatin are reviewed. Pravastatin sodium is a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor for the treatment of hypercholesterolemia. Its structural formula is similar to those of lovastatin and simvastatin, but it is active in the parent form. It competitively inhibits HMG-CoA reductase, reduces hepatic cellular cholesterol synthesis, increases the expression of hepatic low-density lipoprotein (LDL) receptors, and reduces hepatic very low-density lipoprotein (VLDL) synthesis. Pravastatin has been demonstrated to reduce cholesterol in patients with familial and nonfamilial polygenic hypercholesterolemia and patients with diabetes mellitus. In doses of 10-40 mg/day, pravastatin has been shown to reduce total cholesterol by 15-30% and LDL cholesterol by 15-40%. It also increases high-density lipoprotein cholesterol by 2-20% and reduces triglycerides. It is generally well tolerated, with few adverse effects reported in clinical trials. Pravastatin reduces LDL cholesterol and increases HDL cholesterol comparably to lovastatin but possibly with fewer adverse effects. Further studies and clinical use will be needed to confirm potential differences in adverse effect profiles between the two drugs.

Nephrotoxicity associated with concomitant ACE inhibitor and NSAID therapy.

Angiotensin-I converting enzyme (ACE) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) can be nephrotoxic and may synergistically compromise renal function. A computer-assisted study was done to asses the prevalence of compromised renal function and the clinical importance of this drug interaction. A search of the records of all patients seen in the University of Nebraska Medical Center Internal Medicine Clinic was conducted to identify cases involving renal insufficiency, therapy with ACE inhibitors, or therapy with NSAIDs. Records of cases meeting these criteria were reviewed for clinical correlation and revealed 2278 patients treated with NSAIDs, 328 with ACE inhibitors, and 162 with both. No nephrotoxicity was found in conjunction with monotherapy, but three cases of reversible renal failure were found in conjunction with combination therapy. Significant nephrotoxicity during the concomitant use of ACE inhibitors and NSAIDs is not uncommon, and attention should be drawn to this potentially important interaction.

Severe reversible thrombocytopenia resulting from butoconazole cream.

A 54-year-old woman with a 19-year history of rheumatoid arthritis developed life-threatening thrombocytopenia one week after beginning butoconazole therapy for a vaginal yeast infection. This was complicated by upper gastrointestinal hemorrhage that probably resulted from ibuprofen and methotrexate therapy. Sepsis, myelophthisic anemias, and other potential etiologies were ruled out. Once stabilized, the patient was rechallenged with other medications without incident. These findings indicate that a potentially serious thrombocytopenia may result from the administration of butoconazole vaginal cream or in combination with methotrexate and/or ibuprofen.

Acceptability of cholestyramine or colestipol combinations with six vehicles.

Preferences for cholestyramine or colestipol in combination with orange drink, orange juice, grape juice, apple juice, water, or apple sauce were evaluated in 40 healthy adults. Each subject evaluated the taste, texture, and smell of 30-mL samples of 12 drug-vehicle combinations (two drugs, six vehicles) using modified five-point wine-tasting scales. Samples were prepared to contain either cholestyramine 1.0 g or colestipol hydrochloride 1.3 g. The products were tested at room temperature and were administered in a random order. Subjects and observers were blinded to the identity of the products. Acceptability scores for taste, texture, and smell were significantly higher for cholestyramine than for colestipol. Total mean preference scores for cholestyramine-vehicle combinations ranged from 9.9 to 11.7; for colestipol, 6.3 to 8.9. Orange drink, apple juice, grape juice, and orange juice were the preferred vehicles for cholestyramine. The preferred vehicles for colestipol were orange drink, apple sauce, and apple juice.