Evidence of early pyrometallurgy in the kerman range in iran.

Physical and chemical anal ysis of pottery fragments, including a crucible shard and ore samples from Tal-i-Iblis, Iran, suggests that copper smelting may have been well advantced late in the fifth millennium B.C.

Multicenter comparison of naproxen and indomethacin in rheumatoid arthritis.

In a double-blind, crossover study, naproxen, 250 mg twice a day, naproxen, 500 mg taken at bedtime, and indomethacin, 25 mg four times a day, were compared in 132 patients with rheumatoid arthritis; six centers participated in the study. Objective indices of arthritis activity, such as number of clinically active joints, walking time, and duration of morning stiffness, were nearly identical for the three treatment regimens. Of particular interest was the observation that efficacy of a single daily dose of naproxen was comparable to that of the twice-daily dosage. Naproxen was better tolerated than indomethacin, as shown by a statistically significant difference in the incidence of CNS complaints.

Serum concentration and dose-response relationships for carprofen in rheumatoid arthritis.

Thirty-eight patients with active, definite, or classical rheumatoid arthritis were tested in a double-blind, 3-week-per-arm, multiple-crossover, randomized, block-design comparison of 100, 300, 600, and 800 mg/day carprofen given b.i.d. A linear dose-response relationship was demonstrated for six of nine efficacy measures (p less than 0.052). A plasma concentration to therapeutic response relationship was shown just before or 1 to 2 hours after a dose (p less than 0.05) for seven efficacy parameters for the patients with at least three serum carprofen concentrations. By nonparametric analysis, with the patients divided into three equal groups, the percent of responders rose from 38.1% to 50% to 59.1%. Sixty-nine percent of patients responded when carprofen concentrations were greater than 10 micrograms/ml, whereas only 9% responded when they were below 1.9 micrograms/ml. Although only seven patients had limiting side effects, there was a tendency toward a dose-toxicity relationship through 600 mg daily carprofen.

A multicenter trial of sulindac in osteoarthritis of the hip.

Sulindac (cis-5-fluoro-2-methyl-l-[(p-methyl sulfinyl)-benzylidene]-indene-3-acetic acid) is a new nonsteroidal antirheumatic drug recently evaluated in a double-blind trial of 91 patients with hip osteoarthritis. Consecutive patients with documented flare following previous drug withdrawal were randomly assigned to one of 3 treatment groups: (1) sulindac given twice daily, (2) sulindac given 4 times daily, and (3) placebo. The dosage of sulindac, 100 to 300 mg daily, was adjusted according to patient global response and tolerance at 3- to 7-day intervals over 3 wk. Of 15 efficacy measurements evalulated, there was no difference between sulindac given 2 or 4 times daily, but differences were disclosed between one or both sulindac treatment groups and placebo in 11 of the 15 efficacy measurements (p less than 0.05, less than 0.01). The frequency of adverse reactions was of the same order for each treatment group. These included gastrointestinal upset, rash, and dizziness, usually transient and mild to moderate in severity. Serial laboratory studies revealed no evidence of renal, hepatic, or hematopoietic toxicity.

Weber-Christian disease. Analysis of 15 cases and review of the literature.

We report 15 patients encountered over 13 years who presented with inflammation of subcutaneous fat and were given clinical and pathologic diagnoses of Weber--Christian disease (WCD). Prominent clinical features included female predominance, lower extremity nodules, fevers, arthritis/arthralgias, and myalgias. Notable laboratory features were elevated erythrocyte sedimentation rate, anemia, leukopenia, and hypocomplementemia, frequently with circulating 7S IgM or immune complexes at times of active symptoms. Histologic findings were lobular--together with frequent septal--panniculitis, fat-laden macrophages, variable cellular infiltrates, necrosis, and occasional vasculitis. Follow-up revealed the death of 2 patients and disease stabilization or improvement in 13 patients. Six patients developed features of other diseases (factitial disease, erythema nodosum, acute myelogenous leukemia, rheumatoid arthritis, systemic lupus erythematosus, and sarcoid) and a seventh may have had erythema induratum. We suggest that classic WCD, as originally described, reflects an increasingly recognized spectrum of panniculitides. These are syndromes of diverse etiology that share many clinical, inflammatory, and immunologic features.

Efficacy and safety of diclofenac sodium in rheumatoid arthritis. Experience in the United States.

Diclofenac sodium is a nonsteroidal, anti-inflammatory drug that has been studied in the United States for the treatment of rheumatoid arthritis in 681 patients, 468 of whom were enrolled in five multicenter, double-blind parallel controlled investigations. Results of these trials indicate that 150 mg daily of diclofenac is more effective than placebo and as effective as 2.4 g daily of ibuprofen or 3.6 g daily of aspirin. Moreover, the safety profile of diclofenac proved to be better than that of aspirin and similar to that of ibuprofen.

Paraneoplastic vasculitis. Unique syndrome of cutaneous angiitis and arthritis associated with myeloproliferative disorders.

Six patients are described whose myeloproliferative disorders were complicated by inflammation in small, predominantly cutaneous blood vessels. The clinical manifestations of the vasculitis included palpable purpura, urticaria, maculopapular lesions, and erythema multiforme. Vascular inflammation was confirmed by skin biopsy. Two patients experienced fleeting, asymmetrical nondestructive arthritis. Transient proteinuria complicated one case and was the only suggestion of visceral vasculitis. The clinical features of cutaneous vasculitis antedated bone marrow deterioration in four patients and diminished as bone marrow function worsened in all patients. Oral corticosteroids or chemotherapy for the underlying disorder inconsistently affected the clinical course of the cutaneous vasculitis. Myeloproliferative disorders should be considered among disorders that are complicated by inflammation in small blood vessels.

Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events.

PURPOSE: The purpose of this study was to better define the toxicity of low dose (less than or equal to 15 mg/d prednisone or equivalent) long-term (greater than 1 year) corticosteroids in the treatment of rheumatoid arthritis (RA). PATIENTS AND METHODS: We examined an historical cohort of 112 RA patients on low dose (6.1 +/- 3.1 mg/d, mean +/- SD) long-term (6.2 +/- 4.6 years) prednisone (CS) and compared them to 112 matched RA patients not using prednisone (CO). CS were matched one-to-one with CO for sex (75% women), age (+/- 5 yrs), race (98% white), and duration of disease (+/- 5 yrs). Subjects were determined by review of unselected medical records from three distinct rheumatology practice settings. For CS, charts were abstracted from the date of prednisone start for predefined adverse events (AEs). RESULTS: Ninety-two (92) AEs were noted in CS versus 31 in CO and included: fracture (CS:21 versus CO:8), serious infections (CS:14 versus CO:4), gastrointestinal (GI) bleed or ulcer (CS:11 versus CO:4), and cataracts (CS:17 versus CO:5). At time of first AE, CS prednisone average dose was 7.0 +/- 2.6 mg with a duration of 4.9 +/- 3.9 years. Stepwise multiple logistic regression analysis was used to create a model which included all clinically relevant variables and all parameters significantly different at the cohort inception. Prednisone average dose of greater than 10 to less than or equal to 15 mg/d correlated most strongly with the development of an AE (Odds Ratio (OR) = 32.3, 95% Confidence Interval (CI) 4.6, 220). Average prednisone 5 to 10 mg (OR = 4.5, 95% CI 2.1, 9.6), RA nodules (OR = 3.9, 95% CI 1.9, 8.0), and bony erosions (OR = 2.4, 95% CI 1.2, 4.7) also entered the final model. Kaplan Meier survival curves for the development of the first AE showed a dose-response relationship between prednisone and AE occurrence, independent of rheumatoid nodules. Subset analyses utilized a nested case control design for the development of three serious AEs: fractures, serious infections, and GI events. These analyses revealed possible relationships between prednisone use and the development of each specific AE (prednisone use OR: fracture 3.9, 95% CI 0.8, 18.1; infection 8.0, 95% CI 1.0, 64.0; and GI event 3.3, 95% CI 0.9, 12.1). CONCLUSIONS: Although disease severity is an important confounding factor, low dose long-term prednisone use equal to or greater than 5 mg/d is correlated with the development of specific adverse events in a dose-dependent fashion.

Sucralfate treatment of nonsteroidal anti-inflammatory drug-induced gastrointestinal symptoms and mucosal damage.

In a randomized, double-blind trial, sucralfate therapy, 1 g four times daily, was compared with placebo in 143 symptomatic patients to assess the treatment of gastrointestinal symptoms and gastric mucosal damage associated with nonsteroidal anti-inflammatory drugs (NSAIDs). All patients followed a fixed regimen of NSAIDs, were assigned to one of two groups based on the presence or absence of gastric erosions at baseline endoscopy, and were then assigned randomly to receive sucralfate or placebo for four weeks. Patients were then followed for up to six months while receiving open-label sucralfate 1 g twice daily to up to 1 g four times daily. After four weeks of double-blind therapy, patients taking either nonsalicylate NSAIDs or long half-life NSAIDs and who were treated with sucralfate experienced a significant reduction in both peptic symptom frequency and intensity (p less than 0.03) as compared with patients receiving placebo. Sucralfate-treated patients with baseline endoscopic lesions showed a significant reduction in lesion scores (p less than 0.005) at four weeks as compared with baseline, whereas no improvement was observed in gastric mucosal lesions of patients given placebo. Long-term sucralfate therapy resulted in continued improvement in gastrointestinal symptoms and gastric lesion scores in patients receiving all types of NSAIDs. The results indicate that sucralfate used in conjunction with NSAIDs may allow patients to continue therapy by relieving gastrointestinal symptoms and mucosal damage associated with NSAID therapy.

Intra-articular corticosteroids. Guide to selection and indications for use.

Physicians have used intra- and periarticular corticosteroids for treating a variety of rheumatic diseases for nearly 50 years. Yet publications that have carefully examined the mechanisms of action, the pharmacokinetics and the comparative safety and efficacy of the available agents are sparse. This limits our ability to choose a drug scientifically. Similarly, we know little about the long term outcomes of joints infected with corticosteroids versus those not injected. Highly branched esters of methylprednisolone or triamcinolone are the preferred agents used by American rheumatologists. Pharmacokinetic studies reveal that triamcinolone hexacetonide, the least soluble of all the corticosteroid esters, is retained in the joint for 2 to 3 weeks. Intra-articular corticosteroids may implement their anti-inflammatory effect by down-regulating genetic expression of several pro-inflammatory proteins. A literature review suggests that judicious use of intra- and periarticular corticosteroids is very helpful in temporarily reducing pain and inflammation in musculoskeletal structures and may facilitate increased motion and function in selected cases. Their use in juvenile arthritis also appears to be safe and beneficial. Infection in or about the joint in the chief contraindication to use. Adverse effects are very few but the number of injections per joint should probably be limited to 4 or less per year.

The efficacy and safety of low-dose corticosteroids for rheumatoid arthritis.

Low-dose corticosteroids (defined as less than or equal to 10 mg/d of prednisone or equivalent) are used increasingly for the management of rheumatoid arthritis. They are frequently substituted for nonsteroidal antiinflammatory drugs (NSAIDs), particularly in patients with gastrointestinal or other intolerance to NSAIDs, or as "bridge therapy" while patients await the benefits of delayed-acting, disease-modifying agents. Despite their clinical acceptance, published data concerning efficacy are meager. Adverse effects to low-dose corticosteroids are not so frequent nor so severe as those that occur with higher doses. Nevertheless, alterations in glucose metabolism, cutaneous atrophy, cataracts, and glaucoma are common. Osteoporosis, steroid-myopathy, a steroid-withdrawal syndrome, and dysfunction of the hypothalamic-pituitary-adrenal axis appear in some patients. Osteonecrosis, gastrointestinal, cardiovascular, infectious, or neurological complications probably do not occur. Fetal wastage, prematurity, or congenital malformations have not been proven with this dosage.

Venoms, copper, and zinc in the treatment of arthritis.

This article discusses the use of venoms, copper, and zinc in the treatment of arthritis. The author examines the history and effectiveness of viper, bee, and ant venoms in order to determine whether these natural ingredients in anti-inflammatory medications help relieve a patient's symptoms. Copper and zinc studies may offer therapeutic benefits, but there is still no solid consensus on the potential role of these elements in treating arthritis.

Trace elements in the treatment of rheumatic conditions.

The role of trace metallic elements (copper, selenium, zinc, gold) in chronic inflammatory states is of great interest because many of them are co-factors in metabolic processes involving articular tissues and immune system function. Deficiencies of several of these have been documented in patients with rheumatoid arthritis. Other than for the clinically approved gold compounds, there exists only inconsistent evidence for a therapeutic role of trace metallic elements in the management of rheumatoid arthritis.

Comparison of the efficacy, safety, and pharmacokinetic profiles of extended-release ketoprofen and piroxicam in patients with rheumatoid arthritis.

The efficacy and safety of two once-daily nonsteroidal anti-inflammatory drugs (NSAIDs) were compared in a single-center, double-blind, randomized, parallel-group study. Sixty patients with rheumatoid arthritis received either extended-release ketoprofen 200 mg or piroxicam 20 mg once daily for 3 weeks. Both treatments produced significant improvements from baseline in the primary efficacy variables (physician's global assessment, patient's global assessment, number of tender joints, number of swollen joints) at most visits. There were no statistically significant differences between treatments in any efficacy variable except the number of tender joints at week 3, favoring piroxicam. Both treatments improved the quality of sleep. Pharmacokinetic/pharmacodynamic evaluations were conducted on a subset of 29 patients, aged 57 to 71 years. No statistically significant differences in the pharmacokinetic parameters were noted between the first and last dose of extended-release ketoprofen; that is, there was no accumulation of ketoprofen. In contrast, a fourfold increase in peak concentration, a twofold increase in area under the concentration-time curve (AUC), and a 53% reduction in clearance were observed in piroxicam-treated patients. There was a direct relationship between AUC at steady state and three of four efficacy variables for ketoprofen. No correlation between the efficacy scores and trough plasma levels was seen with either drug. There were no significant differences between treatments in the number of adverse events. Elevated mean blood urea nitrogen levels and relative hyponatremia persisted 1 week after the end of treatment in piroxicam-treated patients. The results of this study indicate that extended-release ketoprofen and piroxicam are therapeutically comparable. However, extended-release ketoprofen, in contrast to piroxicam, reached steady state after the first dose, was rapidly cleared, and did not accumulate over the 3-week study period.

Psychosocial factors influence control of moderate and severe hypertension.

Factors affecting the degree of blood pressure control achieved by antihypertensive drug treatment in 150 patients with moderate and severe essential hypertension were analyzed. Patients were under continuing treatment for 1-23 years. Most patients were referred for hypertension which was difficult to control. All were managed by the senior author. They received multiple drug regimens and extensive efforts were made to encourage their adherence to the regimens. In spite of these efforts, 16 (11%) had poor blood pressure control. Satisfactory control was achieved in 52 (35%) patients and excellent control in 82 (55%) patients. As a group, their ideal body weight (IBW) was 125 +/- 22% (mean +/- SD) of normal. The mean number of antihypertensive tablets per day was significantly greater (P = 0.0009) in those with poor control as compared to those with satisfactory and excellent control. As % IBW increased, the number of antihypertensive tablets increased (P = 0.0021). We examined the relationship of blood pressure control with an index of compliance, with psychosocial factors (life events score, martial status) and with socioeconomic factors (work status, income). Poor blood pressure control was associated with a lower compliance index (P less than 0.0001) and a higher life events score (P less than 0.006). Poorly controlled patients were more likely to have poor health in general (P = 0.0002), to have kept fewer medical appointments during the preceding year (P less than 0.0001), to be unmarried (P less than 0.0001), to be unemployed (P less than 0.0028) and have a lower income (P less than 0.009). As % IBW increased, compliance index decreased, (P = 0.0045). Therefore, psychosocial and socioeconomic factors, as well as physical factors, influence blood pressure control in moderate and severe essential hypertension.

Practical approach to hypertension. 1. Diagnostic evaluation.

The comprehensive diagnostic evaluation once recommended for hypertension is no longer practical or necessary. In the majority of cases, a thorough history, physical examination, and basic laboratory workup are sufficient to determine the severity of the hypertension and to detect target organ damage. Secondary hypertension is truly rare in clinical practice and should not be pursued with complex, costly, and possibly risky tests unless specific indications are present.

Practical approach to hypertension. 2. Treatment.

With information obtained from the hypertensive workup (described in part 1 of this article), the physician devises a treatment plan. A stepped-care approach is generally favored, with a diuretic, an adrenergic blocker, and a vasodilator being added in turn until blood pressure is brought under control. The indications and contraindications, dosages, and side effects of the most commonly used antihypertensive agents are discussed here, with suggestions for increasing compliance.

Is Running Associated with Osteoarthritis? An Eight-Year Follow-up Study.

Recreational exercise programs, particularly running, remain popular for a variety of reasons. It has been estimated that as many as 20 to 30 million Americans exercise, and that this includes perhaps 5 to 15 million runners/joggers. Until recently, scant information was available regarding long-term effects, if any, of exercise on the musculoskeletal system. We, and others, therefore studied and reported our observations on the possible association of the development of lower extremity osteoarthritis (OA) in runners. This eight-year, follow-up study of our original 18 nonrunners and 17 runners obtained information on 16 runners (12 of whom were re-examined) and 13 nonrunners (10 of whom were re-examined) in 1992. One runner was deceased (cancer), 14/15 were exercising, 11/15 were running, and 3/15 were engaged in other recreational exercises. In 1992, as in 1984, pain, swelling, and range of motion of hips, knees, ankles, and feet were comparable for runners and nonrunners, and radiographic examinations (for osteophytes, cartilage thickness, and grade of OA) of hips, knees, ankles, and feet were without notable differences between groups. Thus, we did not find an increased prevalence of OA among our runners, now in their seventh decade. These observations support the suggestion that running need not be associated with predisposition to OA of the lower extremities.

Endoscopic evaluation of rioprostil in the management of non-steroidal anti-inflammatory drug-induced gastritis: an interim analysis.

The effects of the synthetic prostaglandin E1 analogue, rioprostil, on non-steroidal anti-inflammatory drug-induced (NSAID) gastritis are investigated. The study is of randomized, double-blind design. Patients are included who had classical or definite rheumatoid arthritis or osteoarthritis, had been taking a stable dose of NSAID or aspirin for at least one month and had endoscopically proven gastric lesion. Endoscopy is performed prior to, and at 4, 8 and 12 weeks of the treatment period. Patients receive either rioprostil, 300 micrograms or 100 micrograms q.d.s., or placebo q.d.s. The results of the endoscopies show greater healing of the mucosa in patients taking rioprostil compared with those taking placebo. It is therefore concluded that rioprostil is an effective compound for the management of patients with NSAID-induced gastritis.