Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial.

OBJECTIVE: To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids. METHODS: This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence. RESULTS: The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups. CONCLUSION: Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.

An estradiol matrix transdermal system for the prevention of postmenopausal bone loss.

OBJECTIVE: The aim of this study was to evaluate the efficacy, safety, and tolerability of 2 years' application of an estradiol matrix transdermal system for the prevention of postmenopausal bone loss. METHODS: In this multicenter, randomized, placebo-controlled, parallel-group study, 261 surgically or naturally postmenopausal women were randomized to apply the estradiol matrix transdermal system (0.025, 0.0375, 0.05, or 0.1 mg/d) or matching placebo twice a week for 2 years. The study was double blind with respect to treatment (active vs placebo) but not to the dose levels of active treatment (because of the differing sizes and shapes of the patches). In addition to receiving the assigned treatment, the 100 nonhysterectomized women received 2.5 mg medroxyprogesterone acetate daily throughout the study. RESULTS: The evaluable group (n = 259) had a mean age of 52 years and a mean duration of menopause of 32 months. Following 2 years of treatment, there were significant differences in favor of estradiol between all doses of the estradiol matrix transdermal system and placebo in terms of the percentage change from baseline in the bone mineral density (BMD) of the L1-L4 anteroposterior lumbar spine (0.1 and 0.05 mg/d, P < 0.001; 0.0375 mg/d, P = 0.024; 0.025 mg/d, P = 0.002). Percentage changes from baseline in the BMD of the femoral neck after 2 years of treatment also consistently demonstrated the efficacy of the estradiol matrix transdermal system compared with placebo (all, P < or = 0.044). The estradiol matrix transdermal system was well tolerated. CONCLUSION: The estradiol matrix transdermal system was effective in preventing postmenopausal bone loss at dosages of 0.025 to 0.1 mg/d, and had a safety profile consistent with the known effects of estrogen/progestin.

Effect of specific COX-2 inhibition in osteoarthritis of the knee: a 6 week double blind, placebo controlled pilot study of rofecoxib. Rofecoxib Osteoarthritis Pilot Study Group.

OBJECTIVE: To determine the efficacy and safety of the cyclooxygenase 2 (COX-2) specific inhibitor, rofecoxib in patients with osteoarthritis (OA) of the knee. METHODS: Rofecoxib, 25 mg or 125 mg once daily, was compared with placebo in a 6 week, double blind, parallel group, randomized, multicenter study of 219 patients with knee OA. RESULTS: Both doses of rofecoxib produced clinically significant improvement as assessed by primary (e.g., WOMAC Pain Subscale 0-100 mm, decrease from baseline: placebo: 7.1 mm; rofecoxib 25 mg: 28.1 mm, rofecoxib 125 mg: 28.0 mm; p < 0.001 rofecoxib vs placebo) and secondary efficacy (p < 0.05) criteria compared with placebo. Clinical improvement with the 25 mg dose was similar to that with the 125 mg dose. Both rofecoxib doses were generally well tolerated. CONCLUSION: Specific inhibition of COX-2 by 25 and 125 mg rofecoxib, administered once daily, resulted in clinically meaningful improvements in patients with OA. This study confirms that COX-2 derived prostanoids are important clinical mediators of pain and other symptoms of knee OA and that inhibition of COX-1 is not required to provide clinical benefit.

An open-label extension study of alendronate treatment in elderly women with osteoporosis.

We have recently reported the results of a 24-month, double-blind, placebo-controlled study in 359 elderly osteoporotic women who were treated with daily oral alendronate (ALN) 1, 2.5, or 5 mg or placebo (PBO). We report the results of a 12-month, open-label, extension study during which 246 patients from the original study were treated with ALN 10 mg/day. Significant increases in lumbar spine bone mineral density (BMD) were observed in patients who had previously received PBO or ALN 1 and 2.5 mg/day for 24 months. Significant gains in trochanter BMD were seen in all treatment groups. Small changes were observed in femoral neck, total body, and forearm BMD during the course of this extension study. In general, the greatest increases in BMD during the open-label extension year occurred in patients who received either PBO or the lower doses of ALN during the previous 2-year blinded study. The frequencies of all categories of upper gastrointestinal adverse experiences (AEs) were less during months 25-36 (open-label extension) than during months 0-24 (original study). In conclusion, treatment with ALN 10 mg/day for 12 months in elderly women with osteoporosis who were previously treated for 24 months with PBO or ALN 1, 2.5, or 5 mg/day increased or maintained BMD of the spine, trochanter, and forearm, and was generally safe and well tolerated, especially in the upper gastrointestinal tract.

Flare during drug withdrawal as a method to support efficacy in rheumatoid arthritis: amiprilose hydrochloride as an example in a double blind, randomized study.

OBJECTIVE: To evaluate the use of a randomized, double blind, drug withdrawal design as a means to test the efficacy of longterm therapy with antirheumatic drugs. METHODS: We evaluated 286 patients with rheumatoid arthritis (RA) treated with amiprilose hydrochloride for 1-3 years, with response, with or without other antirheumatic therapy, in a double blind, 12 week withdrawal study that compared patients randomized to continue amiprilose therapy vs patients randomized to placebo. The primary efficacy variable was preventing a predefined degree of clinical reactivation, or flare; the statistical tests of success were a difference in the proportion of flares and in the mean time to flare. RESULTS: Thirty percent of patients taking amiprilose and 43% of placebo patients experienced flare (p = 0.026). Patients taking amiprilose had a longer flare-free interval compared to placebo patients (p = 0.027), with the time to reactivation or flare becoming statistically different 73 days after withdrawal. CONCLUSION: Placebo controlled withdrawal designs are useful as evidence to support the longterm effectiveness of therapy in a proportion of patients with RA.

Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone.

Alendronate, an aminobisphosphonate, is much more potent than etidronate, an older bisphosphonate, in inhibiting osteoclast-mediated bone resorption, and unlike etidronate, therapeutic doses of alendronate are not associated with abnormal mineralization. In the present study, we compared the effectiveness, safety, and tolerability of 6 months of daily oral administration of alendronate (40 mg) with those of etidronate (400 mg) in 89 patients with clinically active Paget's disease. The primary efficacy end point was the percent change in serum alkaline phosphatase. Other end points included changes in urinary deoxypyridinoline excretion, pain, functional impairment scores, and radiological osteolysis. Tetracycline-labeled bone biopsies were obtained for histomorphometric analysis from a subset of 43 patients at the 6-month visit. The alendronate-treated group had significantly greater decreases in both serum alkaline phosphatase (79% vs. 44%) and urinary deoxypyridinoline (75% vs. 51%) than the etidronate-treated group (P < 0.001 in both cases). Normalization of serum alkaline phosphatase was much more frequent in alendronate-treated patients (63.4% vs. 17.0%; P < 0.001). Alendronate was well tolerated and had a safety profile similar to that of etidronate. Histomorphometry revealed decreased bone turnover and no qualitative abnormalities, including no direct negative effects on bone mineralization, with alendronate treatment. One patient receiving etidronate developed frank osteomalacia. Alendronate appears to be a highly effective treatment for Paget's disease of bone that offers an important therapeutic advance over etidronate.

Contributions to neurochemical knowledge considered ecologically.

The development of neurochemical knowledge is traced through the following stages: (1) Beginnings with academic medicine: a dissertation of 1719, (2) Relations with chemistry and scientific journals of around 1800, (3) A review and the naming of neurochemistry in 1856, (4) Government publication of neurochemistry; a full-time chemist of the brain, (5) Success in a biochemical environment, 1900-1940, (6) Neurochemistry with the neurosciences, (7) Neurochemical environments of 1955-1957.

How neurochemistry regained its specific biological components: experimental and cognitive advance, 1935-1955.

Neurochemistry in the 1850s was part of comparative animal chemistry, which became incorporated into physiological chemistry. By 1900, the connection with physiological chemistry had largely lapsed or been vehemently repudiated. Growth of biochemistry, especially from the 1920s to 1950s, provided techniques and findings sufficient to reintegrate chemical knowledge of neural systems with neural functioning. Vitamin, coenzyme, respiratory and other metabolic studies made large contributions to this outcome. Regarding mental illness as a social problem and scientific challenge gave impetus and funds to such work, which resulted in major experimental and cognitive progress.

Intra-articular orgotein in osteoarthritis of the knee: a placebo-controlled efficacy, safety, and dosage comparison.

PURPOSE: Superoxide dismutase (orgotein for injection) has been used in managing osteoarthritis for more than seven years in Europe; however, well-controlled studies to establish an optimum dosage regimen have not been conducted. In this study, three orgotein dose/regimens were compared with placebo in terms of efficacy, safety, and duration of effect in patients with active osteoarthritis of the knee. PATIENTS AND METHODS: A total of 139 patients with osteoarthritis of the knee were enrolled in the study. Nonsteroidal anti-inflammatory agents were withdrawn to induce a flare of disease activity. Patients were then randomly assigned to receive one intra-articular injection of either placebo or orgotein (8 mg to 32 mg) each week for three weeks. Both investigators and patients evaluated disease activity and adverse experiences at a series of follow-up visits for three months. RESULTS: Orgotein was effective in reducing symptoms of osteoarthritis for up to three months after treatment; 16 mg given twice was the most effective and most best-tolerated regimen. Discomfort at the injection site was drug related, although this effect also occurred occasionally after injection of placebo. CONCLUSION: The long-lasting effects of intra-articular superoxide dismutase contribute to a favorable risk-benefit ratio and support the importance of the free-radical anion, superoxide (O2-), in the biochemical pathology of osteoarthritis.

Use of fluoxetine, a selective serotonin-uptake inhibitor, in the treatment of obesity: a dose-response study (with a commentary by Michael Weintraub).

Pharmacologic measures which increase serotonergic activity in the brain decrease food consumption and lead to decreased weight in animals. Fluoxetine, an inhibitor of serotonin reuptake, decreases food intake in animals and is associated with weight loss in depressed and otherwise healthy obese patients. To determine the most effective daily fixed dose which causes weight loss in nondepressed obese patients, fluoxetine (10, 20, 40 or 60 mg) or placebo was administered once daily for 8 weeks to 655 patients consisting primarily of women (mean age 40 years, mean weight 95 kg). Diet and activity were not controlled. The placebo-treated patients lost 0.6 +/- 2.3 kg. With the 60-mg fluoxetine dose, patients lost an average of 4.0 +/- 3.9 kg (P less than 0.001), with intermediate responses at the lower doses. Weight loss was proportional to the initial body mass index (weight/height squared). There were no statistically significant differences between any fluoxetine treatment group and placebo for discontinuations from the study. There were statistically significant dose-dependent increases in reports of asthenia, somnolence and sweating. Thus, fluoxetine 60 mg daily appears to be potentially effective for use in weight reduction.

Piroxicam versus naproxen in the treatment of acute musculoskeletal disorders in athletes.

Safe and effective therapy for acute musculoskeletal disorders would be extremely useful for competitive athletes. These injuries are common in these patients, who are usually highly motivated to return to their previous level of activity and performance. Because nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be useful in inflammation-associated conditions such as rheumatoid arthritis and osteoarthritis, it was believed that their use in competitive athletes may be warranted. This study compared the efficacy and tolerability of two NSAIDs, piroxicam and naproxen, in these patients. The patients included 34 men and women who had acute symptoms including restrictions of movement and limitation of physical activity as a result of sprains to the ankle, acromioclavicular joint, and interphalangeal joint of the hand or acute soft-tissue injury to the shoulder, knee, or about the hip. In a double-blind, comparative, parallel manner, patients were randomly allocated to receive piroxicam 40 mg daily for two days and then 20 mg once daily, or naproxen 500 mg twice daily for two days, then 375 mg twice daily. Both drugs improved virtually all measures of physical discomfort after three and seven days of treatment (p less than 0.0001). Three days after beginning the study, the mean reduction in spontaneous pain, swelling, and tenderness was statistically superior in the piroxicam group (p less than 0.05) compared with the naproxen group. After seven days of treatment, a marginally larger reduction in swelling was associated with piroxicam (p = 0.081); however, no other statistically significant difference was seen. Although improvements in physical movement and strength were assessed, no consistent conclusion could be reached because of the small sample size; no statistically significant differences were seen between the treatment groups with respect to such improvements. Patient and investigator assessments of efficacy and tolerability were primarily excellent or good for both drugs. It was concluded that piroxicam and naproxen are effective and well-tolerated short-term treatments for acute musculoskeletal injuries in athletes.

Neurochemistry and related terms: their introduction and acceptance.

Neurochemical terminology first appeared in the 1850s to describe a broadly-based combination of the chemistry and biology of neural systems. This usage was not maintained and the major theme became "brain chemistry", more narrowly based on the brain and on organic chemistry. This term was used between the 1880s and the 1930s for sections in physiological and biochemical texts and for monographs. Neurochemistry was re-introduced in the 1940s, first as an administrative subdivision, then as a description of neurochemical workers and then of their work. Its widespread use dates from 1955 and the neurochemical literature of this period is described. The success of neurochemical terminology at its second introduction is attributed to the adequate development of core subjects, of applied aspects which gave funding, and to a general development of neurosciences.

Adenosine modifies colchicine-uptake into tissues from the mammalian brain.

Colchicine is taken up by isolated cerebral tissues incubated in glucose-salt solutions and is maintained in the tissues when they are superfused with colchicine-free solutions. Most of the colchicine in such tissues remains uncombined after an hour's incubation; up to 20% is combined with tubulin of cytosolic and particulate fractions. Adenosine, and conditions of stimulation or depolarization which release adenosine, diminish the uptake of colchicine and less appears in combined forms. Uptake is diminished also by 2-chloroadenosine and by cyclic AMP; is increased by theophylline and by adenosine deaminase but unaffected by dipyridamole. Adenylate cyclase complexes, with their known tubulin association, are suggested as involved in a route of colchicine-entry and so could give a means whereby environmental changes modify colchicine toxicity, and colchicine-attachment to cerebral preparations.

The origin and use of the terms competitive and non-competitive in interactions among chemical substances in biological systems.

The terms competition and competitive were in use for appropriate types of interaction in human and animal behaviour from the seventeenth century. In the nineteenth and early twentieth centuries they reached more technical uses in biology, especially in darwinian studies; and in chemistry in describing competing reactions, surface phenomena and the influence of substituent groupings in reactant molecules. Use of competitive and non-competitive to describe enzyme inhibitors had a specific beginning when J. B. S. Haldane (following premonitory work of others) applied the terms in 1927 and 1930 to types of inhibition already differentiated by Michaelis and co-workers. The theoretical background in kinetics and stereochemistry so acquired gave a firmness to the application of the terms in biochemistry. The first examples concerned glycosidases, especially beta-D-fructofuranosidase or invertase, and interactions of carbon monoxide and oxygen at iron-porphyrin systems. They were thus of interest in toxicology and in enzyme and carrier studies. The sphere of application of the biochemically-defined terms expanded greatly when, following investigation of sulphonamide action, it was realized that concepts of enzyme inhibition by structurally related compounds offered a route to understanding the action of existing medicaments and to the production of new ones. Ideas and terminology based on competitive and non-competitive enzyme inhibition and receptor occupancy have subsequently been applied in many ways. Examples include application to the analysis of feedback inhibition and other processes of metabolic control; to receptor relationships among neurotransmitters and medicaments; and to understanding interactions at sensory receptors.

Adenosine in cerebral homeostatic role: appraisal through actions of homocysteine, colchicine, and dipyridamole.

Mammalian neocortical tissues were incubated in [14C]adenine-containing fluids and their newly-synthesized adenine derivatives examined after periods of superfusion. Increased [K+] released adenine derivatives from the tissues, a release diminished by homocysteine. Homocysteine acted also to diminish the tissue content of adenosine plus its metabolites hypoxanthine and inosine, while increasing that of S-adenosylhomocysteine. Hypoxia also increased the tissue content and the output of adenosine plus its metabolites, and again homocysteine augmented the S-adenosylhomocysteine. Glutamic acid also increased tissue content and output of adenosine and derivatives, an action diminished by homocysteine and associated with augmented S-adenosylhomocysteine. Colchicine or dipyridamole did not prevent augmentation of S-adenosylhomocysteine by the reagents described; the sequence from adenosine phosphates to S-adenosylhomocysteine is concluded to be intracellular and not to involve extracellular formation of precursor adenosine. Adenosine displayed properties consistent with its being involved in two distinct categories of homeostasis, and also with its exerting an inhibitory tone in normal cerebral systems.

In the beginning: to celebrate 20 years of the International Society for Neurochemistry (ISN).

The antecedents of the International Society for Neurochemistry are described, especially the parts played by the International Neurochemical Symposia held between 1954 and 1962; the Journal of Neurochemistry between 1956 and 1965; and by other organizations concerned with neural systems though not primarily neurochemical. Description is also given of the foundation of the Society in 1965 and of its first International Meeting in 1967.

Assay-guided isolation of naturally-occurring neuroactive substances.

Ways in which chemical techniques could be applied to the understanding of neural systems, their functioning and their disorders were devised only gradually during the present century. In a particularly successful procedure, now termed assay-guided isolation, neural defects were made good by means of tissue-extracts and the restoration of function was established as an assay-system to guide the chemical separation and identification of the active tissue constituent. Thiamin was so isolated, using an experimental polyneuritis assay; subsequent instances among other metabolites, hormones, neurotransmitters and nerve growth factors are recounted. Procedures of assay-guided characterization ensured that links were retained between specific, sparsely-occurring substances and chosen aspects of their biological roles while their chemical nature was first explored and then established. The procedures discouraged the too-facile postulating of hypothetical molecules and contributed to the distinctiveness of neurochemistry as a subject within the neurosciences.

Fenoprofen calcium versus aspirin in the treatment of acute inflammatory soft-tissue injuries.

The efficacy and safety of fenoprofen calcium (Nalfon, Dista, Indianapolis, IN) and aspirin for treating acute inflammatory soft tissue injuries were compared in a 3 to 10-day randomized, double-blind, parallel study of 100 patients with bruise (1), bursitis (33), ligamentous strain (8), myofascitis (43), and tendinitis (15). Forty-seven of the 50 aspirin-treated and 48 of the 50 fenoprofen-treated patients were evaluable. Results of the study showed that fenoprofen calcium and aspirin were equally effective in treating acute inflammatory soft-tissue injuries; however, adverse experiences occurred in fewer patients and at a lower frequency with fenoprofen calcium therapy. In global assessments, 73% of the patients rated fenoprofen therapy as very good or good compared to 64% of the patients who received aspirin therapy. There were no significant differences in the clinician's and the patients' global assessments of therapy. The study suggests that fenoprofen calcium is effective for use in treating soft-tissue injuries since it is better tolerated than aspirin when given in equally effective doses.

Interaction between adenosine generated endogenously in neocortical tissues, and homocysteine and its thiolactone.

[(14)C]Adenine derivatives in normal guinea pig or rat neocortical tissues maintained by superfusion included ATP, ADP and AMP collectively forming some 98% of the acid-extracted (14)C; adenosine, inosine and hypoxanthine each at less than 0.5% and S-adenosylhomocysteine at about 0.1%. l-Homocysteine and/or its thiolactone increased only a little the S-adenosylhomocysteine. The superfusion fluid carried from the tissue per minute about 0.1% of its acid-extractable [(14)C]adenine derivatives. Electrical stimulation of the superfused tissue increased 10-fold its output of [(14)C]adenine derivatives and diminished the 5?-nucleotides in the tissue to 94% of the acid-extractable [(14)C]adenine derivatives, the remainder being adenosine, inosine and hypoxanthine with little change in S-adenosylhomocysteine. Homocysteine in the superfusion fluids now caused large increases in tissue S-adenosylhomocysteine, which became the preponderant non-nucleotide (14)C-derivative when homocysteine was 0.1 mM or greater. The total [(14)C]adenine conversion to non-nucleotide derivatives then increased and the 5?-nucleotides fell to 88% of the total. It is concluded that concentration relationships observed in the action of homocysteine make it feasible that convulsive conditions and mental changes associated with administered homocysteine and with homocystinuria are due to cerebral adenosine concentrations being diminished through formation of S-adenosylhomocysteine. Adenosine is preponderantly depressant in cerebral actions; effects of the S-adenosylhomocysteine produced may also be relevant.