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.

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.

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.

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.

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.

Colchicine-binding measurements of tubulin in variously sampled and incubated tissues from the mammalian brain.

Tissue preparations from the brain of rats and guinea-pigs were examined for their activity in binding isotopically labelled colchicine, as a measure of their content of tubulin. The amount of binding material extracted into a cold buffered solution was unaffected by keeping tissues at 0 degrees C. It diminished by one quarter when tissues were incubated at 37 degrees C in bicarbonate glucose salines for 1-2 h. This diminution increased when glucose was omitted from incubating solutions and was less when tissues were stimulated electrically. It was modified also by the calcium content of the incubation fluids. Of the binding activity lost on incubation only a little was recovered in surrounding fluids. About half the colchicine-binding activity of the tissues was not extracted by the solution employed; this particulate-attached activity changed little, if at all, on normal incubation but diminished when incubating fluids contained a cyclic AMP-fluoride theophylline mixture which was known to modify tubulin assembly. The retention of both categories of colchicine-binding under normal conditions of incubation is consistent with the ability of such tissues to perform microtubule-dependent processes, notably cytoplasmic transport. Examination of the isolated tissues by the methods reported is of value in indicating which of various factors known to affect separated tubulin and microtubule structures, operate in a cell-containing system under chosen experimental conditions.

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.

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.

The flow of thought and the flow of substance in the brain.

Many neuroactive substances undergo cytoplasmic transport along the axons and dendrites of cerebral neurons, and the expression of their activities is determined by the time occupied by their transport. Such substances include cyclic nucleotides which are formed postsynaptically as mediators by several neurotransmitters including catecholamines, and which are capable of acting at numerous postsynaptic sites during their subsequent intracellular translocation. Temporally patterned changes in cell-firing tendency during some seconds or minutes following brief stimuli are attributed to movement of such compound, as is also the subjective sense of a flow of thought. Descriptions are appraised which indicate that components experienced as part of a stream of thought can be initiated by drive-inducing catecholaminergic systems acting through cyclic nucleotides, thus affording endogenous signals that contribute to electrophysiological matching processes in perception and recall. Roles for satiety mechanisms involving opioid peptides are also assessed.