PubMed · 4293821
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A P Hopkins, R W Gilliatt. 1967-11-18. Acrylamide poisoning.. https://doi.org/10.1136/bmj.4.5576.417
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To investigate the mechanism by which the tryptophan synthase beta subunit accelerates the cleavage of the indole-3-glycerol phosphate catalyzed by the alpha subunit (alpha reaction), kinetic experiments were carried out with wild-type and mutant forms of the alpha 2 beta 2 complex. Previous studies indicate that this activation can be attributed to the conformational changes associated with the formation of a Schiff base between aminoacrylate and pyridoxal phosphate at the beta site. To test this hypothesis, we investigated a mutant form of the alpha 2 beta 2 complex having the lysine-87 of its beta subunits replaced by threonine. The mutant alpha 2 beta 2 complex (K87T) exhibits normal activity for the alpha reaction but fails to catalyze formation of L-tryptophan from L-serine and indole (beta reaction). However, the mutant enzyme can form a Schiff base intermediate with L-serine at the beta site. Using a "chemical rescue" method, we converted K87T L-serine intermediate to an aminoacrylate intermediate. Steady-state kinetic studies reveal that the aminoacrylate derivative exhibits a 7-fold enhancement in kcat/Km for the alpha reaction relative to that of the L-serine derivative of the mutant or the wild-type enzyme in the absence of L-serine. Rapid kinetic data show that the aminoacrylate derivative of the mutant enzyme exhibits a 6-fold increase in the rate constant for the indole-3-glycerol phosphate cleavage reaction. In addition, rate constants for the reverse reaction and product release steps are also altered. Together, these changes lead to a decrease in Km and an increase in kcat.(ABSTRACT TRUNCATED AT 250 WORDS)
The angiotensin II (AII) type 1 receptor antagonists represent a new pharmacologic class of drugs that are specifically designed to displace AII from its type 1 receptor subtype. These drugs antagonize AII-induced biologic actions, including smooth-muscle contraction, sympathetic pressor mechanisms, and aldosterone release. Initial clinical trials suggest that these drugs are effective in the treatment of essential hypertension and hypertensive patients with intrinsic renal disease. Thus, they are the newest addition to the therapeutic armamentarium for the treatment of hypertensive diseases. We review the developmental history and pharmacology of the AII type 1 receptor antagonists. We specifically discuss the following factors: mechanism(s) of action; members under clinical investigation; effects on renal function, salt and water excretion, and plasma renin activity, plasma AII type 1, and plasma aldosterone concentrations; and efficacy and safety. Given the demonstrable benefits of AII type 1 receptor blockade, these drugs should achieve broad utility in the treatment of hypertensive diseases.
The dissolution behaviour of a direct compression compact prepared with sodium diclofenac and dibasic calcium phosphate (DCP) in different weight ratios with or without Biosoluble polymer (acrylic-based resin) was investigated in distilled water and in a medium with changing pH. The results indicate that the amount of sodium diclofenac released from the compact was dependent on the amount of drug and DCP used in the compact, and was also controlled by the amount of Biosoluble polymer added. A chemical reaction forming diclofenac acid might occur on the surface of the sodium diclofenac compact during exposure to the acidic medium, which was confirmed by diffuse-reflectance spectroscopy. The tablet with a 1:2 weight ratio of sodium diclofenac to DCP exhibited a sustained-release behaviour, similar to commercial sustained-release products (Voltaren SR-100 and Grofenac Retard), but a lower release rate was found as compared to the commercial products. The dissolution behaviour of the study tablet and the commercial products was found to be dependent on the dissolution medium and the rotating speeds. Glass beads were added to the dissolution assembly to simulate the influence of food, and the enhanced friction between tablet and glass beads might result in a higher dissolution rate of the tablet and the commercial products.