Uric acid, retention

Although it might seem that adrninistration of enantiomericaHy pure substances would always be preferred, the diuretic indacrinone (3), is an example of a dmg for which one enantiomer mediates the harmful effects of the other enantiomer (4). (+)-Indacrinone, the diureticaHy active enantiomer or eutomer causes uric acid retention. Fortunately, the other enantiomer distomer) causes uric acid elimination. Thus, adrninistration of a mixture of the two enantiomers, although not necessarily racemic, may have therapeutic value. 

Triamterene (31) is a diuretic that has found acceptance because it results in enhanced sodium ion excretion without serious loss of potassium ion or significant uric acid retention. Tautomerism of aminopyrimidines (e.g., 27a and 27b) serves to make the "nonenolized" amine at the 5 position more basic than the remaining amines. Thus, condensation of 27 with benzaldehyde goes at the most basic nitrogen to form 28. Addition of hydrogen cyanide gives the a-aminonitrile (29). Treatment of that intermediate with base leads to the eyelized dihydropirazine compound (30). This undergoes spontaneous air oxidation to afford triamterene (31). ... 

The separation of enantiomers is a very important topic to the pharmaceutical industry. It is well recognized that the biological activities and bioavailabilities of enantiomers often differ [1]. To further complicate matters, the pharmacokinetic profile of the racemate is often not just the sum of the profiles of the individual enantiomers. In many cases, one enantiomer has the desired pharmacological activity, whereas the other enantiomer may be responsible for undesirable side-effects. What often gets lost however is the fact that, in some cases, one enantiomer may be inert and, in many cases, both enantiomers may have therapeutic value, though not for the same disease state. It is also possible for one enantiomer to mediate the harmful effects of the other enantiomer. For instance, in the case of indacrinone, one enantiomer is a diuretic but causes uric acid retention, whereas the other enantiomer causes uric acid elimination. Thus, administration of a mixture of enantiomers, although not necessarily racemic, may have therapeutic value. 

Some drugs, such as the two-substituted thiodiazole and acetazolamide (Diamox), increase serum uric acid by stimulating uric acid synthesis (K9). Others, such as chlorothiazide (Diuril), increase uric acid retention by decreasing uric acid excretion (K9). Hydrochlorothiazide inhibits tubular secretion and has been shown to increase pretreatment mean uric acid values from 6.5 mg/100 ml to 10.3 mg/100 ml by the third treatment day. In a patient with gout, the level increased from 8 mg/100 ml to 12 mg/100 ml (H6). In a single case a paradoxical hypouricemia occurred (H6). 

Pharmacology Thiazide diuretics increase the urinary excretion of sodium and chloride in approximately equivalent amounts. They inhibit reabsorption of sodium and chloride in the cortical thick ascending limb of the loop of Henie and the early distal tubules. Other common actions include Increased potassium and bicarbonate excretion, decreased calcium excretion and uric acid retention. At maximal therapeutic dosages all thiazides are approximately equal in diuretic efficacy. 

Diflunisal 375 mg twice daily caused the plasma levels ofhydrochlorothiazide to rise by 25 to 30%, but this does not appear to be clinically significant. Diflunisal also has uricosuric activity, which counteracts the uric acid retention that occurs with hydrochlorothiazide. 

Second, uric acid retention was not observed after administration of several parasympathomimetic agents. 

Even today, after the development of many powerful and useful new drugs, the organomercurials are unique among these potent diuretics, in spite of their several disadvantages. The mercurials cause little or minimal potassium loss and, in fact, under certain conditions, may exhibit a potassium-sparing action. They are not known to disturb carbohydrate metabolism. They do not cause uric acid retention and certain of them have been shown to have a uricosuric action in man. Whether these desirable properties are a consequence of their structure and mode of action or result from the intermittent or spaced manner of administration is not clear. But these properties of the mercurials continue to be a challenge to the medicinal chemist and present objectives for the design of new structures. 

This approach to the design of structures that mimic the diuretic activity of the mercurials has led to the extremely potent compounds that lack certain of the disadvantages of the mercury-containing drugs and may share, in part, a common mechanism of action. However, other desirable attributes of the mercurials have not been reproduced. Ethacrynic acid, the only compound that has had extensive study both in animals and in man, causes potassium loss and uric acid retention and perhaps some disturbance of glucose metabolism although this latter effect appears to be minimal compared to that observed with many diuretics of the sulfonamide class. 

However, it, too, causes potassium loss, uric acid retention and an alteration in glucose metabolism. How two compounds, ethacrynic acid and furosemide, of such diverse structures elicit similar biological responses lacks, so far, a chemical interpretation. 

In connection with the uric acid retaining property of diuretics. It Is significant to note that several of the thiazides and also ethacrynlc acid, when administered Intravenously, first elicit a uricosuric response of brief duration followed by uric acid retention. However, after oral administration, only the retention Is observed. This two-phase response Is presumably related to the blood concentration of the drugs presented to the kidney. It will be recalled that certain uricosuric drugs that are not natriuretic, particularly probenecid and salicylic acid, at low levels, show a uric acid retention dille higher levels produce uric acid excretion. Further, certain compounds, particularly of the pyrazolldlne-dlone series, have some actions that are the opposite of the diuretics. 

Consider briefly the disease gout, which is characterized by the precipitation of urates in tissues and by the presence of hyperuricemia. Bauer and Klemperer state, 11 "The etiology of the disease is unknown." As has been pointed out by other writers, the presence of high concentrations of uric acid in the blood may be due to (1) overproduction, (2) lowered excretion, (3) lowered destruction, or, of course, any combination of the three. Let us consider two hypothetical individuals, A and B, 30 years of age who have exactly the same uric acid blood level (4 mg. per cent) and exactly the same amount of blood (8 liters). The total uric acid in their respective bloods is 320 mg. Let us suppose further that the rate of production of uric acid in the two individuals is continuously exactly the same, the rate of destruction in the two is continuously the same, and that they consume exactly the same food. One hypothetical individual, A, however, continuously excretes on the average 0.1 mg. less uric acid per day than the other. This is very little, compared with the usual total excretion of 700 mg. per day. In the course of 10 years, A s uric acid blood level will, however, have more than doubled, due to this increased retention, and he will be in the range of "gouty" as contrasted with "normal" individuals. This could happen by a very gradual increase, in one individual, of the renal threshold for uric acid. Whether excretion, production, or destruction is responsible for the difference between individuals, the total accumulation of uric acid in hyperuricemia is small. 

In acidic eluents (Figure 3.9C and D), the retention of acidic compounds becomes stronger and that of basic compounds becomes weaker. In this system, uric acid (h) is not suitable as a void volume marker due to its longer retention time. In neutral and basic eluents, an ionized acid can be used as the marker because no other compounds are eluted more rapidly. Fructose (c) is a very... 

Further investigation on the chemistry of the very potent diuretic drug ethacrinic acid W led to a compound that retained the high potency of the parent with reduced propensity for causing side effects, such as loss of body potassium and retention of uric acid. Friedel-Crafts acylation of dichioroanisole with phenyl acetyl chloride gives ketone 10. This is then reacted in a variant of the Mannich reaction which involves the aminal from dimethyl-... 

In contrast to the reabsorptive defect of acute lead nephropathy, saturnine gout is characterized by renal retention of uric acid [18]. The clearance (Cp ) and maximal secretion rate (Tmp ) for p-aminohippurate (PAH) have been found to be variable in patients with occupational lead nephropathy. 

Secondary gout is a result of hyperuricemia attributable to several identifiable causes. Renal retention of uric acid may occur in acute or chronic kidney disease of any type or as a consequence of administration of drugs diuretics, in particular, are implicated in the latter instance. Organic acidemia caused by increased acetoacetic acid in diabetic ketoacidosis or by lactic acidosis may interfere with tubular secretion of urate. Increased nucleic acid turnover and a consequent increase in catabolism of purines may be encountered in rapid proliferation of tumor cells and in massive destruction of tumor cells on therapy with certain chemotherapeutic agents. 

HPLC methods using ion-exchange or reversed-phase columns have been used to separate and quantify uric acid. The column effluent is monitored at 293 nm to detect the eluting uric acid. HPLC methods are specific and fast, mobile phases are simple, and the retention time for uric acid is less... 

By Ring Transformations with Retention of the Ring Size 2.3.1.2.1. Conversion of Uric Acid... 

The precolumn was first characterized by evaluating the retention times of NADH and the known electrochemical interferences. Spectroscopic detection was used for this, since the electrode passivators (IgG, HSA), uric acid, and NADH absorb at 280 nm, and IgG and HSA are electroinactive at 750 mV versus Ag/AgCI. Figure 16 shows a chromatogram of a blank human serum—NADH mixture which was injected into the Lichrosorb-DIOL precolumn. The first peak (retention time of 113 sec) was primarily composed of IgG and HSA. The second peak (173 sec) was NADH the shoulder that appears at approximately 190 sec was uric acid. Therefore a heart-cut should be from 150 sec (to remove the macro-molecular fraction) to 185 sec (to remove the late-eluting uric acid among other possible interferences). 

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