ck~nidine’s therapeutic potential and side- effects with the standard t~~tn~ents. If clonidine is al~\~ to be used to test NA involvement in anxiety. independent meas- ures of NA activity should also be obtained along with objective rating measurements.

Since ~loaidi~ has some primary or see- ondary effects on other brain systems. addi- tional specdic strategies for testing the role of brain NA systems in normal or patholog- ical anxiety are needed. So far, the effects of ctonidine on anxiety do seem insistent with neurophysiological and phurmocolog- ical hypotheses implicating increased cen- tral NA activity as a necessary, but not suf- fiiient, neural &s&ate for anxiety.

2 Gold. M,. S.. Redmond. D. E.. Jr and Klcber.

H. D. f1978)LMcer u. WJ-W?

3 Cedsbaum. 1. M. and A@+nian. G. K. (1977)

High intakes of vitamin Cr A contributor to oxalate fo~mat~un in man? U. Moser and Il. Homig Depamnm of Yitamin and h’unirion Uesearcfz. F. fio@mmn-Ln R&e & Co.. Ltd., C&#Ot?2 &A*, .%&&znd.

lntroductlon Since its first detection in the urine in

tW%by Dorm~l, oxafica&I has remained a leading topic in medical science for its coo- tribution to kidney and bladder stones. The excreted oxalates might be of exogenous or endogenous r&gin, the latter being the prrkkct of several met&ok pathways (Fig. t 1:. Oxaiates are widely di~but~ in plant tissues where they accasionally accumulate to comprise 35-2096 of the totJ dry weight. However, diet contributes fit& to the urinary make level, most of which is derived from endogenous metabolic processe3.

Ascort+c acid accounts for 35-W% of tk 30-W mg excreted oxalatc: per day; giycine. &&ate and other sources add up ta the differen&. In the jnresence of caC cium ions, oxalic acid forms the very slightly soluble salt calcium ox&ate which may precipitate to form calcium oxalate stones in the arinary tract. For the sohrbifity in water is oniy about 9 mg 1-I at 37°C. and

all urines are normatly su~~tumted with respect to calcium oxalate and therefore metastabIe, whether they are from nor- mal or stone-forming ~~v~~ls. Several urinary constituents have been suggested as inhibitors of stone formation in&d- ing glucuronides, inorganic phosphates, colloids, various peptides and several ions. Urinary calcium ions may be complexed with eitmte, phosp~te and sulfate which may therefore influence the availability of calcium for stone formation. Most patients with oxalate calculi Itave no primary disor- der of oxalate metabolism and exm% nor- mal amounts of oxaiate in the urine. On the

Ethylenc Clycol

I - Glycoialdehyde

T1P.S - IhTenlbcr I WC

other hand, different genesis of hyper- oxaluria is known’:

Primary hyperoxuluriu is a relatively rare gcnrtic disorder of oxalate metabolism with calcium oxalate nephmlithiasis. nephrocalcinosis, and progressive renal damage leading to death.

Seconciary hyperoxaluria i-eludes all kinds of oxalate poisoning, w ,ic is seen more frequently in animals than w man.

The major causes of hyperoxaluria are summarized in Table I. Three mechanisms have been proposed to explain increased endogenous production of oxalate leading to hyperoxaluria (Fig. 1): (I) increased production of oxalate due to intake of metabolic precursors. such as the antifreeze solution ethylene glycol; (2) deticiency of pyridoxine acting as coenzyme in several metabolic pathways’; and (3) the primary hyperoxalurias. Abnormalities of the deg- ,radation of ascorbic acid to oxalic acid O:ould not be observed.

‘The contribution of ascorbic acid to oxalate formation

One of the major problems in dealing with oxalate metabolism arises from the

TABLE I. Causes of hyperonahuia

1. tncreawd endokwms praiuct~an of oxatme

A: Increased intake of an oxatae precurnr

El: Pyridoxine deficiency

C: Primary hypmxaluria

It. Incre. seed oxalare intake or absorption

difficulty of measuring oxalate in urine. A large number of methods have been des- cribed. Volumetric procedures such as permanganate titration or cerate oxidometry are not specific, since these oxidants react with many reducing subs tances. A variety of calorimetric methods have been used for the analysis of oxalic acid in biological materials but most arc of limited specificity due to the fairly critical quantitative reduction of oxalic acid to glyoxylic acid. Enzymes like oxalate oxid- ase (EC I .2.3.4) or oxalate decarboxylase (EC 4.1.1.2) may be used as highly specific tools fclr the analysis of oxalate but the catalytic activity may be inhibited by various urinary constituents such as phosphate or sulfate. Analvtical isotachophoresis has recently been intro. duced as a rapid and sensitive method for the quantitative determination of urinar)) oxalateO.

Of the daily mean urinary oxalate excre.. lion, about 35-W% results from ascorbic acid metabolism under normal physiologi- cal conditions. The turnover of metabolites derived from ascorbic acid approaches sat-

60,

40.

20.

0.

0

00 0 0 l

0 l

l l

0

t eb I 40 & 160

TOTAL TURNOVER (KG/ DAY)

uration at approximately 40-50 mg merabo- Investig.:tionz usmg colorlmetnc ~lr lites per day at daily intakes of ascorbic acid enzymatic methods fo: oxalate determma in the physiological range (up to 200 mg) lion arc summarizes? m Table II’. II is (Fig. 2)‘. This implies that the metabolic Important to emphasirr that the obseened contribution of ascorbic acid to oaalate &ght incre;lse in oxalats ctcrstion does not formation is limited. exceed phjsiotogicai fluctuations even m

Due to the increasing use of large intake> jrohthiasis patients. Hanever, there SC .I of ascorbic acid new interest is given to uri- few reports &XWi e-tc-*sive oxalair prioduc- nary oxalate excretion. Investigations on :ion which could be the result of ms~dbolic the urinary excretion of oxalate folluuia; dcfccrb. In 3 patient uith urman hjperox- intakes of ascorbic acid in gram amounfs 3luria and a tin time> urin;in e\crrrlon af revealed contradictory results. but ti\srd; lxalate compared IO nclrmal rxcrrnon I[ of these studies were poorly controlled o: H as pho% n lhar WI> > -“>I of the Wdl r\abtc even uncontrolled and some results arc res.dled from ascorbic d,-id mctah~hsm partly anecdotal. This *u_qe~la that Ihr breakdo\\n of

I?

-II

3

h7

482

EXPERIMENTAL Pf%fOD (DAYS]

ascorbic acid is only a smaff coRtrihution lo t;xafate excretion in this type of disorder. f_r.r,ing isotachophoresis for the specific derermination of oxalic acid in urine it was shown thar the metabolic conversion of a%orbiNc acid to oxalic acid is fimited and more or fess independent of the mode of ingestion of ascorbic acid (single or muf- tipfe dose). Asczrba~e (5 .w S g over 4 days) increavsd the daily oxalate excretion on avrragc by only 14.8 mg (range 1.2-28.6 mg) over the excretion witbout ascorfJic acid toading. Thus, fess than 10% of &e absorbed asccrbate is converted to oxalate. In four male volunteers maintained on an ascorbic acid and oxafatqoor diet, sup plementE1 intakes of 5 x 2 g of ascorbic acid ove- 5 days increased the mean urinary 0xaI~Ke excretion from 50 to 87 mg (range W-f26 mgf pr day (Fig. 3)“. Of the in- gested f0 g of ;;scorbic acid up to 2.7 g dtiy L were found in the urine indicating a rather fimited 3~~tion capacity of tfuz intestine for iarge oral doses of ascnrhate. in this stud) a rel:atively strong individual factor in the metabolism of ascorbzc acid IO oxafate could he observed. As expected. on terminati In of the high ascorbic acid regi- men ox&ale excretion returned rapidly ICI prestudy values.

In anotir experiment the time course of oxafate excretion was followed when sub. jects ingested 2 g samples of vitamin C every 2 h. (Fig. 4p. The rate of urinary ascorbarr increased rapidly, but reached a plateau after *he third ingestion with 20 fig uC’min_‘, which was maintained for up to 6 h following the fast in&e. The mean uri-

nary excnztion rate of oxalatc reached a plateau IOO following the third intllke of’the 2 g ;portion, and returned then to baseline levels, Th2s experiment again demonstrates that the metabolic system converting asct tbic acid to oxalic acid is sdturablc.

11 addit~~, one should keep in mind that the increases in oxelate excretion evoked by hipt intakes of ascorbic acid are compar- able to the changes in urinary oxalate excre tion as a result from consuming normal diet I or provoked hy alimentary changes. The content of oxalate in normal diets has bee] 1 reported’ to vary up to intakes of WI mg )xalateday -I.

Car cfusion P ccording to these results and to a criti-

cal + valuation of the available literature it is con:luded that the metabolism of ascorbic acic is conlributing a certain amount to uri.

nag. excretion of oxalit acid. But. even Fol. lowlng large daily intakes of ascorbate. uri- narr’ oxalate excretion does no1 exceed the critical value of oxalate which is considered to be one of the contributors in the multifac-

T T

toriid process ot oxalate stone formatlon.

Patirnts wun meta~lonc disorders. however,

who convert glycine in ahnormally large

quantities into oxalic acid’” should avoid all sources of addItional oxalate.

Theref(>re. it is suggested that the intake of ascorbic acid, tven in gram amounts, is

no longer discussed as a risk factor in oxa late stone fomiation.

Reading list

9 Schmldr. K H . Hagmaier. V , Homq. D ,

Pharmacological and biochemical studies of stimulus-secretion coupling in the human neutrophil have revealed an under-

Iyin? I+ for citlcium. Indeed. the neutro-

Phil, which contains an inactive nucleus

and fen mitochondria. may he the ideal I,,odel in which II explore general mechan-

isms of cellular responses to external

stimuli, respcm>es which obey the dictum

of otto Loew y , c ‘d3um isr d/CT !

Neutrophils The phagoqtic capacity of neutrophils is

perhaps their most striking property.

Indeed, their normal physiological role is to respond to microbial invasion by ingestion

and eventual destruction of the intruder. This process involves a number of events, starting with their adherence to blood vessel walls and migration toward the site of infec- tion under the direction of chemotactic fdc- tars. Once in contact with the invaders, the

neutrophils phagoqtizc the micr+

organisms. 1)sosomc-i then fuse pith the

phagosomes. disshargmp bactericidal and

degraddtive enzyme% against the entrappd

target I a process called degranulatinn j. In

addition. neutrophds generate react&r

derivattves of ox)pen uhich assist m the

desrruction of microbes. Hotrever. under

terrain patho1ogic.d conditions. g~~ule

contents and 11x1 grn derivative,, m

released into the exm~c~lluktr q-me il!x:td of being safely sequesrered in ph3gos4mes.

This secretory process leads 10 the c:c&on of. or exacerbation of. intlamnWtoq reac-

tions. and is of particular importance in rheumatoid arthritis and gout. Secrerian can he launched not only when neutrophils ingest particles. but also when they are exposed tochemoattractants. Iecrins, tumor promoters and calcitml ionophores (sec- retagogues). For the sake of experimental convenience. this exrracellular relrax of