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Hyperventilation Syndrome, Treatment With
L-Tryptophan and Pyridoxine; Predictive Values
of Xanthurenic Acid Excretion.
M.J.A.J.M. Hoes, M.D.1, P. Colla2, H. Folgering, M.D., Ph.D.3
A case is made for the pathophysiological The hyperventilation syndrome (HVS) is a importance of the cerebral serotonergic functional syndrome (van Dis, 1978) caused by neurons in the hyperventilation syndrome stress (Hermann et al., 1978). Important (HVS). Their function depends on the systemic features of the HVS are the increased respir- ation, the anxiety, and an often occipitocervical The role of L-tryptophan metabolism is headache and muscular hypertonia (Hardonk studied in 13 HVS patients, by administration of pyridoxine 125 mg t.i.d. and L-tryptophan two The cerebral serotonergic neurotransmission grams for four weeks. The xanthurenic acid (CST) is important to these symptoms on the excretion (XA) is measured as an index of the basis of the following evidence from animal peripheral L-tryptophan metabolism, before experiments: CST activates the inhibition of treatment. The treatment resulted in freedom of respiration that is found during an acute alcohol hyperventilation attacks in nine patients. The intoxication (Smith et al., 1975) or during XA was elevated or low in eight and normal in one of the nine responders and normal in the experimental models of anxiety (Ellison, 1975). The extremes in the XA excretion had dis- CST is important in the inhibition of pain appeared after treatment. Treatment results and (DeSousa and Wallace, 1977; Hoes, 1979-c). XA data indicate that the L-tryptophan CST inhibits muscle tone as a result of an metabolism is important in the pathophysiology inhibition of afferent input (Hoes, 1979-c), a of the HVS, and that the XA discriminates stimulation of Ren-shaw interneurons (Meyers- responders from non-responders to pyridoxine, monosynaptic reflexes (Clineschmidt and Andersen, 1970). Because of this evidence, underactivity of the CST is proposed as a pathophysiological model for HVS. As a matter 1 Lecturer for Biological Psychiatry, University of of fact, the effectiveness of clomipramine in Nijmegen, The Netherlands; Dept. of Psychiatry, Bethesda Hospital, Tiel, The Netherlands. 2 Psychologist, Dept. of Social Psychiatry, University of Nijmegen. 3 Dept of Physiology, University of Nijmegen. ORTHOMOLECULAR PSYCHIATRY, VOLUME 10, NUMBER 1,1981, Pp. 7-15
enhancement of the CST (Hoes et al., 1980- plasma (Fernstrom and Lytle, 1976). The plasma concentration of L-tryptophan is lowered by a The CST is dependent on the cerebral syn- diet short of L-tryptophan, or by increased thesis of serotonin from L-tryptophan. The rate-limiting step in this process is the cerebral biosynthesis of nicotinamide (NiA) (Figure 1). L-TRYPTOPHAN-NICOTINAMIDE BIOSYNTHESIS A shorthand version of the nicotinamide
biosynthesis. Hypercorticism induces the pyrrolase; enhanced pyrrolase activity will pull more L-tryptophan in this synthesis, activating
the pyridoxal-5-phosphate containing enzymes (vitamin B6). This activation by substrate and the induction of other pyridoxal-containing
enzymes by hypercorticism, leads to a relative pyridoxal-deficiency. To this pyridoxal-deficiency the kynureninase is the most sensitive
enzyme in the nicotinamide biosynthesis. The xanthurenic acid excretion will rise by the enhanced pyrrolase and diminished
kynureninase activity. The xanthurenic acid excretion may eventually diminish, only when not enough pyridoxal is available for the
mitochondrial transaminase in the xanthurenic acid side-chain, this enzyme being less sensitive to a pyridoxal-deficiency.

A good diet supplies about one gram of L- pyrrolase; this is notably caused by gluco- tryptophan a day. Man synthesizes about 12-15 corticosteroids (Green, 1978). This induction of mg NiA a day. For the synthesis of one mg of the pyrrolase may engender a considerable loss NiA, 60 mg L-tryptophan are needed. So, man of L-tryptophan from the systemic circulation, needs 720-900 mg of L-tryptophan a day for his and thus deprive the cerebral serotonin synthesis NiA synthesis. Two thirds of his daily NiA- of its mother-substance (Curzon, 1969; Hoes, requirements are covered by his own synthesis; the remaining one third is covered by uptake The functional state of the NiA biosynthesis is from the food. Thus, the NiA synthesis is the studied by measuring the urinary excretion of major metabolic pathway for L-tryptophan in intermediates such as 3-hydroxyky-nurenine, or side-chain products such as xanthurenic acid Increased utilization of L-tryptophan in the (XA), after oral intake of a loading dose of L- NiA synthesis is caused by induction of the XANTHURENIC ACID IN HYPERVENTILATION
1980-b). The excretion of XA in this loading test, positive feedback in the HVS pathophysiology as is elevated in anxiety, and this is explained by long as the anxiety persists. As a matter of fact, effects of elevated glucocorticoid plasma Lewis (1959) proposed on clinical evidence in his concentrations on the NiA synthesis (Hoes, 1979- model of sequence of events characterizing the a). HVS patients are anxious in general, and so HVS, that apprehension reinforces the HVS one expects that HVS patients will have an (Figure 2). The HVS provokes a hypocapnia, the elevated XA excretion in the L-tryptophan hypocapnia aggravates the HVS symptomatology, loading test. the perception of these symptoms leads to When the HVS patients have an elevated XA apprehension and this apprehension reinforces the excretion, this indicates that they derive L- tryptophan from the cerebral serotonin synthesis. If the peripheral metabolism is that important to Since underactivity of the CST is proposed as the pathophysiology of the HVS, then two pathophysiological mechanism of HVS, an predictions should be investigated: elevated XA excretion indicates a SEQUENCE OF EVENTS CHARACTERIZING HYPERVENTILATION SYNDROME (after Lewis, 1959).
The disorders in the L-tryptophan metabolism facilitate the different steps in the sequence, inducing a positive feedback in the
development of the disorder. (See text, under discussion.)
1) In HVS patients the excretion of XA in a Patients and Methods
Thirteen patients (4f, 9m; age: 34.5+9.2 yrs, range 22-56 yrs) were selected according to the HVS criteria specified elsewhere (Folgering and Colla, 1978). Patients with another psychiatric a) Correction of the XA-excretion. Pyrid- diagnosis but anxiety neurosis according to the oxine 125 mg t.i.d. during four weeks will Feighner criteria (Feigh-her et al., 1972) were b) Supplementation of L-tryptophan to contraceptives or other hormones. First, the XA correct any L-tryptophan-deficiency state. Two grams of L-tryptophan are sufficient (Hoes, 1979-b). 9 ORTHOMOLECULAR PSYCHIATRY, VOLUME 10, NUMBER 1, 1981, Pp. 7-15
in urine, collected during 24 hours after oral (28.8±2.2 years) (Table 2). The L-tryptophan intake of 5 grams of L-tryptophan at 22.00 loading test had to be repeated just in the hours, as described previously (Hoes, 1979-a; responders whereas the non-responders excreted Hoes et al, 1980-b). Then the patients received normal amounts of XA (Table 3). All checks for pyridoxine 125 t.i.d. + L-tryptophan 2 g vesp., diabetes mellitus were normal in all 13 patients. both for four weeks, as described previously The XA-excretion in the responders is high (Hoes, 1979-a). During the fifth week they were interviewed about their frequency of attacks and treatment one high excretor (nr.3) is still high, HVS symptoms (Folgering and Colla, 1978). while one low excretor (nr.7) excretes a high The L-tryptophan loading test was repeated if amount XA. Because a parametric approach like abnormal at the first time or if the treatment had the the t-test, addressed at differences in central resulted in an absence of attacks for at least the pathological extreme low and high values, the At the time of these experiments the only available reference values of the XA excretion appropriate (Siegel, 1956). Furthermore the t-test were those of 648 neurologic and psychiatric is not permissible be cause the distribution of the patients. Many of these persons may not have XA-values of the patient group is evidently non- suffered any condition influencing the XA normal and there is too great a difference excretion. The XA values are however between the variances of the treatment positively skewed, with a modus of 50 umol/24 responders and the reference group (coefficient hours and a median 78 umol/24 hours. On the of variance 1.01 vs 0.25). The pre-treatment val- basis of the distribution curve, 40-120 umol/24 ues of XA differ significantly from the reference hours (n=347) was considered normal. Recently values (p(sh< nc-2h+g)=0.00003). The properly the XA excretion could be investigated in different values are exclusively found in the healthy volunteers, 68.8±19.0 umol/24 hours responder group. The XA excretion values of the (n=31), median 70 umol/24 hours, range 82 nine responders after the treatment differ umol/24 hours (Hoes et al, 1980-b). The significantly from the pre-treatment values determination method of XA by (Moses test: p=0.025), i.e. extreme low and spectrophotometry is accurate (Hoes et al, extreme high values tend to disappear. The post-1980-b). treatment values do not differ significantly from During their first visit to the out-patient de- the reference values, viz. in extreme reactions partment, all patients were checked for diabetes mellitus by determination of the fasting plasma- The nine treatment responders received no glucose concentration and of glucose and further medication after the four trial weeks; they ketone bodies in the morning urine. remained symptom-free during a three months Statistical analysis was performed by Student t-test and the Moses test of extreme reactions. Discussion
The patients included in this study suffered patients studied is small. The data are however 0.5-3 years from HVS, and had at least two attacks/week during the last two months before The XA-excretion shows two types of disorder; it is either too high or too low. Since either Of the 13 patients, nine were symptom-free disorder is corrected by the pyrid-oxine-L- after three weeks of treatment (3f, 6m) and four tryptophan treatment, the supply of the substrate were not so (1f, 3m) (Table 1). The mean age of L-tryptophan is not important to this normalizing the responders (37.1 ±10.1 years) does not effect, but the pyridoxine is. Two enzymes are differ significantly by t-test (p=0.069) from the relevant, both containing the active principle of XANTHURENIC ACID IN HYPERVENTILATION
oxal-5-phosphate (PAL), as co-factor (Figure containing enzymes is induced directly by e.g. 1). These two are the supernatant enzyme hormones (Schepartz, 1973). In HVS, both kynureninase and the mitochondrial trans- mechanisms can occur by enhanced secretion of glucocorticosteroids. These hormones induce the enzyme-cofactor (PAL) binding-constant is pyrrolase (Figure 1), the rate-limiting enzyme of weaker for the kynureninase than for the the NiA synthesis; thus more L-tryptophan is transaminase (Adams et al., 1976; Green et al., pulled into this synthesis, activating PAL 1978). So, in any PAL disorder, corrected by containing enzymes (Curzon, 1969; Green, pyridoxine supplementation, the excretion of 1978), and lowering the PAL levels in serum XA in a L-tryptophan loading test will first rise and then fall, compared to the reference values, glucocorticosteroids induce the synthesis of PAL- and during more pronounced PAL disorders it containing enzymes, such as the tyrosine will fall. The low XA-ex-cretion thus is the transaminase, tryptophan transaminase, alanine most pathological of the two XA disorders. Each disorder in the XA-excretion is caused decarboxylase. The kynureninase is not induced. either by competitive inhibition of the PAL Thus the total body supply of PAL will be binding sites of the enzymes, or by a PAL de- lowered. To such PAL consuming activities the ficiency. Competitive inhibition of PAL bind- dietary intake will soon yield, because the ing sites has been described for steroid hor- required 2 mg a day are just supplied by a regular mones (Mason et al., 1969). Because the HVS diet (Bogert et al, 1973). In pyridoxine loading is a stress disorder, glucocorticoster-oids will studies 60 percent of a physiological dose of be hypersecreted (Selye, 1976), intermittently pyridoxine is recovered in the subsequent 24 during attacks or chronically; however, they hours urine (Wozenski et al., 1980) and 35 were not measured in this study. But for percent of a megadose of 750 mg (O'Reilly et glucocorticosteroids no competitive inhibition al., 1980). The initial distribution phase of of the kynureninase has been described in the pyridoxine and PAL has a t1/2 of two hours; the t literature. The transaminase has even a more /2 of the elimination phase could not exactly be stable apo-enzyme-cofactor binding and is computed (O'Reilly et al, 1980). One can better protected in the mitochondrion against conclude that the body does not have any competitive inhibition than the supernatant pyridoxine pools of any importance. Thus, a kynureninase. So, in any case, the relative (to the adequate diet) pyridoxine and mitochondrial transaminase will be better PAL deficiency is to be considered the causative protected against the influence of factor for the disordered XA-excretion. The glucocorticosteroids than the kynureninase. plasma concentration of L-tryptophan will be Competitive inhibition in general can also be lowered as soon as the pyrrolase is induced by the exerted by metabolic products; thus, the NiA glucocorticosteroids because thus L-tryptophan inhibits the pyr-rolase by endproduct inhibition. will be pulled into the NiA synthesis from the No inhibition of enzymes by substrate has been systemic circulation (Curzon, 1969; Hoes, 1980; described for PAL-containing enzymes in the Moussaoui, 1978). This is illustrated by the NiA synthesis, neither by the endproduct NiA elevated XA-excretion in a L-tryptophan loading test in women using oral contraceptives (o.c). The disorder in the XA-excretion must be They had no confirmative signs of a pyridoxine deficiency (Adams et al., 1976), and the XA elevation had to be explained by induction of the The PAL deficiency has not a dietary source, because the diet of the patients was adequate, supplying the required 2 mg pyridoxine a day However, Green et al., (1978) measured the (Bogert et al., 1973). A PAL deficiency occurs plasma concentrations of L-tryptophan and the also when PAL-containing enzymes are XA excretion during the same L-tryptophan activated by augmented supply of substrate (Wynne, 1975), or if the synthesis of PAL- ORTHOMOLECULAR PSYCHIATRY, VOLUME 10, NUMBER 1, 1981, Pp. 7-15
found an elevated XA excretion but refute an balance. Patients with an elevated XA excretion can induction of the pyrrolase as explanation, because show a diabetes mellitus-like state. This is they found a comparably large area under plasma explained either by complex forming of the elevated tryptophan versus time curve in their patients XA with insulin, thus inactivating the latter (Rose et than in controls. But there are two contra- al., 1975); or by diminished production of arguments: First, any deficiency of L-tryptophan quinolinic acid, an intermediary product in the NiA in the diet can be counteracted by increased synthesis from below the kynureninase step. Quino- mobilisation of L-tryptophan from body-protein linic acid is an inhibitor of the hepatic phos- (Niskanen et al., 1976). Secondly, in the figure of phoenolpyruyatecarboxykinase, an important Green et al., the curve of plasma concentrations enzyme in the gluconeogenesis (Adams et al., of L-tryptophan in the o.c. users stays under that 1976). These hyperglycemic patients can develop a of the controls! More important is that the plasma ketosis. A ketosis facilitates the hyperventilation concentration of L-tryptophan at the end of the and neuromuscular irritability symptoms. The absorption phase is in the figure significantly experience of this reinforcement can evoke (p<-0.05) lower for the o.c. users than for the apprehension. The disorder in L-tryptophan and controls, although Green et al. claim that the area glucose metabolism is completely restored by pyrid- under the curve is the same. The difference in oxine suppletion (Adams et al., 1976; Rose et al., the absorption peaks cannot be explained by 1975). This derangement can however induce a altered elimination kinetics, because the positive feedback, because in animal experiments it descending parts of the curves of controls and was shown that hyperglycemia induces the o.c. users run strictly parallel. So, the absorption described disorder in the NiA metabolism, with peak differs because L-tryptophan reaches the enhanced XA excretion (Akarte and Shastri, 1974)! systemic circulation more slowly in the o.c. users 3) The apprehension can be reinforced by than in the controls. Altered gut movements or diminished production of NiA, the ketosis aside. gut absorption kinetics are not described in o.c. NiA was shown in recent experiments to possess users, to account for the difference in L- benzodiazepine-like action and benzodiazepines are tryptophan kinetics. The second possibility is the antianxiety drugs (Mohler et al., 1979). The HVS first pass effect through the liver. If in o.c. users patients studied did not show signs of a fullblown more L-tryptophan is pulled into the liver than in clinical (Bogert et al., 1973) or subclinical (Green, controls, this means that the pyrrolase activity in 1973) pellagra. Yet when the patients have a PAL the o.c. users has been enhanced. Definite separa- disorder, as proved by the therapeutic effect of the tion of a pyrrolase-and a PAL effect require the pyridoxine (and L-tryptophan) suppletion in this execution of a L-tryptophan and kyn-urenine study, the production of endogenous NiA (2/3 of the total requirements) is diminished. Besides, anxiety The described disorders of the L-trypto-phan- is a prominent feature of HVS and of subclinical NiA metabolism can sustain the HVS pellagra. symtomatology in several ways. This is best understood according to the sequential steps in SEX OF THE HVS PATIENTS
deractive CST is reinforced by the loss of L- tryptophan from the systemic circulation into the liver by the pyrrolase pull. When besides the plasma concentrations of kynurenine rise, the RESPONDERS
kynurenine may inhibit the cerebral uptake of L- tryptophan, although this effect probably is small in man (Green, 1978). 2) The next mechanism concerns the acid-base There is no significant difference by t-test in sex between the
patients who responded and who did not respond to treatment.

4) As long as the apprehension (and anxiety) the orthomolecular treatment by pyridoxine and persist, the elevated glucocorticoster1 oid secretion will keep the pyrrolase activity underactive CST in the HVS is considerably induced, deriving more L-tryptophan in the Further study along this line should include L- substrate keeps the PAL containing enzymes tryptophan and kynurenine loading tests (Wolf et hyperactivated, thus further emptying the PAL al., 1980), determinations of plasma Cortisol (Selye, 1976) and quantification of respiration positive feedback is introduced in the L-tryp- tophan derivation, because the brain is deprived of steadily more L-tryptophan and the anti- AGE OF THE HVS PATIENTS
anxiety substances serotonin (Ellison, 1975) RESPONDERS (9)
In the patients studied, the possibilities two 37.1 10.0
and three are excluded as a reinforcement of the 28.8 2.2 34.5 9.2
HVS, because the fasting glucose levels in RESPONDERS (4)
plasma were normal and the fasting morning TOTAL (13)
urine was negative for glucose and ketone bodies. The possibilities one and four reserve however serious consideration in the treatment There is no significant difference by t-test in age between
the patients responded and who did not respond to
treatment. The age-range for all patients (N=13) is 22-56

The treatment responder with a normal years.
preteatment excretion of XA, probably has had a disturbed CST in view of his therapeutic response. His normal excretion of XA is either XANTHURENIC ACID EXCRETION OF HVS PATIENTS
an accidental finding, or the turning point in XANTHURENIC ACID (XA)
XA excretion from a high to a low excretor of ( umol/24 hrs)
In the four non-responders to treatment, the XA excretion was normal. Both findings argue against a disorder in the L-tryptophan 4
metabolism and the CST. In these patients the CST was functionally deranged during the HVS Summarizing, this study shows that there is a RESPONDERS
peripheral L-tryptophan metabolism. This i
disorder measured by the XA excretion in a L- tryptophan loading test is however not specific for HVS patients (Hoes, 1979-a, 1979-b); a low XA excretion is more pathological than a high one. Any XA disorder is perfectly correlated with a favorable response to the pyridoxine + L-tryptophan treatment. The excretion of XA in 24 hours urine after oral intake of 5 grams of L-tryp-
tophan was measured. This was done in all patients before (1) treatment; it was

So, one can conclude that because there are repeated after (2) treatment, only if it had been abnormal the first time or if the
therapeutic response had been favorable. At the time of these experiments the range

HVS patients with a disturbed XA excretion, of XA excretion considered normal was 40-120 umol/24 hrs. So, the first 5 values in
the responder group are elevated, the 6th is normal and the last 3 are low. The non-

and because the XA disorder accurately responders show just normal values.
predicts the therapeutic response of the HVS to
chosomatischen Medizin, 485-492. Urban und Schwarzenberg, Mun-chen, 1978. The statistical analysis was performed by P. Colla and N. Sijben, research psychologist, HOES, M.J.A.J.M.: Pyridoxine, L-Tryptophaan en Zinksulfaat voor Dep- ressieve Patienten. Tijdschr. Psychiat. 21,301-321,1979-a. HOES, M.J.A.J.M.: The Clinical Significance of an Elevated Excretion of Xanthurenic Acid in Psychiatric Patients. Acta Psychiat. Belg. 79, 648- This paper is an adaption of a lecture delivered HOES, M.J.A.J.M.: Tolerance and Dependence on Psychoactive Drugs. at the symposium of the Dutch Hyperventilation Study Croup, Utrecht, 19 October, 1979, by HOES, M.J.A.J.M.: L-Tryptophaan en Pyridoxine Huishouding in Depres- sieve Patienten: Een Serotonine Hypothese voor Corticosteroid Regu-latie en Adaptatie. TGO/J. Drug Res. 5,685-694,1980. References
HOES, M.J.A.J.M., COLLA, P. and FOLGERING, H.: Clomipramine Treat- ment for Hyperventilation Syndrome. Pharmakopsychiat.-Neuropsy- ADAMS, P.W., WYNN. V., FOLKARD, J. and SEED, M.: Influence of Oral Contraceptives. Pyridoxine (vitamin B6), and Tryptophan on Carbohydrate Metabolism. Lancet 1,759-764,1976. HOES, M.J.A.J.M., KREUTZEN, E. and SIJBEN, N.: Xanthurenic Acid Ex- cretion in Urine After Oral Intake of 5 grams of L-Tryptophan by Healthy AKARTE, N.R. and SHASTRI, N.V.: Studies on Tryptophan-niacin Metab- Volunteers: Standardization of the Reference Values. Accepted by J. Clin. olism in Streptozotocin Diabetic Rats. Diabetes 23,977-981,1974. BOGERT, L.J., BRIGGS. G.M. and CALLOWAY, D.H.: Nutrition and HOFFMAN, W.S.: The Biochemistry of Clinical Medicine, 787-789 (niacin); Physical Fitness. 133-142 (niacin), 142-146 (vitamin B6), Saunders, 789-790 (pyridoxine). Year Book, Chicago, 1970. JOUVET, M.: The Role of Monoamines and Acetylcholine-Containing CLINESCHMIDT, B.V. and ANDERSEN, E.G.: The Blockade of Neurons in the Regulation of the Sleep-waking Cycle. Ergeb.z. Physiol. Bulbospinal Inhibition by 5-Hydroxytryptamine Antagonist. Exp. Brain LEWIS, B.I.: Hyperventilation Syndrome. A Clinical and Psysiological Eval- CURZON, G.: Tryptophan Pyrrolase — A Biochemical Factor in Depres- sive Illness? Brit. J. Psychiat. 115,1367-1374,1969. MASON, M., FORD, J. and WU, H.L.C.: Effects of Steroid and Nonsteroid DeSOUSA, C. and WALLACE, R.B.: Pain: A Review and Interpretation. Metabolites on Enzyme Configuration and Pyridoxal Phosphate Binding. ELLISON, G.D.: Behavior and the Balance Between Norepinephrine and MEYER-LOHMAN, J.: Renshaw Cell Activity and Monaoamine Liberation. Serotonin. Acta Neurobiol. Exp. 35,499-515,1975. Proc. Int. Union Physiol. Sci. IX, 389,1971. FEIGHNER, J.P., ROBINS, E., GUZE, S.B., WOODRUF, R.A., MOHLER, H., POLC, P., CUMIN, R., PIERI, L. and KETTLER. R.: WINOKUR. G. and MUNOZ, R.: Diagnostic Criteria for Use in Nicotinamide is a Brain Constituent with Benzodiazepine-like Actions. Psychiatric Research. Arch. Gen. Psychiat. 26,57-63,1972. FERNSTROM, J.D. and LYTLE, L.D.: The Interaction of Diet and Drugs MOUSSAOUI, D.: Biochimie de la Depression. Analyse de la Literature. in the Modification of Brain Monoamine Metabolism. In: Usdin, E. and Forrest, I.S., Eds. Psychotherapeutic Drugs, Volume II, 359-387. Marcel Dekker. New York, 1976. NISKANEN. P., HUTTUNEN, M., TAMMINEN. T. and JAASKELAINEN, J.: The Daily Rhythm of Plasma Tryptophan and Tyrosine in Depression. FOLGERING, H. and COLLA, P.: Some Anomalies in the Control of PA Co2 in Patients With a Hyperventilation Syndrome. Bull. Europ. Physio-path. Resp. 14, 503-512,1978. O'REILLY, W.J., GUELEN. P.J.M. HOES, M.J.A.J.M. and VAN DER KLEYN, E.: HPLC Determination of Pyridoxine and Congeners in Bio- GREEN, R.G.: Subclinical Pellagra. In: Hawkins, D. and Pauling, L., Eds. logical Fluids of Man After High Dose Therapy. Biomed. Appl. 183,492- Orthomolecular Psychiatry, 411 -434. Freeman, San Francisco, 1973. GREEN, A.R.: The Effects of Dietary Tryptophan and its Peripheral Metab- ROSE, D.P., LEKLEM, J.E., BROWN, R.R. and LINKSWILLER, H.M.: Ef- olism on Brain 5-Hydroxytryptamine Synthesis and Function. In: fect of Oral Contraceptives and Vitamin B6 Deficiency on Carbohydrate Youdim. M.B.H., Lovenberg, W., Sbarman, D.F. and Lagnado. J.R., Eds. Metabolism. A. J. Clin. Nutr. 28, 872-878,1975. Neurochemistry and Neuropharmacology, Volume 3, 103-129, Wiley, New York, 1978. SCHEPARTZ, B.: Regulation of Amino Acid Metabolism in Mammals. GREEN, A.R., BLOOMFIELD, M.R., WOODS, H.F. and SEED, M.: Metabolism of an Oral Tryptophan Load by Women and Evidence SCHULZ, M., GRIMM, W., SCHMITZ. W. and KNAPP, A.: Tryptophan- Against the Induction of Tryptophan Pyrrolase by Oral Contraceptives. stofwechsel-untersuchungen Bei Oligofrenen Kindern. 1 Mitteilung: Ergebnisse der Kynurenin - und Zanthurensaureausscheidung nach Try-ptophanbelastung und deren Abhangigkeit von der Vitamin B6 Zufuhr. HARDONK, H.J. and BEUMER, H.M.: Hyperventilation Syndrome. In: Psychiat. Neurol. Med. Psychol. 25, 98-106.1973. Vin-ken, P. and Bruyn, G.W., Eds. Handbook of Clinical Neurology, Volume 38,309-360. North-Holland, Amsterdam, 1979. SIEGEL, S.: Nonparametric Statistics for the Behavioral Sciences. McGraw- HERMANN, J.M., SCHONECKE, O.W. and VON UEXKULL. TH.: Das Hyperventilation Syndrome. In: Von Uexkull, Th., Ed. Lehrbuch der Psy- XANTHURENIC ACID IN HYPERVENTILATION
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