neuropharmacological therapy of the neuroendocrine carcinoid

The Journal of Applied Research • Vol. 5, No. 1, 2005 109

Neuropharmacological Therapy ofthe Neuroendocrine CarcinoidSyndrome: Report of Two Cases Fuad Lechin, MD, PhDBertha van der Dijs, MDBeatriz Orozco, MDSimon Rodríguez, MDScarlet Baez, MD

Departments of Neurophysiology, Neurochemistry, Neuropharmacology and Neuroimmunology,Faculty of Medicine, Universidad Central de Venezuela, Caracas, Venezuela

syndrome. The fact that patients affect-ed by carcinoid presented common neu-roautonomic disorders led us toprescribe the neuropharmacologicaltherapy addressed to revert that abnor-mal profile. Although we have assessedseveral of the above-mentionedpatients, we refer here only to these twowell-investigated, treated, and followed-up patients.

INTRODUCTIONOur laboratory of neurochemistry andimmunology has investigated some25,000 normal and diseased subjects.Circulating neurotransmitters andimmunological parameters are routinelyassessed before and after neuropharma-cological manipulations through severalstress tests, such as the supine-resting,one-minute orthostasis, and five-minuteexercise challenges. The results of thesetests enable us to evaluate the contribu-tion of the two branches of the periph-eral autonomic sympathetic system:neural and adrenal.1-3 However, because

KEY WO R D S : carcinoid syndromet r e a t m e n t , n e u r o i m m u n o m o d u l a t i o nand carcinoid syndrome, a u t o n o m i cnervous system, carcinoid syndrome

ABSTRACTWe discuss two cases of patients affectedby the carcinoid syndrome who showedadrenal over neural sympathetic pre-dominance and a TH-2 immunologicalprofile. Both received neuropharmaco-logical therapy addressed to revertingthis autonomic nervous system imbal-ance. Clinical, autonomic nervous systemand immunological improvements wereregistered as of the first 4-week post-treatment period. No relapses have beenrecorded up to the present (4 and 3years later, respectively). The neu-ropharmacological therapy addressed toenhancing central nervous system-nora-drenergic activity, which is able to revertadrenal over neural sympathetic pre-dominance, seems to be a valuable toolin treating patients affected by carcinoid

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plasma acetylcholine levels are notdetectable at peripheral circulation, weemploy indirect evidence concerning theparasympathetic system activity throughthe assessment of circulating serotonin.This indolamine circulating pool is inte-grated by the addition of platelet- (p-

5HT) and plasma- (f-5HT) serotonin.Normal f-5HT/p-5HT ratio is 0.5% to2%. This ratio increases because hyper-parasympathetic activity (acetylcholine[ACh]) interferes with platelet uptake4

and hyperadrenergic activity secondaryto platelet aggregation.5 In addition to

Figure. Changes registered throughout the neuropharmacological therapy in two carcinoidpatients. Maximal improvement was reached since the first month of therapy, and was paral-leled by normalization of f-5HT plasma values. No further relapses were registered. NA indicatesnoradrenaline; Ad, adrenaline; p-5HT, platelet serotonin; and f-5HT, plasma serotonin. (f-5HT x 10at pre-treatment period, only).

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the above, the measurement of plasmatryptophan reflects central nervous sys-tem (CNS) serotonergic activity.6Assessment of the immune profile iscarried out through the evaluation ofthe usual immunological parameterswhich might help to design the profileaccording with the TH-1 versus TH-2paradigm.7,8

CASE REPORTSCase OneA. A. is a 46-year-old man who under-went surgical resection of the terminalileum (59 cm) and appendix because ofa big carcinoid tumor. Ganglional andhepatic metastases were detected. Herejected chemotherapy and was referredto our department on February 2, 2000.

An assessment of circulating neuro-transmitters revealed high levels of cate-cholamines: noradrenaline (NA),adrenaline (Ad) and dopamine (DA);plus raised levels of indolamines: intra-platelet serotonin (p-5HT) + free sero-tonin in the plasma (f-5HT). Plasmalevels of tryptophan, considered the hall-mark of CNS serotonergic activity, werelower than normal. Although the sum ofNA and Ad was greater than normal,the NA/Ad ratio was very low (< 1) atsupine-resting condition. This ratio didnot increase but rather decreased atone-minute orthostasis. As this abnor-mal response is a trustworthy index ofpoor neural sympathetic release, suchraised levels of circulating cate-cholamines necessarily arise from theadrenal glands. It should be rememberedthat sympathetic nerves release 90% ofNA and 10% of DA. Conversely, adrenalglands secrete 80% of Ad and 20% ofNA and DA. Furthermore, consideringthat neural sympathetic but not adrenalsympathetic response would normallyoccur at one-minute orthostasis,9 maxi-mal reduction of the NA/Ad ratioobserved in this patient reflects theabsolute predominance of adrenal over

neural sympathetic activity.3 Withrespect to the above, it should be point-ed out that whereas neural sympatheticrelease depends on NA neurons locatedat the pontine locus coeruleus nucleus(LC), the adrenal glands are ruled byAd-C1 medullary neurons located at therostral ventrolateral medulla. These twoCNS sympathetic systems can functionin association or dissociation,10 in accor-dance with physiological requirements.However, the Ad-C1 medullary systemis responsible for peripheral sympatheticactivity when the LC-NA nucleusbecomes exhausted, as occurs duringstressful situations.3

Both platelet serotonin (p-5HT) andplasma serotonin (f-5HT) levels werevery high. Plasma tryptophan showedlower than normal values, indicatingpoor CNS serotonergic activity.1Immunological investigations showedpositive antinuclear autoantibodies(ANA) (++), plus very low NK cell cyto-toxicity against K562 target cells (23%),raised IgG, and IgE plasma levels.Summarizing, the above results are con-sistent with the postulation of a deficitin neural sympathetic activity by NAneurons located at the LC-NA neurons,and an excess adrenal (Ad) gland sym-pathetic activity triggered by Ad-C1medullary nuclei.1 In light of this, a neu-ropharmacological therapy addressed toenhancing both CNS-NA and CNS-5HTactivities was administered: doxepin (25mg once daily) plus 5-OH-tryptophan(25 mg three times daily). Doxepin is aninhibitor of NA uptake (60%) and aninhibitor of 5-HT-uptake (40%), while 5-OH-tryptophan is a serotonin precursorthat crosses the blood brain barrier easi-ly.11 Further, considering that circulatingserotonin arises from enterochromaffincells triggered by parasympatheticdrive,12 7.5 mg of propantheline wasadministered before meals. This nico-tine-receptor antagonist does not crossthe blood brain barrier; it interrupts the



pre- to post-synaptic connection at theparasympathetic ganglia. Finally, a halftablet (0.075 mg) of oral clonidine wasgiven before bed. This alpha 2-agonistcrosses the blood brain barrier and bri-dles the Ad-C1 medullary nuclei respon-sible for adrenal gland secretion.13

Progressive and significant improvementwas obtained and sustained. The treat-ment covered three months, followed bytwo weeks of rest, after which it wasrestarted. Circulating neurotransmitterswere controlled every 4 weeks. Parallelclinical and ANS improvements wereobserved. Increases of the NA/Ad ratioand tryptophan values were seen as ofthe first 4-week control. Platelet sero-tonin values remained greater than nor-mal (Figure). Free-serotonin (f-5HT)showed significant decrease throughoutthe treatment. NK cell activity rose from23% to 35%. This patient showed auto-nomic, immunological, and clinical nor-malization after the first three months oftherapy. The improvement persists up tothe present (December 2004). No metas-tases were detected (CAT scan).

Case TwoI.V.R. is a 43-year-old woman who wasreferred to our institute suffering from aneuroendocrine carcinoid disease,polipoid tumors located at small intes-tinal level were diagnosed when she wassubmitted to surgery for uterine fibro-matosis and endomethriosis. She reject-ed chemotherapy. On entering ourinstitute in September 17, 2001, she wasexhaustively evaluated, having presentedwith flushing, tachycardia, and manyother symptoms despite undergoingsomatostatin therapy. The ANS investi-gation was evaluated throughout thesupine-resting, orthostasis, and moderateexercise test, which showed greatlyraised circulating catecholamine levels(NA, Ad, DA). However, not only NA,but Ad rose at one-minute orthostasisand increased during the 5-minute exer-

cise period. NA/Ad ratio was very low atsupine-resting state, and far from rising,fell during the two other periods(Figure). Diastolic blood pressure(DBP) showed a decrease rather thanan increase, at one-minute orthostasistest. This DBP fall is attributed to theinhibition of NA release from sympa-thetic terminals exerted by prior releaseof DA from the DA pool there.14 Finally,although both p-5HT and f-5HT weregreatly increased, and tryptophan plas-ma values were lower than normal,immunological investigation showed adecreased CD4/CD8 ratio (0.9), positiveantinuclear antibodies (+), and lowerthan normal NK cell activity (21%). Thispatient received similar therapy to thatgiven to patient A.A. Clinical improve-ment was so quick that after the first 4-week period, NA/Ad ratio was normal;although p-5HT values remained high, f-5HT dropped to normal values.Immunological parameters also showednormalization. NK cell activity rose from21% to 32%. The patient has remainedfree of symptoms up to the present(December 2004). All neurochemicaland immunological parameters werefound normal, also.

DISCUSSIONTwo carcinoid patients, presenting adre-nal over neural sympathetic predomi-nance plus raised levels of circulatingplatelet serotonin (p-5HT) and plasmaserotonin (f-5HT), as well as TH-2immunological profile, were treated andimproved by neuropharmacologicaltherapy addressed to reverting adrenalover neural sympathetic predominance.This finding obliges us to think that bothneuroautonomic and immunological dis-orders should be included among thepathophysiological mechanisms underly-ing this disease (TH-2 profile). Thisinference is reinforced by the findingthat all clinical, ANS, and immunologicalimprovements were triggered by neu-



ropharmacological manipulations similarto those used to revert AD over NApredominance.

The raised circulating serotoninlevel found in both patients agrees withthe enterochromaffin-cell overactivityalways present in this disease. Further,the fact that platelet serotonin (p-5HT)remained elevated, whereas the plasmaserotonin (f-5HT) was normalized inthese two carcinoid patients after clini-cal improvement, suggests that althoughtheir enterochromaffin cells remainedoveractive, the symptoms were relatedto the raised f-5HT plasma levels. Boththe physiologic disorders and their clini-cal symptoms were paralleled by adrenalover neural sympathetic predominanceperiods. This phenomenon may be asso-ciated with the maximal ability of theneural sympathetic system to annul theparasympathetic drive that is responsi-ble for enterochromaffin cell secretionand for increased f-5HT levels. This phe-nomenon would operate not only at theGI level, but at the metastatic extra-intestinal nodes. Circulating serotoninarises from enterochromaffin cells thatrelease 5HT in response to parasympa-thetic drive.15 Although most 5HT issecreted into the intestinal lumen, a frac-tion reaches portal circulation. Serotoninthat escapes through liver and lungsuptake is trapped by platelets.15

However, some fraction of serotoninalways remains free in the plasma (f-5HT). The normal f-5HT/p-5HT circu-lating ratio is about 0.5% to 1%. Thisratio increases during platelet aggrega-tion5 and deficit of platelet uptake.Platelet uptake is interfered by both cir-culating acetylcholine4 (hyperparasym-pathetic activity) and circulating DA.16

The former occurs during excessiveparasympathetic drive. The increase of f-5HT registered in these circumstancesmay be exacerbated because theindolamine excites 5HT3 and 5HT4receptors located at the medullary area

postrema (outside the blood brain barri-er), which is connected to the motorvagal complex.17 This fact results in afurther increase of the peripheralparasympathetic drive discharge overthe enterochromaffin cells (Bezold-Harisch reflex). Such mechanisms mayexplain the hyper-serotonergic stormoccurring in carcinoid patients.

The enhancement of NK-cell cyto-toxicity, as well as the shifting of TH-2 toTH-1 immunological profile, triggeredby the neuropharmacological therapyprescribed to these two carcinoidpatients, merits special mention. In 1987,we found that neuropharmacologicaltherapy demonstrated clinical improve-ment in patients with different types ofcancer.18 In addition, we demonstratedthat the clinical improvement was paral-leled by an increase in NK cell activi-ty7,19 These reports were furtherconfirmed.20-22 It was also demonstratedthat clinical severity in cancer patientscorrelated negatively with NA/Ad ratio,whereas clinical improvement showed apositive correlation with NA/Ad. Theforgoing findings are in line with thoseby other authors who demonstrated thatsome drugs able to improve colon andlung cancer, trigger NK cell activation.22

REFERENCES1. Lechin F, van der Dijs B, Amat J, et al.

Neuroautonomical basis. In: Lechin F, van derDijs B, eds. Neurochemistry and ClinicalDisorders: Circuitry of some Psychiatric andPsychosomatic Syndromes. Boca Raton, Fla:CRC Press; 1989:1-48

2. Lechin F, van der Dijs B, Lechin ME.Depression. In: Lechin F, van der Dijs B,Lechin ME, eds. Neurocircuitry andNeuroautonomic Disorders. Reviews andTherapeutic Strategies. Basel, Switzerland:Karger; 2002:23-27.

3. Lechin F, van der Dijs B, Orozco B, et al.Plasma neurotransmitters, blood pressure andheart during supine-resting, orthostasis andmoderate exercise in severely ill patients: Amodel of failing to cope with stress.Psychother Psychosom. 1996;65:129-36.



4. Rausch JL, Janowsky SC, Risch SC, et al.Physostigmine effects on serotonin uptake inhuman blood platelets. Eur J Pharmacol.1985;109:91-96.

5. Larsson PT, Hjemdahl P, Olsson G, et al.Altered platelet function during mental stressand adrenaline infusion in humans: evidencefor an increased aggregability in vivo as mea-sured by filtragometry. Clin Sci. 1989;76:369-376.

6. Lechin F, van der Dijs B, Villa S, et al. Centralnervous system circuitry involved in bloodpressure regulation. In: Lechin F, van der DijsB, eds. Neurochemistry and ClinicalDisorders: Circuitry of some Psychiatric andPsychosomatic Syndromes. Boca Raton, Fla:CRC Press; 1989:121-150.

7. Lechin F, van der Dijs B, Lechin S, et al.Neurochemical, hormonal and immunologicalviews of stress: Clinical and therapeutic impli-cations in Crohn’s disease and cancer. In:Velazco M, ed. Recent advances inPharmacology and Therapeutics.International Congress Series Vol 839.Amsterdam, Netherlands: Excerpta Medica;1989:57-70.

8. Lechin F, van der Dijs B, Lechin ME.Concluding remarks. In: Lechin F, van derDijs B, Lechin ME, eds. Neurocircuitry andNeuroautonomic Disorders. Reviews andTherapeutic Strategies. Basel, Switzerland:Karger; 2002:69-74.

9. Robertson D, Goldberg MR, Onrot J, et al.Isolated failure of autonomic noradrenergicneurotransmission. Evidence for impairedbeta-hydroxylation of dopamine. N Engl JMed. 1986;314(23):1494-1497.

10. Robinson RL, Culberson JL, Carmichael SW,et al. Selective CNS control of epinephrineand norepinephrine release by the adrenalmedulla. Fed Proc. 1977; 36:381-387.

11. Lechin F, van der Dijs B, Lechin A, et al.Doxepin therapy for postprandial sympto-matic hypoglycemic patients neurochemical,hormonal and metabolic disturbances. ClinSci. 1991;80:373-384.

12. Tobe T, Izumikawa F, Sano M, et al. Releasemechanisms of 5-HT in mammalian gastroin-testinal tract—especially vagal release of 5-HT. In: Fujita T, ed. Endocrine Gut-Pancreas.Amsterdam, Netherlands: Elsevier; 1976:371-390.

13. Lechin F, van der Dijs B, Jakubowicz D, et al.Effects of clonidine on blood pressure, nora-drenaline, cortisol, growth hormone and pro-lactin plasma levels in low and high intestinaltone subjects. Neuroendocrinology.1985;40:253-261.

14. Wilfert B, Smit G, de Jonge A, et al.Inhibitory dopamine receptors on sympathet-ic neurons innervating the cardiovascular sys-tem of the pithed rat. Characterization androle in relation to presynaptic alpha 2-adrenoceptors. Naunyn Schmiedeberg’s ArchPharmacol. 1984;326:91-98.

15. Lechin F, van der Dijs B. Serotonin and pul-monary vasoconstriction. J Appl Physiol.2002;92:1363-1364.

16. De Keyser J, De Waele M, Convents A, et al.Identification of D1-like dopamine receptorson human blood platelets. Life Sci.1988;42:1797-1806.

17. Reynolds DJM, Leslie RA, Grahame-SmithDG, et al. Localization of 5-HT3 receptor bin-ding sites in human dorsal vagal complex.Eur J Pharmacol. 1987; 174:127-130.

18. Lechin F, van der Dijs B, Azocar J, et al.Stress, immunology and cancer: effect of psy-choactive drugs. Arch Ven Farm Clin Terap.1987;6:28-43.

19. Lechin F, van der Dijs B, Lechin AE. Naturalkiller cells activity and neuroimmunologicaltreatment of cancer. Clin Cancer Res. Inpress.

20. Lechin F, van der Dijs B, Vitelli G, et al.Psychoneuroendocrinological and immunolo-gical parameters in cancer patients: involve-ment of stress and depression.Psychoneuroendocrinology. 1990;15:435-451.

21. Lechin F, van der Dijs B, Lechin ME.Illustrations of some therapeutic results. In:Lechin F, van der Dijs B, Lechin ME, eds.Neurocircuitry and NeuroautonomicDisorders. Reviews and Therapeutic Strategies.Basel, Switzerland: Karger; 2002:75-94.

22. Krause SW, Gastpar R, Andreesen R, et al.Treatment of Colon and lung cancer patientswith ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: aclinical phase I trial. Clin Cancer Res.2004;10:3699-3707.


neuropharmacological therapy of the neuroendocrine carcinoid

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