Pharmacokinetics Octreotide Hypertension; Relationship ...quently, octreotide has a muchlonger circulat-ing half-life than somatostatin in healthy volunteers [4, 5]. In normal healthy

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Pharmacokinetics of Octreotide in Patientswith Cirrhosis and Portal Hypertension;Relationship Between the Plasma Levelsof the Analogue and the Magnitudeand Duration of the Reduction in CorrectedWedged Hepatic Venous PressureS. A. JENKINS*’**, D. M. NOTT and J. N. BAXTER*University Department of Surgery, Royal Liverpool University Hospital, Liverpool L7 8XP

(Received in final form 3 June 1997)

In healthy subjects octreotide is largely metabolisedby the liver suggesting that the plasma half-life of thesomatostatin analogue may be prolonged in patientswith hepatic dysfunction. The aim of this study wastherefore (a) to determine the pharmacokinetics ofoctreotide following its subcutaneous injection in 6patients with cirrhosis and portal hypertension and(b) compare the magnitude and duration of the effectsof intravenous administration of 250 Ig somatostatinand 50g octreotide on corrected wedged hepaticvenous pressure (WHVP) and to relate the findings tothe plasma levels of the analogue lh after adminis-tration in 13 patients with cirrhosis and portalhypertension. Following subcutaneous administra-tion of 50g octreotide the circulating half life(range2.4 to 4.79 h) was prolonged whereas the clearance(range 2.101 to 4.775 L/h) was decreased compared tohealthy controls. Intravenous bolus administration of250g somatostatin or 50g octreotide resulted in areduction in WHVP of approximately the samemagnitude and duration despite appreciable quan-tities of the analogue in the blood lh after admin-istration (1944 +-. 226 pg/ml). These results indicate

that the circulating half-life of octreotide is pro-longed in cirrhotic8 suggesting that the dosageregimens should be modified in such patients toavoid accumulation of the analogue in the bloodwhich may result in undesirable side-effects ortoxicity. Furthermore, since the magnitude andduration of the reduction in WHVP elicited by IVoctreotide is similar to that obseved with somatosta-tin, the analogue, like the native hormone, must beadministered by continuous IV infusion to produce asustained response and hence a therapeutic effect inthe management of acute variceal bleeding.

Keywords: Pharmacokinetics, octreotide, somatostatin, cir-rhosis, wedged hepatic venous pressure

INTRODUCTION

Somatostatin, a naturally occuring 14-aminoacid peptide has a plethora of effects on gas-trointestinal function leading to the suggestion

Present address: Department of Surgery, Postgraduate Medical School, Morriston Hospital, Morriston Swansea SA6 6NL.Present address: Academic Department of Surgery, Chelsea and Westminster Hospital, London SW 10 9NH.**Corresponding author.

13

14 S.A. JENKINS et al.

that it might have a therapeutic role in a varietyof gastrointestinal indications. However, sincesomatostatin has a short half-life (1-2mins).[1]and requires intravenous administration tomaintain therapeutic levels, longer acting analo-gues have been developed. Octreotide, one suchanalogue, is an octapeptide in which the 4 aminoacid sequence essential for the biological activityof the native hormone is retained. However,incorporation of N-terminal phenyalanine, C-terminal amino alcohol, D-tryptophan and acysteine bridge makes the molecule veryresistant to metabolic degration [2, 3] and conse-quently, octreotide has a much longer circulat-ing half-life than somatostatin in healthyvolunteers [4, 5]. In normal healthy volunteersoctreotide is largely metabolised by the liver, thehepatic excretion being in the order of 30-40%[5]. No data is available on the plasma half-life ofoctreotide in cirrhotic patients but it is reason-able to assume that the hepatic extraction isreduced according to the degree of liver dys-function and that the circulating half-life is likelyto be prolonged compared to normal subjects.Consequently, the relationship between dosageregimens and the clinical effects of octreotideare likely to be different in cirrhotic patientscompared to healthy volunteers. Since interestis accumulating in the use of octreotide for thecontrol of the acute variceal hemorrhage and inthe long-term management of portal hyperten-sion, we have investigated the circulatory half-life of octreotide following its subcutaneousadministration in cirrhotics. Furthermore, wealso studied the relationship between the mag-nitude and duration of response of octreotideon corrected wedged hepatic venous pressure(WHVP) and the circulating levels ofthe analogueafter intravenous administration.

Subcutaneous Administration of Octreotide

Six patients (4 males and 2 females), receiving50tg octreotide s.c. twice daily to preventrecurrent varieceal hemorrhage were studied 4weeks after commencing treatment with theanalogue. These patients were participating ina randomised controlled trial and had alreadyundergone a baseline measurement of correctedwedged hepatic venous pressure (WHVP) priorto being commenced on octreotide (50 tg.sc.bd).Furthermore, since all patients were scheduledto have their WHVP measured at the end ofstudy (six months), it was considered unethicalto subject them to a further haemodynamicinvestigation four weeks into the trial. Sinceoctreotide administered subcutaneously acts asa slow release preparation, there is no informa-tion on the temporal relationships between thetime of administration and the reductions incorrected WHVP in patients already receivingthe analogue. Consequently, it would not havebeen practical to measure corrected WHVPfor the duration of this part of the study (12h).One patient had severe (Child’s C), 2 moderate(Child’s B) and 3 mild (Child’s A) liver dys-function. Following an overnight fast, bloodsamples were removed immediately prior to asubcutaneous injection of 50tg octreotide andthen at 2 hourly intervals for the following 12 h.The blood samples were collected in hepari-nised bottles containing Trasylol, centrifugedat 0C, the plasma snap frozen and stored at-20C for subsequent analysis of the octreo-tide levels.

INTRAVENOUS ADMINISTRATIONOF OCTREOTIDE

MATERIALS AND METHODS

This study was approved by the Royal LiverpoolUniversity Hospital Ethical Committee and allpatients gave written informed consent.

Thirteen patient with cirrhosis and portal hy-pertension admitted for a thorough investigationof the etiology and severity of their liver diseaseunderwent measurements of their correctedwedged hepatic venous pressure (WHVP).

PHARMACOKINETICS OF OCTREOTIDE 15

Two introducer sheaths (Cordis 8F, CordisCorporation, Miami, USA) were inserted intothe right femoral vein under local anaesthesia. A7F occlusion ballon Sidewinder catheter (CordisCorporation, Miami, USA) was guided into ahepatic vein under fluoroscopic control. Withthe ballon inflated, confirmation of wedging wasobtained by the absence of the reflux into theinferior vena cava following the injection of 2 mlof intravenous contrast. A straight 7F Cordiscatheter was inserted into the femoral vein viathe second introducer and guided under fluoro-scopic control until its tip lay free in the inferiorvena cava (IVC) at the level of the ballon catheterfor the measurement of free hepatic veinpressure. The right femoral artery was cannu-lated with a 7F Cordis cannula via a 8F Cordisintroducer. Pressure were recorded with iso-lated Medex 860 transducers (Medex MedicalInc. Rossendale, UK) connected via amplifiersto an Electromed multichannel chart recorder(Electromed UK Ltd., Letchworth, Herts, UK).The midchest region was chosen as the zerolevel for transducer calibration. Correctedwedged hepatic venous pressure was calculatedby subtracting the free pressure (IVC catheter)from the wedged (balloon catheter). Using twocatheters allowed continuous measurement ofwedged and free hepatic venous pressuresduring administration of the vasoactive drugsor saline. When not being used to measurewedged hepatic venous pressure the balloon ofthe Sidewinder catheter was deflated and thecatheter withdrawn 1-2 cm. The free pressuremeasurements obtained from both catheterswere compared to ensure that the inferior cavapressure measurements were representativeof the free wedged hepatic venous pressure.The Sidewinder catheter was then reintroducedinto the hepatic vein, the balloon inflated andconfirmation of wedging reconfirmed as de-scribed above.Heart rate was recorded using a pressure

sensitive cuff connected to a Cardiocaps monitor(Dataex Ltd, Helsinki, Finland).

A small catheter was introduced into anantecubital vein for the administration of thevasoactive drugs or saline. Ideally, the bestexPerimental design would have been to ran-domise the administrations of somatostatin andoctreotide in a double-blind manner. However,at the time of study we expected octreotide tohave a prolonged duration of action on hepatichaemodynamics and therefore we considered itwas not practical to administer the drugs in adouble-blind randomised fashion. Conse-quently, all patients received bolus injections ofsaline, 250 tg somatostatin, saline, 50 tg octreo-tide and saline consecutively, all in a volume of2 ml. All injections were given 10 min after thehaemodynamic parameters had stabilised fol-lowing the previous administration of saline orvasoactive drug and during this period theballoon on the Sidewinder catheter was deflated.The patients were unaware of whether or notthey were receiving saline, somatostatin oroctreotide. The magnitude and duration of theeffects of somatostatin, octreotide and saline onwedged and free hepatic venous pressures,arterial blood pressure and heart rate wererecorded.One hour after completion of the investiga-

tions a blood sample was removed from allpatients and stored for subsequent determina-tion of octreotide levels.

Analytical Methods

The concentration of octreotide in the plasmasamples was measured using a specific radio-immunoasay (Sandoz Pharmaceuticals, Basle,Switzerland) as previously described [5]. Thesensitivity of the assay was 5 pg/ml, the crossreactivity with somatostatin less than 0.01% andthe intra- and inter-assay coefficients less than10%. The plasma half-life of octreotide wascalculated by linear regression over the period2-12h after administration. The area underthe curve (AUC) 2-12 h after administration ofoctreotide was calculated by the Trapezoidal


rule correcting for the declining basal levels bysubtracting Co/K and for the AUC 2-12 h bysubtracting C12/K where:-Co and C12=concentrations at times 0 and 12 h

0.693 0.693K=

tl/2 T1/2

These allowances used to calculate the AUCvirtually cancel each other indicating a steadystate. Clearance (CL) was derived from Dose/AUC 2-12 h and the volume of distribution (Vd)from CL/K.

Statistical Analysis

Differences in corrected WHVP levels beforeand after administration of somatostatin, octreo-tide and saline were evaluated using a MannWhitney test for paired data.

RESULTS

Subcutaneous Administration of Octreotide

All patients had been receiving 50 tg octreotides.c.b.d, for 4 weeks with the last injection beingadministered 12 h prior to commencement of thestudy. Consequently, all patients had detectablebaseline levels of octreotide in the plasmaimmediately prior to the s.c. injection of 50 tgof the analogue for the pharmacokinetic study.Furthermore, the baseline octreotide levels werehighest in the patient with severe hepaticdysfunction and lowest in the 3 with good liverfunction (Tab. I).Peak plasma concentrations of octreotide were

observed 2 h after subcutaneous administration

TABLE Baseline and peak plasma levels of octreotide inthe 6 patients participating in the pharmacokinetic study

Patient Child’s grade Plasma octreotide levels (pg/ml)Basal Peak

A 148 25882 A 88 21983 A 178 20924 B 396 29425 B 720 32766 C 1195 3511

of 50 tg octreotide and thereafter declined in allpatients. The lowest peak levels of octreotidewere observed in patients with good liverfunction and the highest in the one patient withsevere hepatic dysfunction (Tab. I). The plasmahalf-life of octreotide in the 6 patients wasvariable (range 2.4 to 4.89 h) being appreciablyshorter in patients with good liver functionthan those with moderate or severe hepatic dys-function (Tab. II). Nevertheless, overall, theplasma half-life of octreotide in the six patients(3.44 4-1.01 h; mean 4- SD) was increased and theclearance decreased (3.04 4- 0.9 L/h mean 4- SD)compared to those previously reported fornormal healthy subjects [5].

Intravenous Administration of Octreotideand Somatostatin

Approximately 15-20 seconds after intravenousbolus administration of either 250tg soma-tostatin or 50tg octreotide, wedged andcorrected wedged hepatic venous pressurebegan to decrease, the maximum reductionsbeing observed approximately 50-60 secondsafter administration of both drugs (Tab. III).Thereafter, both wedged and corrected wedged

TABLE II Pharmacokinetic variables of octreotide (50 g s.c.) in six patients with cirrhosis and portal hypertension

Patient Child’s grade 1/2 (h) K (h-1) AUC (ng/ml.h) Clearance (L/h) Volume of distribution (L)1 A 2.40 0.271 10.47 4.775 17.622 A 2.76 0.251 17.21 2.892 11.513 A 2.56 0.288 16.55 3.021 10.474 B 4.03 0.172 18.08 2.765 16.075 B 4.04 0.172 18.49 2.704 15.776 C 4.89 0.142 23.79 2.101 14.82


TABLE III The effects and duration of action of somatostatin, octreotide and saline on hepatic venous pressure, mean arterialblood pressure and pulse in 13 patients with cirrhosis and portal hypertension

Saline Somatostatin Saline Octreotide SalineBefore After Before After Before After Before After Before After

Wedged hepaticvenous pressure(mm Hg)Free hepaticvenous pressure(mm Hg)Corrected hepaticvenous pressure(mm Hg)Mean arterialblood pressure(mm Hg)Pulsebeats (min)Duration of hepaticvenous response(min)

31.6+1.9 32.1+1.9 31.6+1.8 27.2+1.7"* 31.5+2.0 31.7+2.0 31.8+1.8 29+2.1" 31.6+1.8 31.8+1.9

8.4+1.8 8.7+1.9 8.3+1.6 8.6+1.8 8.4+1.6 8.4+1.7 8.4+1.9 8.6+1.7 8.5+1.8 8.6+1.9

23.1+1.5 23.4+1.7 23.3+1.8 18.6+1.8"* 23.1+1.9 23.3+1.8 23.4+1.7 18.4+1.5"* 23.1+1.6 23.2+1.5

103+5 104+4 105+4 121+8" 103+4 102+5 101+4 115+5" 102+5" 103+4

75+3 76+4 78+3 65+3* 75+4 75+4 76+3 63+3* 77+3 76+4

1.9+0.4 2.3+0.6

Results are expressed as mean + SEM.*p < 0.01.**p < 0.001.The changes shown after administration of somatostatin, octreotide and saline are the maximal responses from the baseline for each patient.

hepatic venous pressures began to increase.Thus, somewhat surprisingly there was nosignificant difference in the duration of thereduction of wedged or corrected wedgedhepatic venous pressures following somatoatinor octreotide administration (Tab. III), despitethe presence of appreciable amounts of octreo-tide in the plasma (1944 4-226 pg/ml) one hourafter administration. Saline administered before,between or following the administration ofsomatostatin and octreotide had no significanteffect on wedged or corrected wedged hepaticvenous pressures.Between administrations of somatostatin, oc-

treotide and saline when the balloon wasdeflated and the Sidewinder catheter withdrawnfrom the wedged position, there was excellentagreement between the free pressures recordedfrom this catheter and the other lying free in theinferior cava, the differences in the readings notexceeding 0.2mm Hg. Somatostatin, octreotideand saline had no significant effect on the freehepatic venous pressure.

Approximately 30-40 seconds after intra-venous bolus administration of either 250tgsomatostain or 50tg octreotide mean arterialpressure began to increase, the maximal re-sponse occurring 70-80 seconds after adminis-tration of both drugs (Tab. III). Thereafter,arterial pressure began to decrease. There wasno significant difference in the duration of theincrease in mean arterial blood pressure follow-ing somatostatin (2.1 4-0.6 min) or octreotide(2.34-0.5 min) administration. Saline had noeffect on arterial blood pressure (Tab. III).Forty to fifty seconds after intravenous

administration of 250 tg somatostatin or 50 tgoctreotide, the heart rate began to decrease, themaximum reduction occurring approximately80-90 seconds after administration of bothdrugs (Tab. III). Thereafter, the pulse rate beganto return to normal. There was no significantdifference in the duration of the bradycardiafollowing somatostatin (2.0 4- 0.6 min) or octreo-tide (2.3 4- 0.5 min) administration. Saline had nosignificant effect on the pulse rate (Tab. III). No


major side effects of somatostatin or octreotidewere observed in this study.

DISCUSSION

The results of this study demonstrate thatfollowing subcutaneous administration the plas-ma half-life of octreotide is increased and theclearance decreased in cirrhotic patients com-pared to those previously reported for normalhealthy controls [4, 5] using the same radio-immunoassay kit. Furthermore, there appearedto be a considerable variation in the plasma half-life of octreotide in cirrhotic patients accordingto the severity of the liver disease. Thus incirrhotics with severe (Child’s C) or moderate(Child’s B) hepatic dysfunction the plasma half-life of octreotide was appreciably longer than inpatients with mild disease (Child’s A), althoughthe small number of patients studied limits anydefinitive conclusions. These observations areperhaps not unexpected since the liver is theprincipal site for the elimination of octreotide,the hepatic excretion being estimated to bebetween 30-40% in normal healthy volunteers[5]. Consequently it is reasonable to assume thatthe hepatic excretion of octreotide varies accord-ing to the severity of the liver disease, a hypo-thesis supported by the findings of the presentstudy. Further support for this suggestionis provided by the finding that half of thedosage of octreotide resulted in almost identicalarterial concentrations of the analogue in cirrho-tic patients compared to the levels observedin normal healthy controls after a full dose [6].Further studies are,. however, required to fullyestablish the relationship between the degree ofhepatic dysfunction and the plasma half-life ofoctreotide.The six patients who participated in the

pharmacokinetic part of this study had beenreceiving 50 tg of octreotide s.c.b.d, for 4 weeksprior to investigation. In all these patientsappreciable levels of octreotide were present

in the baseline blood samples, i.e., 12 h after thelast injection of the analogue prior to the study.Furthermore, the highest plasma levels wereobserved in those with moderate (Child’s B) orsevere (Child’s C) liver disease. These observa-tions suggest that even with a relatively lowdosage regime, i.e., 50 tg octreotide s.c.b.d, thereis accumulation of the analogue in the blood,particularly in patients with moderate or severeliver disease, presumably as a result of theincrease in the plasma half-life. These observa-tions have obvious implications for the thereapeutic use of octreotide in cirrhotic patients.Thus, particularly during prolonged periods ofadministration in cirrhotic patients, dosage regi-mens should be modified to avoid accumulationof octreotide in the blood which may result inundersirable side-effects or toxicity.

Intravenous bolus administrations of either250 tg somatostatin or 50 tg octreotide resultedin a significant decrease in wedged and cor-rected wedged hepatic venous pressures. Theseresults are therefore in accord with previousobservations indicating that intravenous admin-istration of both somatostatin and octreotide andsubcutaneous administration of the analoguedecrease portal pressure [7-14]. However, itshould be pointed out that other reports sug-gests that octreotide and somatostatin have noeffect on corrected WHVP in portal hypertensivepatients [15-17]. These conflicting observationson the effects of somatostatin and octreotideon corrected WHVP are difficult to reconcile butmay be related to the amount given, the modeof administration and the severity of the portalhypertension. Nevertheless, the consensus ofopinion is that both somatostatin and octreotidereduce corrected WHVP in cirrhotic patients byeliciting a splanchnic vasoconstriction therebyreducing portal flow and portal pressure [18].The increase in arterial blood pressure anddecrease in heart rate elicited by both octreotideand somatostatin in the present study occurredafter the wedged and corrected wedged hepaticvenous pressures began to decrease suggesting


that they may be secondary reflex responses tocompensate for the increase in splanchnicvasoconstriction.The precise mechanism whereby somatostatin

and octreotide elicit splanchnic vasoconstrictionis not known. The rapidity of onset of thereduction in corrected WHVP following soma-tostatin or octreotide administration supportsthe suggestion that both compounds act directlyon receptors on the smooth muscle of thesplanchnic vasculature [19]. Alternatively, so-matostatin and octreotide may elicit vasocon-striction by inhibiting the release and end-organaction of vasoactive substances responsiblefor maintaining the hyperdynamic circulationin portal hypertensive patients. Clearly, furtherwork is required to establish more precisely themechanism of action of somatostatin and octreo-tide on hepatic and splanchnic haemodynamics.Nevertheless, irrespective of their mode ofaction, the reduction in portal venous inflow,portal pressure and azygos blood flow second-ary to splanchnic vasoconstriction is presumedto be mechanism whereby both drugs are effec-tive in controlling the acute variceal bleed.

In the present study a bolus injection of 250somatostatin or 50 tg octreotide elicited a reduc-tion in corrected WHVP of approximately thesame magnitude. Furthermore, the duration ofthe response to octreotide was not significantlygreater than that elicited by somatostatin,despite the presence of appreciable amounts ofthe analogue in the blood I h after administra-tion. The short duration of action of octreotideon WHVP was perhaps surprising since othereffects of the analogue such as the suppressionof growth hormone or.growth hormone releas-ing factor are prolonged and proportional tothe blood levels [20]. However, it is now evidentthat there are a family of receptors that bindsomastostatin and octreotide with differentbinding affinities [21, 22, 23]. Furthermore, thesomatostatin receptor sub-types have variablebut specific structural requirements to facilitatebinding with either somatostatin or its analo-

gues [21, 22,23]. Differences in the somatostatinreceptor sub-type responsible for a specificaction of somatostatin would offer an explana-tion for differences between the pharmacody-namic characteristics of octreotide with respectto its effect on growth hormone and insulinrelease [24]. Thus, after a single dose ofoctreotide in rhesus monkeys, the inhibition ofgrowth hormone release persists for muchlonger periods than that of insulin [24]. Thesomatostatin receptors in gastrointestinal tissueappear to consist of at least two subtypes viz.high affinity receptors similar to those foundin the cerebral cortex and low affinity, highcapacity subtypes to which analogues such asoctreotide bind poorly or not at all [23]. If theselow affinity somatostatin receptors are involvedin the events leading to a reduction in correctedWHVP by somatostatin or octreotide, the lowbinding of the analogue to such sites would offeran explanation for the relatively short durationof response. However, this hypothesis requiresconfirmation by identification of the somatosta-tin receptor subtypes involved in reducingWHVP. Nevertheless, regardless of the mechan-isms involved, the results of this study clearlysuggest that in terms of reducing portal pres-sure, octreotide is not long-acting and requiresintravenous administration to produce a sus-tained decrease in portal pressure. This sugges-tion is supported by the results of clinical trialson the efficacy of octreotide in controlling acutevariceal bleeding. Thus, one such trial reportedthat intravenous administration of octreotide(25 tg/h) was more efficacious than glypressinplus nitroglycerin (86% and 62% respectively)in controlling bleeding over a 12 h period [25].Over the next 36 h of the trial during whichoctreotide was given subcutaneously, morepatients in the analogue-treated group experi-enced rebleeding than in the glypressin-nytro-glycerin group so that the overall control ofbleeding was not significantly different betweenthe 2 groups over the 48 h assessment period(55% and 48% overall control of bleeding


respectively) [25]. In contrast, two trials havereported that intravenous octreotide is as goodas one course of injection sclerotherapy in control-ling variceal bleeding and preventing recurrenceover a 48 h trial period [26- 27].

In summary, the results of this study indicatethat the plasma half-life of octreotide in cirrhoticpatients is prolonged, presumably as a result ofdiminished hepatic excretion. However, in termsof reducing portal pressure, the duration of actionof octreotide is not significantly longer than thatof somatostatin. Consequently, like somatostatin,octreotide has to be administered intravenouslyto produce a sustained response and hence atherapeutic effect in the management of theacute variceal bleed.

Acknowledgments

We are grateful to Sandoz Pharmaceuticals Ltd.Camberley, UK for providing the octreotide andits specific radioimmunoassay kit and to SeronoPharmaceuticals, UK for the supply of somato-statin. We would also like to thank Mr. T. Hine,Department of Clinical Chemistry, RoyalLiverpool Hospital for carrying out theradioimmunoassay.

Re[erences

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[3] Rosenthal, L. E., Yamashiro, D. J., Rivier, J. et al. (1983).Structure-activity relationship of somatoastatin analo-gues in the rabbit ileum and rat colon. J. Clin. Invest.,71, 840-849.

[4] del Pozo, E., Neufield, M., Schlutr, K. et al. (1986).Endocrine profile of a long acting somatostatinderivative SMS 201-995. Study in normal volunteersfollowing subcutaneous administration. Acta Endocri-nologica, 111, 433-439.

[5] Kutz, K., Nuesch, E. and Rosenthaler, J. (1986).Pharmacokinetics of SMS 201- 995 in healthy subjects.Scan J. Gastroenterology, 21 (sup 119), 65-72.

[6] Erikson, L. S., Brundin, T., Soderlund, C. and Wahren,J. (1987). Haemodynamic effects of a long-standing

somatostatin analogue in patients with liver cirrhosis.Scand. J. Gastroent., 22, 919-925.

[7] Tyden, G., Samnegaard, H., Thulin, L. and Friman, L.(1978). Treatment of bleeding oesophageal varices withsomatostatin. New Engl. J. Med., 22, 919-925.

[8] Bories, P., Pomier-Layragues, G., Chotard, J. P., Jacob,C. and Michel, H. (1980). Lasomotostatine dimuel’hypertension portale chez le cirrhotique. Gastroenter-ologie et Biologique, 4, 616-617.

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[10] Naeije, R., Hallemans, R., Mois, P., Melot, C. H. andReding, P. (1982). Effects of vasopressin and somato-statin on haemodynamics and blood gases in patientswith liver cirrhosis. Crit. Care Med., 10, 578-582.

[11] Eriksson, L. S., Law, D., Sato, Y. and Wahren, J. (1984).Influence of somatostatin on splanchnic haemo-dynamics in patients with liver cirrhosis. ClinicPhysiol., 4, 5 11.

[12] Navasa, M., Bosch, J., Chesta, J. et al. (1988). Haemo-dynamics effect of subcutaneous administration ofSMS 201-995, a long-acting somatostatin analogue inpatients with cirrhosis and portal hypertension.J. Hepatol., 64, 123.

[13] Pringle, S. D., McKee, R. F., Garden, O. J., Lorimer, P.R. and Carter, D. C. (1988). The effects of a long-actingsomatostatin analogue on portal and systemic hameo-dynamics in cirrhosis. Alimentary Pharmacol and Ther-apeutics, 2, 451-459.

[14] Merkel, C., Gatta, A., Zuin, R. et al. (1985). Effect ofsomatostatin on splanchnic haemodynamics in patientswith cirrhosis of the liver and portal hypertension.Digestion, 32, 92- 98.

[15] Sonnenberg, G. E., Keller, U., Perruchoud, A., Bur-khardt, D. and Gyr, K. (1981). Effect of somatostatin onsplanchnic haemodynamics in patients with cirrhosisof the liver and in normal subjects. Gastroenterology, 80,526-532.

[16] Burroughs, A. K., Santana, J. A., Dux, T., Dick R. andMcIntyre, N. (1985). Effect of a long-acting analogue ofsomatostatin (SMS 201-995) on hepatic venous pres-sures and azygos blood flow in cirrhotics. Gastroenter-ology, 26, 562.

[17] McCormick, P. A., Dick, R., Siringo, S. et al. (1990).Octreotide reduces azygos blood flow in cirrhoticpatients with portal hypertension. Eur. J. Gastroenteroland Hepatol., 2, 489-492.

[18] Hanisch, E., Doertenbach, J. and Usadel, K. H. (1992).Somatostatin in acute bleeding oesophageal varices.Pharmacology and Rationale for use. Drugs, 44 (sup 2),24-35.

[19] Samnegaard, H., Thulin, L., Andreen, M. et al. (1979).Circulatory effects of somatostatin on anaesthetizeddogs. Acta Chir Scand, 145, 209-212.

[20] Marbach, P., Briner, U., Lemaire, M., Schweitzer, A.and Teraski, T. (1993). From somatostatin to sandosta-tin; pharmacodynamics and pharmacokinetics. Diges-tion, 5 (sup 1), 9-13.

[21] Yamada, Y., Post, S. R., Wang, K., Tager, H. S., Bell, G. I.and Seino, S. (1992). Cloning and functional character-isation of a family of human and mouse somatostatinreceptors expressed in brain; gastrointestinal tract andliver. Proc. Natl. Acad. Sci., USA, 78(87), 3930-3934.


[22] Srikant, C. B. and Patel, Y. C. (1992). Somatostatinreceptors. Identification and characterisation in brainmembranes. Proct. Natl. Acad. Sci., USA, 78, 1183 1193.

[23] Miller, C. V., Preston, Sr., Woodhouse, L. F., Farmery,S. M. and Primrose, J. H. (1993). Somatostatin bindingin human gastrointestinal tissues: effects of cations andsomatostatin analogues. Gut., 34, 1351-1356.

[24] Marbach, P., Andrew, H., Azria, M. et al. (1988).Chemical structure and pharmacodynamic propertiesof SMS 201-995 (Sandostatin) in the treatment ofacromegaly. In "The Treatment of Acromegaly",Berlin, Springer, 53-60.

[25] Silvain, C., Carpentier, S., Sautereau, S. et al. (1991). Arandomized trial of glypressin plus transdermalnitroglycerin versus octreotide in the control of acutevariceal haemorrhage. Hepatology, 14, 1339.

[26] Jenkins, S. A., Copeland, G., Sutton, R., Kingsnorth, A.N. and Shields, R. (1992). Octreotide (SMS) versussclerotherapy for variceal bleeding: preliminary re-sults. Br. J. Surg., 79, 1224.

[27] Sung, J. J. Y., Chung, S., Lai, C.-W. et al. Octreditideinfusion or emegency aclecthocopy for variocal has-marhage. Lancet, 342, 637-641.

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Pharmacokinetics Octreotide Hypertension; Relationship ...quently, octreotide has a muchlonger circulat-ing half-life than somatostatin in healthy volunteers [4, 5]. In normal healthy