I CurrentReviews

Domperidone, a new dopamine antagonist

Malcolm Charles Champion, MB, FRCPCMichael Hartnett, BScMargaret Yen, Pharm D

Domperidone is a dopamine antagonist that hasrecently been released in Canada. Unlike meto-clopramide hydrochloride, the other availabledopamine antagonist, it does not readily enterthe central nervous system. Domperidone acts asboth an antiemetic and an upper gastrointestinaltract prokinetic agent. It is rapidly absorbedafter oral administration, and few side effectshave been reported. Domperidone has beenapproved for use in Canada for the symptomaticmanagement of upper gastrointestinal tract mo-tility disorders and to prevent gastrointestinalsymptoms associated with the use of dopamineagonist agents in Parkinson's disease. The phar-macologic features, indications and side effectsof domperidone are reviewed.

Revue de la pharmacologie, des indications etdes effets secondaires de la domperidone, qui estdepuis peu disponible au Canada. Ce nouvelantagoniste de la dopamine possede sur le chlo-rhydrate de mdtoclopramide l'avantage de nepas penetrer d'emblee dans le systeme nerveuxcentral. I1 est antiemetique et stimule la motilitedes voies digestives hautes. Pris par la bouche, ils'absorbe promptement et produit peu d'effetssecondaires. Au Canada, on approuve son em-ploi dans le traitement symptomatique des dys-kinesies digestives hautes et la prevention destroubles gastro-intestinaux causes par les ago-nistes de la dopamine dans le traitement de lamaladie de Parkinson.

From the Division of Gastroenterology and the PharmacyDepartment, Ottawa Civic Hospital

Reprint requests to: Dr. Malcolm Charles Champion, Al-GIUnit, Ottawa Civic Hospital, 1053 Carling Ave., Ottawa, Ont.Kl Y 4E9

D omperidone, a new dopamine antagonistwith antiemetic and gastroprokinetic prop-erties, has recently been released in Cana-

da as Motilium (Janssen Pharmaceutica Inc., Mis-sissauga, Ont.). Its action is similar to that ofmetoclopramide hydrochloride. Unlike metoclo-pramide, it does not readily cross the blood-brainbarrier and therefore has fewer of the side effectsthat have limited the use of metoclopramide.

Pharmacologic features and pharmacokinetics

The pharmacologic features of domperidonehave been well reviewed.1'2 The drug is a benz-imidazole derivative with a molecular weight of426 that acts peripherally by dopamine blockade.Metoclopramide, a procainamide derivative, actsby both peripheral and intracerebral dopamineblockade. It has a lower molecular weight (354)and is more lipid soluble. The higher molecularweight and lower lipid solubility of domperidoneare felt to explain its inability to cross the blood-brain barrier. Low brain concentrations of dom-peridone after both oral and intravenous adminis-tration have been found in animal studies.2 Thisselective peripheral effect and lack of central effecthave been used effectively to block the undesirableperipheral side effects of dopamine agonist agentsused in the treatment of Parkinson's disease.

Domperidone's antiemetic action is on thechemoreceptor trigger zone, which is on the bloodside of the blood-brain barrier, on the floor of thefourth ventricle. Metoclopramide's antiemetic ac-tion is thought to be on the chemoreceptor triggerzone as well as on the intracerebral vomitingcentre. Despite their different foci of antiemeticactivity, the two drugs appear to be equally effec-tive as antiemetics. In addition, an importantcomponent of the antiemetic action is related to

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each drug's gastroprokinetic properties. Bothagents have been shown to increase basal loweresophageal sphincter pressure, inhibit relaxation ofthe gastric fundus, enhance antral contractility andrelax the pyloric sphincter. Both also stimulate andcoordinate gastroduodenal motility.L13

In fasting subjects, peak plasma levels ofdomperidone are reached within 15 to 30 minutesafter intramuscular or oral administration. Sinceabsorption of the drug requires some gastric acidi-ty, concomitant administration of high doses ofantacids or H2 receptor antagonists may impair itsabsorption.4 Its elimination half-life is 7.5 hours.Domperidone is strongly bound to plasma proteinsand is rapidly metabolized by the liver to inactivemetabolites, which are excreted in the urine (33%)and feces (66%).

Indications

In Canada domperidone has been approvedfor the symptomatic management of upper gas-trointestinal tract motility disorders associated withchronic and subacute gastritis and diabetic gas-troparesis. It may also be used to prevent gastroin-testinal symptoms associated with the use of dopa-mine agonist agents in Parkinson's disease.4

There is an extensive literature on domperi-done, mostly uncontrolled studies and publishedabstracts. In this article I review the controlledstudies that have been published on the approvedindications as well as other controlled studies withpossible future indications.

Gastroparesis

There is now much evidence suggesting thatdopamine plays an important physiologic role inthe regulation of gastric emptying by producinggastric relaxation and inhibiting gastric motility.Domperidone antagonizes this effect on gastricmotility by its action on peripheral dopaminereceptors.1 Studies in animals and humans haveshown the efficacy of the agent in promotinggastric emptying of several types of liquid andsolid meals.5-7 The gastroprokinetic properties ofdomperidone have not been directly comparedwith those of metoclopramide in healthy subjectsor patients with gastroparesis. Comparison is fur-ther complicated by the different methods ofgastric emptying used in various studies because ofthe changing technology in assessment of gastricemptying.

In a double-blind placebo-controlled trial asingle 10-mg intravenous dose of domperidonesignificantly shortened the half-time emptying of asemisolid homogenized meal in 6 patients withsevere symptomatic diabetic gastroparesis but notin 10 healthy control subjects.8 Horowitz andcolleagues9 studied gastric emptying with a doubleradioisotopic method in 12 patients with insulin-

dependent diabetes mellitus complicated by auto-nomic neuropathy and in 22 control subjects.Acute administration of domperidone, 10 mg takenorally before meals and at bedtime, increased therate of emptying of both solids and liquids. Thedrug was most effective in patients with thegreatest delay in baseline gastric emptying. Thesymptoms of gastroparesis were greatly alleviatedafter long-term administration, during which therewas increased emptying of liquids but no signifi-cant increase in the rate of emptying of solids.

In postprandial dyspepsia 20 mg of domperi-done given intravenously was found to signifi-cantly accelerate gastric emptying of both solidsand liquids in a double-blind placebo-controlledstudy.10 The increase in gastric emptying was morepronounced with the solid phase of the meal.

McCallum" recently reported that the gastro-prokinetic effect of domperidone was dose related:10 mg of the drug did not significantly accelerategastric emptying in a variety of conditions, but 20or 30 mg given orally accelerated delayed empty-ing in diabetic and postsurgical gastroparesis, gas-troesophageal reflux disease, scleroderma and idio-pathic gastric stasis.

Dyspepsia

There have been at least nine double-blindcontrolled studies of domperidone in patients withchronic postprandial dyspeptic symptoms.12-20 In-terpretation of these studies is complicated by theheterogeneous nature of patients with dyspepsia.In addition, most of the investigators did notmention whether other upper gastrointestinal tractdisorders were objectively excluded. In four studiesan upper gastrointestinal tract barium series orendoscopy was performed to confirm the diagnosisand exclude other disorders.'2"5'518'20

In six of the studies domperidone was shownto be superior to placebo in controlling dyspepticsymptoms. In three of these studies, in 105 pa-tients, therapy with domperidone, 20 mg threetimes a day for 2 to 4 weeks, resulted in goodsymptomatic improvement in 81% of patients,compared with 17% of those taking placebo.'2-'4 Inthe other three studies, in 107 patients, 10 mg ofdomperidone three times a day for 3 to 8 weekswas superior to placebo in controlling postprandialdyspeptic symptoms.'5-'7

Both 20 mg of domperidone three times a dayand the same dosage of metoclopramide reducedthe incidence of abdominal distension, epigastricburning, belching and nausea in 40 patients, 22with endoscopically confirmed gastritis and 18with a variety of gastrointestinal diagnoses."8 How-ever, extrapyramidal side effects of metoclopra-mide necessitated discontinuation of therapy inthree patients. In a randomized crossover study of67 patients, both 10 mg of domperidone four timesa day and the same dosage of metoclopramidewere significantly better than placebo overall and

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in controlling individual dyspeptic symptoms.19Domperidone was superior to metoclopramideoverall and in controlling seven of the nine targetsymptoms.

Finally, in a large double-blind study in 484patients, domperidone was compared with meto-clopramide in the symptomatic control of dyspep-sia.20 All patients had at least two symptoms ofdyspepsia and had radiologic or endoscopic confir-mation of the diagnosis. Domperidone was foundto be superior to metoclopramide in reducing theseverity of nausea and vomiting, abdominal disten-sion and abdominal pain. Control of heartburn andanorexia was also more marked in those treatedwith domperidone, but the difference between thetwo groups was not statistically significant.

Reflux esophagitis

Domperidone, 10 mg given intravenously, hasbeen shown to increase lower esophageal sphincterpressure in healthy subjects, whereas the responseto intravenous domperidone in patients with refluxesophagitis has been equivocal.2 Studies on theeffect of oral domperidone in clinical dosages havenot shown any increase in lower esophagealsphincter pressure in healthy subjects21 or in pa-tients with reflux esophagitis.2223 Del Genio andcolleagues24 found that 10 mg of the drug givenintravenously increased delayed emptying of asolid meal in eight patients with esophagitis buthad no effect on four patients with esophagitis andnormal gastroduodenal transit. There have been nostudies of the effect of oral domperidone on gastricemptying and reflux esophagitis.

Clinical evaluation of domperidone in refluxesophagitis has produced conflicting results. Val-enzuela22 compared domperidone, 20 mg fourtimes a day, with placebo in a double-blind trial in23 patients over 8 weeks. Domperidone was signif-icantly superior to placebo in reducing regurgita-tion but had no effect on the incidence of heart-burn or on healing of the esophageal mucosa asassessed by repeat endoscopy. In a 4-week studyin 22 patients maintained on a standard alginate-antacid regimen, Blackwell and associates23 foundthat 20 mg of the drug four times a day decreasedthe amount of antacid required when comparedwith placebo. The average daily incidence of heart-burn and number of reflux episodes were de-creased to a similar extent by domperidone andplacebo. Neither of these studies demonstrated anyincrease in lower esophageal sphincter pressure.Goethals25 found domperidone, 10 mg four times aday for 2 weeks, significantly better than placeboin alleviating heartburn, regurgitation, belchingand nausea in a randomized crossover trial. Thepatients had a variety of gastrointestinal tractdisorders, and the diagnosis of gastroesophagealreflux or esophagitis was not confirmed by endo-scopic investigation before the study.

In a recent study 40 patients with reflux

esophagitis were randomly assigned to receivedomperidone, 20 mg three times a day for 6 weeks,or ranitidine, 150 mg twice a day for 6 weeks, orboth.26 The three therapeutic regimens were signif-icantly and equally effective in reducing symptomsand promoting endoscopic and histologic disap-pearance or alleviation of esophagitis. The combi-nation of an acid-suppressing agent (ranitidine)and an antireflux agent (domperidone) failed toshow any additional benefit when compared withtreatment with either drug alone.

Nausea and vomiting

The efficacy of domperidone as an antiemeticfor a wide variety of underlying causes has beenreviewed by Reyntjens.27 In most studies the drugwas administered parenterally or as a suppository.I will not review these studies except for purposesof comparison with metoclopramide, as the paren-teral and suppository forms of domperidone arenot available in Canada.

In a double-blind study in 23 patients receiv-ing chemotherapy, 12 mg of domperidone and 12mg of metoclopramide, both given intravenously,appeared to be equally effective as antiemetics.28However, limiting side effects occurred in threepatients who received metoclopramide. In anotherdouble-blind study domperidone was found to besuperior to metoclopramide in preventing hemodi-alysis-related vomiting.27

There have been no double-blind studies oforal domperidone as an antiemetic. In three openstudies the drug appeared effective in preventingnausea and vomiting due to a variety of causesincluding radiotherapy.27 Studies are under way inEurope to evaluate large doses (100 mg) of oraldomperidone in postchemotherapy nausea andvomiting. Definition of the exact role of oraldomperidone as an antiemetic must await theresults of these studies.

Parkinson's disease

The use of the dopamine agonists levodopaand bromocriptine in patients with Parkinson'sdisease is limited by their peripheral side effects,nausea and vomiting. Several investigators havestudied the efficacy of domperidone in selectivelysuppressing peripheral side effects while leavingthe desired central dopaminergic effects un-changed.

In a crossover study in 15 patients takinglevodopa, 10, 20 or 40 mg of domperidone givenorally, intravenously or intramuscularly had abeneficial antiemetic effect.29 The parkinsonismdisability score decreased with an increase in thebioavailability of levodopa and in the initial rate ofabsorption. In a double-blind study Agid andcolleagues30 found that 20 mg of domperidonethree times a day reduced vomiting, psychic distur-

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bance and involuntary movements in 76% ofpatients receiving large doses of bromocriptine,compared with 48% of those receiving placebo.Patients in the domperidone group could toleratelarger doses of bromocriptine, which resulted in asignificant reduction in the parkinsonism disabilityscore. In another double-blind study Quinn andassociates31 reported that 50 mg of domperidonethree times a day did not diminish the beneficialcentral effects of bromocriptine in 20 patients, andthe combination of the two drugs permitted bro-mocriptine dosages to be rapidly increased.

Migraine

Amery and Waelkens32 studied 19 patientswith classic migraine in a double-blind studycomparing domperidone, 30 mg given orally, withplacebo. Acute attacks were prevented when thepatients were given domperidone in the prodromalperiod. Each patient was studied during four con-secutive attacks. No aura or headache was experi-enced in 66% of the attacks that occurred duringtherapy with domperidone, compared with 5% ofthose with placebo. The mechanism of action ofdomperidone in this condition is not known. Incontrast to the-results of this study, migraine andheadache are recognized side effects of domperi-done, occurring in up to 1.2% of patients.4

Therapy in children

No controlled studies have been published ontherapy with domperidone in children with uppergastrointestinal tract motility problems. In the onlyopen study published, Grill and coworkers33 re-ported that domperidone, 0.3 to 0.6 mg/kg givenorally three times a day, significantly reduced themean total symptom scores in 15 infants (mean age7.9 months) with moderate to severe gastro-esophageal reflux and upper gastrointestinal tractmotility disturbances. Vomiting, spitting andcoughing were significantly reduced, and post-prandial reflux time (defined as esophageal pH ofless than 4.0) and percentage of peristaltic esopha-geal contractions improved significantly. The meangastric emptying of an isotope-labelled formula,esophageal peristaltic amplitude, lower esophagealsphincter pressure and esophageal acid clearancewere unchanged.

Domperidone has not been approved for usein children in Canada, and no liquid form isavailable.

Dosage and route of administration

In Canada domperidone is available only as10-mg tablets. A liquid preparation and supposito-ries are available in Europe but are unlikely to bereleased in Canada.

For the treatment of upper gastrointestinaltract motility disorders, the initial adult dosage is10 mg taken orally 15 to 30 minutes before mealsand at bedtime. The dosage may be increased to amaximum of 20 mg four times daily, which ap-pears to be more effective. For nausea and vomit-ing associated with agents for the treatment ofParkinson's disease, the recommended adult dos-age is up to 20 mg four times a day.

Dopamine antagonists should not be used inconjunction with monoamine oxidase inhibitorsbecause of the increased risk of drug interaction.The concomitant use of anticholinergics mayweaken the gastroprokinetic effect of domperi-done.

Side effects

Some of the side effects of domperidone andmetoclopramide are an unavoidable extension ofthe dopamine antagonistic properties of thesedrugs. In clinical studies of oral domperidone theoverall incidence of side effects was less than 7%.4This compares favourably with an overall inci-dence of 20% reported with metoclopramide.3Most side effects of domperidone resolve sponta-neously during continued therapy or are easilytolerated. Dry mouth (in 1.9% of patients), head-ache/migraine (in 1.2%) and endocrinologic prob-lems related to hyperprolactinemia (in 1.3%) ap-pear to be the most troublesome.4 Arrhythmias,sudden death and cardiac arrest have been report-ed with high intravenous doses in nine patientswith cancer who were receiving chemotherapy.Although the manufacturer re-emphasized the ap-propriate dosage regimen,34 it withdrew the paren-teral form of the drug in 1984.

Mastalgia, galactorrhea, gynecomastia andmenstrual irregularities are due to stimulation ofprolactin release from the pituitary. Hyperprolac-tinemia occurs with both domperidone and meto-clopramide therapy and is due to blockade ofendogenous dopamine in the pituitary. Dopamineappears to be a physiologic inhibitor of prolactinrelease from the pituitary. There is no directcorrelation between dosage and prolactin response,though the increase in prolactin secretion riseswith increasing dosages of both domperidone andmetoclopramide.2'3 Increased serum prolactin con-centration is greater in women, particularly in thehyperprolactinemic state after childbirth. However,domperidone has not been shown to increaseprolactin release from prolactin-secreting tumours.?

The somnolence and extrapyramidal side ef-fects found in up to 10% of patients takingmetoclopramide have not been reported with oraldomperidone in adults. There have been four casereports of extrapyramidal problems with thedrug.35 Two were in infants aged 3 and 4 months,at which age the blood-brain barrier is thought notto be fully formed. The infants received liquiddomperidone in the recommended dosage. Ex-

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trapyramidal side effects have also been reportedwith parenterally administered domperidone in a12-year-old girl with Ewing's sarcoma and in a27-year-old woman who had had similar problemswith metoclopramide.

Conclusion

Domperidone is a new peripheral dopamineantagonist that appears to have fewer side effectsthan the currently available metoclopramide. Clini-cal studies have shown its efficacy in gastroparesis,as adjunctive therapy with agents for the treatmentof Parkinson's disease and in dyspepsia. Furtherstudy is necessary to define the exact role of oraldomperidone as an antiemetic and its efficacy inreflux esophagitis.

References

1. Reyntjens AJ: Clinical pharmacology and therapeutics ofdomperidone. Clin Res Rev 1983; 3: 91-100

2. Brogden RN, Carmine AA, Heel RC et al: Domperidone: areview of its pharmacological activity, pharmacokineticsand therapeutic efficacy in the symptomatic treatment ofchronic dyspepsia and as an anti-emetic. Drugs 1982; 24:360-400

3. Riyad A, McCallum RW: Metoclopramide: pharmacologyand clinical application. Ann Intern Med 1983; 98: 86-95

4. Domperidone (Motilium) Tablets (product monogr), JanssenPharmaceutica, Mississauga, Ont, 1985

5. Jacobs F, Akkermans LMA, Hongeo 0 et al: Effects ofdomperidone on gastric emptying of semi-solid and solidfood. In Towse G (ed): Progress with Domperidone, aGastrokinetic and Anti-emetic Agent (R Soc Med Interna-tional Congress and Symposia ser, no 36), R Soc Med,London, 1981: 11-20

6. Broekaert A: Effect of domperidone on gastric emptyingand secretion. Postgrad Medj 1979; 55 (suppl 1): 11-14

7. Baeyens R, Van De Velde E, De Schepper A et al: Effects ofintravenous and oral domperidone on the motor function ofthe stomach and small intestine. Ibid: 19-23

8. Heer M, Muller-Duysing I, Benes M et al: Diabetic gas-troparesis: treatment with domperidone - a double-blind,placebo-controlled trial. Digestion 1983; 27: 214-217

9. Horowitz M, Harding PE, Chatterton BE et al: Acute andchronic effects of domperidone on gastric emptying indiabetic autonomic neuropathy. Dig Dis Sci 1985; 30: 1-9

10. Corinaldesi R: The effect of domperidone on the gastricemptying of solid and liquid phases of a mixed meal inpatients with dyspepsia. Curr Ther Res 1983; 34: 982-986

11. McCallum RW: Review of the current status of prokineticagents in gastroenterology. Am J Gastroenterol 1985; 80:1008-1016

12. O'Shea M, Fennell HP: Domperidone in the symptomatictreatment of flatulent dyspepsia: a double-blind placebo-controlled study. IrJMed Sci 1979; 148: 25-26

13. Arts E, Anthoni H, de Roy G et al: Domperidone in thetreatment of dyspepsia: a double-blind placebo-controlledstudy. J Int Med Res 1979; 7: 158-161

14. Van Ganse W, Van Damme L, Van de Mierop L et al:Chronic dyspepsia: double-blind treatment with domperi-done or a placebo. A multicentre therapeutic evaluation.Cuff TherRes 1978; 23: 695-701

15. Haarmaann K, Lebkuchner F, Widmann A et al: A double-blind study of domperidone in the symptomatic treatment

of chronic postprandial upper gastrointestinal distress.Postgrad MedJ 1979; 55 (suppl 1): 24-27

16. Agorastos I, Zssis NP, Kaprinis I et al: Double-blindevaluation of domperidone in acute vomiting and dyspepticdisorders.J IntMed Res 1981; 9: 143-147

17. Englert W, Schlich D: A double-blind crossover trial ofdomperidone in chronic postprandial dyspepsia. PostgradMed J 1979; 55 (suppl 1): 28-29

18. O'Shea M: A double-blind comparison of domperidone andmetoclopramide in the treatment of postprandial dyspepticsymptoms. Curr Ther Res 1980; 28: 367-370

19. De Loose F: Domperidone in chronic dyspepsia: a pilotopen study and a multicentre general practice crossovercomparison with metoclopramide and placebo. Pharma-therapeutica 1979; 2: 140-146

20. Moriga M: A multicentre double-blind study of domperi-done and metoclopramide in the symptomatic control ofdyspepsia. In Towse G (ed): Progress with Domperidone, aGastrokinetic and Anti-emetic Agent (R Soc Med Interna-tional Congress and Symposia ser, no 36), R Soc Med,London, 1981: 77-79

21. Wallin L, Madsen T, Boesby S: Effect of domperidone ongastroesophageal function in normal human subjects.ScandJ Gastroenterol 1985; 20: 150-154

22. Valenzuela JE: Effects of domperidone on the symptoms ofreflux esophagitis. In Towse G (ed): Progress with Dom-peridone, a Gastrokinetic and Anti-emetic Agent (R SocMed International Congress and Symposia ser, no 36), RSoc Med, London, 1981: 51-56

23. Blackwell JN, Heading RC, Fettes MR: Effects of domperi-done on lower esophageal sphincter pressure and gastro-esophageal reflux in patients with peptic esophagitis. Ibid:57-65

24. Del Genio A, Di Martino N, Piccolo S et al: The effect ofdomperidone on gastric emptying in reflux esophagitis: aradioisotopic study. J Nuci Med Allied Sci 1984; 28: 251-256

25. Goethals C: Domperidone in the treatment of postprandialsymptoms suggestive of gastroesophageal reflux. Curr TherRes 1979; 26: 874-880

26. Masci E, Testoni PA, Passaretti S et al: Comparison ofranitidine, domperidone maleate and ranitidine and dom-peridone maleate in the short term treatment of refluxesophagitis. Drugs Exp Clin Res 1985; 10: 1-6

27. Reyntjens A: Domperidone as an anti-emetic; summary ofresearch reports. Postgrad MedJ 1979; 55 (suppl 1): 50-54

28. D'Souza DP, Reyntjens A, Thornes RD: Domperidone inthe prevention of nausea and vomiting induced by anti-neoplastic agents: a three-fold evaluation. Curr Ther Res1980; 27: 384-390

29. Schindler JS, Finnerty GT, Towlson K et al: Domperidoneand levodopa in Parkinson's disease. Br J Clin Pharmacol1984; 18: 959-962

30. Agid Y, Pollak P, Bonnet AM et al: Bromocriptine associat-ed with a peripheral dopamine blocking agent in treatmentof Parkinson's disease. Lancet 1979; 1: 570-572

31. Quinn N, Illas A, Lhermitte F et al: Bromocriptine anddomperidone in the treatment of Parkinson disease. Neu-rology (NY) 1981; 31: 662-667

32. Amery WK, Waelkens J: Prevention of the last chance: analtemative pharmacologic treatment of migraine. HeadacheJ1983; 23: 37-38

33. Grill BB, Hillemeier AC, Semeraro LA et al: Effects ofdomperidone therapy on symptoms and upper gastrointes-tinal motility in infants with gastroesophageal reflux. JPediatr 1985; 106: 311-316

34. Cameron HA, Reyntjens AJ, Lake-Bakaar G: Cardiac arrestafter treatment with intravenous domperidone [C]. Br MedJ1985; 290: 160

35. Franckx J, Noel P: Acute extra-pyramidal dysfunction afterdomperidone administration: report of a case. Helv PaediatrActa 1984; 39: 285-288

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