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birthday of James Parkinson) described another operationfrom Nashville, Tennessee, with the patient’s husbandoverjoyed at the prospect of his wife’s recovery-"I amthrilled to death," he said." However, only four operationshave been reported in the scientific press. What has beenachieved?These trials would not have been attempted without

many years of basic research. After the pioneering studies ofGeoffrey Raisman and others at the National Institute forMedical Research, Mill Hill, many laboratories worldwidehave shown that the central nervous system of animals,contrary to earlier belief, has a definite capacity for repair; inparticular, damage to amine systems is recoverable at a

histological, pharmacological, and behavioural level. Cellgrafts into the brain are not necessarily rejected; and thecerebrospinal fluid (CSF) provides a rich cell-culturemedium.8 The critical animal study for parkinsonism wasthe demonstration that impaired animal mobility followinglesions to the dopamine system could be overcome by braingrafts of catecholamine-producing cells.9 This work leddirectly to autografting of human adrenal medullary tissue,with the eventual possibility of human fetal cell or cell-linetransfer to the brain.At this stage it is necessary to review the results of six

grafts in monkeys and four in men, although doubtless manymore replication studies will appear this year. Redmond andhis colleagues successfully transplanted into the brain of twomale monkeys, multiple 1 cu mm blocks of substantia nigrafrom fetal monkeys.10 The grafts appeared to survive inthese animals, who had been given methylphenyltetra-hydropyridine (MPTP) 3-4 weeks previously and had signsof severe parkinsonism. These signs decreased over 3-7weeks after the transplant while CSF homovanillic acidconcentration, as an index of central dopamine turnover,increased. Bakay and King reported similar results in fourother monkeys.11 In the Swedish operations two severelydisabled parkinsonian patients were given approximatelyfifteen small segments of their own adrenal medulla (1-2 cumm/piece) suspended in a cage in the right caudate nucleus.2There were minor changes in severity of parkinsonism, withrevision of levodopa requirements, and alteration in CSFhomovanillic acid concentration. But there was no clearevidence that the graft itself was responsible for any of thesechanges.The reported Mexican experience has been far more

dramatic. After right adrenalectomy and transplantation ofabout 0.8-1 g of adrenal medullary tissue via the lateralventricle into a bed on the right caudate nucleus bathed inCSF, one wheelchair-bound patient recovered sufficientlyto play soccer with his five-year-old son. Another patientprogressed from total dependence on others to walking well,speaking clearly, and losing his tremor. These results wereachieved within 3-10 months of grafting; in both casesimprovement started within a few days of operation.Unilateral graft caused bilateral benefit3-how could thisbe? Clearly unilateral stimulation of damaged dopamineneurons cannot be the mechanism.

4 Gillie O. Parkinson’s disease cured by brain graft. Independent, Wednesday, Apnl 8,1987

5. Anon. On the brain. Guardian, Saturday, April 4, 1987.6. Anon Brain graft experiment on woman with Parkinson’s. New York Post, Saturday,

April 11, 1987.7 Bignami A, Bloom FE, Bolis CL, Adeloye A, eds. Central nervous system plasticity

and repairs. New York: Raven, 1985. 184.8 Rosenstein JM, Brightman MW. Intact cerebral ventricle or a site for tissue

transplantation. Nature 1978, 276: 83-85.9. Dunnett SB, Björklund A, Stenevi U. Dopamine-rich transplants m experimental

parkinsonism. Trends Neurosci 1983; 6: 266-70.

The Mexican report has been hailed as a milestone paperand a very promising step forward by Dr Robert Moore,Chairman of the Department of Neurology at the StateUniversity of New YorkY There is a natural tendency forinitial disbelief, and the Mexican workers’ themselves arecautious in appraising their results, but these studies have atleast demonstrated that grafts are tolerated well, perhapswith surprising consequences. There are obvious

difficulties, with small patient numbers, lack of controls,failure to account for natural variation in disease, andabsence of adequate physiological or biochemical studies(eg, positron emission tomography assessment of pre andpost graft dopamine turnover in the brain). In addition, theproposed use of human fetal material, rather than adrenalautografts, raises serious ethical issues.13The eventual outcome of many tissue transplant

experiments-blood, kidney, liver, and heart-has owed asmuch to initial enthusiasm as to subsequent detailedscientific evaluation. The Mexican report undoubtedly hasits drawbacks, but Cotzias’ first account of oral dopa inparkinsonism also met with considerable scepticism. 14 Whatis needed now is a model scientific approach, such as thatapplied to the study of lymphokine-activated killer cells andinterleukin-2 in cancer patients. is There are comparablestrategies for looking at brain disease which should be usedto evaluate intracerebral or intraventricular cell therapy forparkinsonism, and to prevent cruelty to patients from thepremature announcement of apparent breakthroughs intreatment. Verdict? Cautious optimism.

REPEATED ORAL ACTIVATED CHARCOAL INACUTE POISONING

TECHNIQUES to increase poison elimination such asalkaline diuresis, dialysis, and haemoperfusion are not

always effective; they also require intensive monitoring andexperience of their use. It has now been shown that repeateddosing with oral activated charcoal-a technically simplerand less invasive procedure-will increase the elimination ofmany drugs.Neuvonen and Elonen1 gave adult volunteers 17 g of

activated charcoal at 10, 14, 24, 36, and 48 h after oraladministration of 200 g phenobarbitone and reported areduction in mean elimination half-life of phenobarbitonefrom 110 to 20 h. Berg and colleagues2 subsequentlyestablished that the non-renal elimination of intravenous

phenobarbitone was also significantly increased, withreduction in mean half-life from 110 to 45 h. These sameworkers gave repeated oral charcoal to two patients acutelypoisoned with phenobarbitone and noted a reduction notonly in the elimination half-life (to under 24 h) but also in theduration of coma and the need for supportive care.3 Pond et

10 Redmond DE, Sladek JR, Roth RH, et al. Fetal neuronal grafts in monkeys givenmethylphenyltetrahydropyridine. Lancet 1986; i: 1125-27.

11. Bakay RA, King FA. Transplanted fetal monkey neurons Lancet 1986; ii: 163.12 Moore RY. Parkinson’s disease—a new therapy? N Engl J Med 1987; 316: 872-7313. Anon. Swedish implant plans cause international excitement The Parkinson

Newsletter (London: Parkinson’s Disease Society) no 60, March, 1987: 1-214. Cotzias GC, Papavasiliou PS, Gellene R. Modification of parkinsonism—chronic

treatment with 1-dopa. N Engl J Med 1969; 280: 337-45.15. Rosenberg SA, Lotze MT, Muul LM, et al A progress report on the treatment of 157

patients with advanced cancer using lymphokine-activated killer cells and

interleukin-2 or high-dose Interleukin-2 alone N Engl J Med 1987; 316: 889-97.1. Neuvonen PJ, Elonen E. Effect of activated charcoal on absorption and elimination of

phenobarbitone, carbamazepine and phenylbutazone in man Eur J ClinPharmacol 1980; 17: 51-57

2. Berg MJ, Berlinger WG, Goldberg MJ, Spector R, Johnson GF. Acceleration of thebody clearance of phenobarbital by oral activated charcoal N Engl J Med 1982; 307:642-44

3. Goldberg MJ, Berlinger WG. Treatment of phenobarbital overdose with acnvatedcharcoal JAMA 1982; 247: 2400-01

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al4 attempted to confirm these findings in a randomisedstudy of ten comatose patients who required intubation andmechanical ventilation. Both control and treatment groupsreceived 50 g activated charcoal on presentation and, inaddition, patients in the treatment group were given 17 gactivated charcoal together with sorbitol four-hourly untilthey had recovered to the extent that they could beextubated. Although with treatment the mean pheno-barbitone elimination half-life was shortened from 93 to36 h, the period of mechanical ventilation and the durationof hospital stay were not reduced. These results may havebeen due to inadequate doses of charcoal andcoadministration of a cathartic, which can reduce drugadsorption to charcoal.**

In an uncontrolled study Boldy et al6 showed thatcharcoal given alone in larger (50 g) doses not only greatlyenhanced the elimination of phenobarbitone but alsodecreased time to recovery. Six adult patients with moderateto severe phenobarbitone intoxication admitted to the

poisons units in Birmingham and Edinburgh were given50 g activated charcoal four-hourly after an initial dose of50-100 g. Mean total body clearance of phenobarbitoneduring and for up to 12 h after administration of charcoalwas 84 ml/min, which is greater than that achieved byhaemodialysis7 or haemoperfusion.8 Mean rate of fall inplasma phenobarbitone concentrations corresponded to ahalf-life of 11 ’7 h and the patients recovered consciousnessin a mean time of 16-2 h.

Repeated oral dosing with charcoal enhances theelimination of many other drugs and poisons, particularlythose that are weakly acidic and slowly eliminated with asmall volume of distribution. This technique increasesnon-renal elimination of salicylate,9,lO dapsone,"diazepam,12 digitoxin,13 digoxin,14,15 meprobamate,16,17 andtheophyllinei$°l9 with a significant decrease in the plasmahalf-life of each drug; in this issue (p 1027) Dr Boldy and hiscolleagues add carbamazepine to the list. Controlled trials

4 Pond SM, Olson KR, Osterloh JD, Tong TG. Randomized study of the treatment ofphenobarbital overdose with repeated doses of activated charcoal. JAMA 1984;251: 3104-08.

5. Van de Graaff WB, Leigh Thompson W, Sunshine I, Fretthold D, Leickly F, DaytonH. Adsorbent and cathartic inhibition of enteral drug absorption. J Pharmacol ExpTher 1982; 221: 656-63.

6. Boldy DAR, Vale JA, Prescott LF. Treatment of phenobarbitone poisoning withrepeated oral administration of activated charcoal. Quart J Med 1986; 235:997-1002.

7. Takki S, Gambertoglio JG, Honda DH, Tozer TN. Pharmacokinetic evaluation ofhemodialysis in acute drug overdose. J Pharmacokinet Biopharm 1978; 6: 427-42.

8. Jacobsen D, Wiik-Larsen E, Dahl T, Enger E, Lunde PKM. Pharmacokineticevaluation of haemoperfusion in phenobarbital poisoning. Eur J Clin Pharmacol1984; 26: 109-12

9. Hillman RJ, Prescott LF. Treatment of salicylate poisoning with repeated oralcharcoal. Br Med J 1985; 291: 1472

10. Boldy D, Vale JA. Treatment of salicylate poisoning with repeated oral charcoal BrMed J 1986, 292: 136

11. Neuvonen PJ, Elonen E, Haapanen EJ. Acute dapsone intoxication. clinical findingsand effect of oral charcoal and haemodialysis on dapsone elimination Acta MedScand 1983, 214: 215-20.

12. Traeger SM, Haug MT Reduction of diazepam serum half-life and reversal of comaby activated charcoal in a patient with severe liver disease. Clin Toxicol 1986, 24:329-37

13. Pond S, Jacobs M, Marks J, Gamer J, Goldschlager N, Hansen D Treatment ofdigitoxin overdose with oral activated charcoal. Lancet 1981; ii: 1177-78.

14 Lalonde RL, Deshpande R, Hamilton PP, McLean WM, Greenway DC.Acceleration of digoxin clearance by activated charcoal Clin Pharmacol Ther 1985;37: 367-71.

15. Boldy DAR, Smart V, Vale JA. Multiple doses of charcoal in digoxin poisoning.Lancet 1985; ii: 1076-77.

16. Linden CH, Rumack BH. Enhanced elimination of meprobamate by multiple doses ofactivated charcoal Vet Hum Tox 1984, 26 (suppl 2) 47.

17 Hassan E. Treatment of meprobamate overdose with repeated oral doses of activatedcharcoal Ann Emerg Med 1986; 15: 73-76.

18. Gal P, Miller A, McCue JD. Oral activated charcoal to enhance theophyllineelimination in an acute overdose JAMA 1984, 251: 3130-31

19 Sessler CN, Glauser FL, Cooper KR. Treatment of theophylline toxicity with oralactivated charcoal Chest 1985; 87: 325-29

will be necessary to establish a reduction in morbidity andmortality. The influence of repeated oral charcoal on theelimination of tricyclic antidepressants is not consistent

-plasma half-lives of amitriptyline20 and doxepin 21 but notimipramine2Z are reduced-and it is unlikely that any usefulreduction in elimination half-life of these drugs will beachieved because of their very large volume of distribution.How do repeated doses of activated charcoal exert their

beneficial effect? After absorption, a drug may re-enter thegut by active secretion into bile and by passive diffusion intogastrointestinal fluids, provided that the concentration thereis lower than in the blood. The rate of passive diffusiondepends on the concentration gradient and the intestinalsurface area, permeability, and blood flow. Repeated oralcharcoal is thought to act in two main ways: it combines withdrugs and labile conjugates which are secreted into bile andprevents their intestinal reabsorption, and, probably moreimportantly, it binds and removes any drug diffusing backinto the gut. Under these "sink" conditions a concentration

gradient is maintained and drug passes continuously fromthe circulation into the gut lumen where it is bound by thecharcoal. This process has been termed "gastrointestinaldialysis".23 The small intestine has a large surface area and isprobably the most important site of transfer. Thus, formaximum efficiency, charcoal should be given at a rate whichkeeps the small intestine filled, with passage onwards toavoid saturation not only by drug but also by endogenouscompounds in biliary and enteric secretions.6Treatment with repeated oral charcoal has no serious

side-effects, but it is unpalatable; administration via a

nasogastric tube may be necessary in conscious as well asunconscious patients. Moreover, if charcoal is to be

retained, particularly by those who are nauseated andvomiting, administration by nasogastric tube is mandatory.Occasionally, intractable vomiting (eg, in theophyllinepoisoning) may preclude its use. Pulmonary aspiration ofcharcoal seldom occurs and does not usually produceclinically important complications, although severe airwaysobstruction was reported in an infant given charcoal aftersyrup of ipecacuanha.24

After charcoal administration bowel motions become

black; this coloration provides a guide to the transit time.Although activated charcoal has a reputation for causingconstipation, one of the preparations (’Medicoal’) causesdiarrhoeab and it is possible that the faster transit time soobtained may have a therapeutic advantage. Osmoticcathartics such as mannitol and sorbitol have been used toreduce the risk of constipation and hasten intestinal transit,2sbut both these agents decrease the efficacy of charcoal invivo.s In addition, cathartics increase the volume ofintestinal fluid5 and delay gastric emptying,26 therebyreducing the amount of charcoal available in the small bowelfor drug adsorption.The optimum dose of activated charcoal has not been

20 Swartz CM, Sherman A. The treatment of tricyclic antidepressant overdose withrepeated charcoal J Clin Psychopharmacol 1984; 4: 336-40.

21 Scheinin M, Virtanen R, Iisalo E. Effect of single and repeated doses of activatedcharcoal on the pharmacokinetics of doxepin. Int J Clin Pharmacol Ther Toxicol1985; 23: 38-42.

22 Goldberg MJ, Park GD, Spector R, Fischer LJ, Feldman RD. Lack of effect of oralactivated charcoal on imipramine clearance. Clin Pharmacol Ther 1985; 38: 350-53.

23 Levy G. Gastrointestinal clearance of drugs with activated charcoal. N Engl J Med1982, 307: 676-78

24. Pollack MM, Dunbar BS, Holbrook PR, Fields AI. Aspiration of activated charcoaland gastric contents. Ann Emerg Med 1981, 10: 528-29.

25. Krenzelok EP, Keller R, Stewart RD. Gastrointestinal transit times of catharticscombined with charcoal. Ann Emerg Med 1985, 14: 1152-55

26. Hunt JN, Stubbs DF. The volume and energy content of meals as determinants ofgastric emptying. J Physiol (Lond ) 1975; 245: 209-25

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established, but a reasonable regimen is 50-100 g activatedcharcoal orally or via a nasogastric tube when the patientarrives at hospital, followed by 50 g four-hourly untilrecovery or until plasma drug concentrations have fallen tosafe levels. Repeated oral activated charcoal is a simple,effective, and inexpensive therapy for many types ofintoxication. For some patients, it may be a satisfactoryalternative to haemoperfusion and haemodialysis and cantherefore be used in hospitals that do not have facilities forsuch procedures.

PANCREATIC TRANSPLANTATION INDIABETES

INSULIN-DEPENDENT diabetes mellitus (IDDM) is twiceas common in young people as all other endocrine deficiencydiseases combined.1 Whilst replacement therapy has beenavailable for more than 60 years, treatment is still

unsatisfactory, with those diagnosed in the 1930s showing afifteen-fold excess mortality after 15-30 years andsubstantial morbidity in many survivors. Relative mortalityhas decreased by a third in the past 40 years2 and the diseaseitself may be preventable in the future. At present,however, the main hope of preventing, delaying, or

reversing microvascular complications lies in maintainingnearly normal blood sugar levels 24 h a day for years on end.4With new strategies of insulin replacement by pumps ormultiple injections, this goal can be achieved in selectedsmall groups, without excessive hypoglycaemia or

disruption of lifestyle.s Nevertheless, there will always bepatients who cannot or will not comply with such intensiveregimens, and for whom the only treatment may bereplacement of insulin-producing cells by transplanting thewhole pancreas or merely the islets of Langerhans.The pace of pancreas transplantation is quickening, with

three-quarters of the one thousand operations since 1966having been done in the past 4 years. Before 1980 suchtransplants were carried out only in uraemic patients withadvanced complications; the results were disappointing,with frequent failures due to vascular thrombosis and

difficulty in disposing of the exocrine secretions. Thesuccess rate is still well below that of other solid organtransplants, but technical advances, better patient selection,and use of cyclosporin have led to overall 1-year graftfunction and patient survival rates of 42% and 79%,respectively, in the 736 transplants carried out worldwidebetween 1983 and 1986. Most transplants are still done inuraemic diabetics, either simultaneously with or after kidneytransplantation, the justification being that a functioningendocrine pancreas will protect the renal graft and stabiliseother diabetic complications. If pancreas transplantation

1. Nabarro JDN, Mustaffa BE, Morris DV, Walport MJ, Kurtz AB. Insulin deficientdiabetes contrasts with other endocrine deficiencies. Diabetologia 1979; 16: 5-12.

2. Borch-Johnsen K, Kreiner S, Deckert T. Mortality of type 1 (insulin dependent)diabetes mellitus in Denmark: a study of relauve mortality in 2930 Danish type 1diabetic patients diagnosed from 1933 to 1972. Diabetologia 1986; 29: 767-72.

3. Rubenstein AH, Pyke D. Immunosuppression in the treatment of insulin-dependent(type I) diabetes. Lancet 1987; i: 436-37

4. Sherwin RS, Tamborlane WV. Metabolic control and diabetic complications. In:Olefsky JM, Sherwin RS, eds. Contemporary issues in endocrinology andmetabolism, vol 1. Edinburgh. Churchill Livingstone, 1985 1-30.

5. Tamborlane WV, Champion MC, Rizza RA, Service FJ, Bergenstal RM.Observations on the control of glycaemia with conventional insulin therapy orcontinuous sub-cutaneous insulin infusion. Diabetes 1985; 34 (suppl 3): 22-26.

6. Sutherland DER, Kendall D. Clinical pancreas and islet transplant registry report.Transplant Proc 1985; 17: 307-11.

7. Sutherland DER, Moudry K. Report of the Pancreas Transplant Registry In:Terasaki PI, ed Clinical transplants 1986. Los Angeles UCLA Tissue TypingLaboratory, 1986.

8. Sutherland DER. Pancreas transplantation: an update. Diabetes. Annu (in press).

was both safe and effective, it would be logical to undertakethe procedure earlier, since both macrovascular andmicrovascular complications enter an accelerated phase withthe onset of uraemia. The only unit to have done this is at theUniversity of Minnesota, where most transplants are nowbeing carried out in non-uraemic patients with persistentproteinuria or proliferative retinopathy.9 For 62 such

transplants between 1983 and 1986, 1-year patient survivalwas 92% and 1-year graft survival 46%. Many animalstudies have shown that successful islet or pancreas

transplantation can prevent or lead to regression of earlylesions in the eye, nerves, and kidneys;10 anecdotal evidencesuggests that the same may be true in human beings, asreported by Mr Sells and Professor Brynger in this issue(p 1024).

The enthusiasm with which surgeons have pressed onwith pancreas transplantation has not generally been echoedamong physicians" for several reasons.

(1) There has been a tendency to define success as graftsurvival and insulin independence, whereas true successshould mean persistent normoglycaemia and totalrestoration of metabolism, which may not be possible with adenervated organ draining into the systemic circulation.

(2) Doing a transplant to prevent future complications isradically different from the clinical situation in which

kidney, heart, or liver transplants are carried out: not only isthere an alternative and safer (if less effective) treatment butalso it is difficult to predict early in the course of the diseasewhich patients are going to do badly on conventionaltreatment.

(3) Another worry of physicians is whether it is justifiableto exchange the burden and risks of diabetes for those oflong-term immunosuppression. These and other problemscan only be resolved by a proper randomised trial in whichpancreas transplantation is compared with conventionalmedical treatment.

If pre-proliferative retinopathy were shown to be a validindication for transplantation, there would be a grossmismatch between the number of potential recipients andavailable donor organs. Use of living donors to give asegment of their pancreas is one solution, but in the longterm hope rests with the possibility of transplanting isletcells which have been persuaded to grow and multiply inculture, especially if their immunogenicity can be reduced toprevent rejection. 12 Unfortunately, even the transplantationof non-immunogenic islet cells will not remove the need forimmunosuppression, since it has been shown by identicaltwin transplants that the "immune memory" of the recipientrapidly reproduces the original disease in the transplantedorgan.

IMMUNITY TO SCHISTOSOMIASIS

FOR many years people have been arguing about

immunity in schistosomiasis. One school has held that ifimmunity occurs at all, then it is slight and of little

epidemiological importance. The fact that the prevalenceand intensity of infection both rise to a peak in childhood and

9. Sutherland DER. Transplantation in nonuremic diabetic patients. Transplant Proc1986; 18: 1747-49.

10. Sutherland DER, Kendall DM. Pancreas transplantation: clinical aspects. DiabetesAnnu 1986, 2: 94-119.

11. Lemkes HHPJ. Pancreas transplantation. In Radder JK, Lemkes HHPJ, KrausHMJ, eds. Pathogenesis and treatment of diabetes mellitus. Dordrecht: MartinusNijhoff, 1986 152-55.

12. Tuch BE, Turtle JR. Long term organ culture of large numbers of human fetalpancreata analysis of their insulin secretion. Diab Med 1987, 4: 116-21