83

normal individuals, in whom it has been proved a reliablescreening test." The medicolegal implications of our

findings need to be explored further, since a high proportionof our encephalopathic patients had a positive screeningurine test despite no apparent ingestion of those drugs.Studies evaluating the efficacy of the benzodiazepineanatagonist, flumazenil, in the treatment of hepaticencephalopathy exclude patients with positivebenzodiazepine screening assays in plasma or urine.22 Thisexclusion criterion will have the desired effect of excludingpatients who have ingested benzodiazepine drugs, but itmay also exclude patients who have not. This potentiallyerroneous exclusion criterion might explain the poorresponse rate to flumazenil treatment in that study ZZ Clearlythe source of benzodiazepine activity in body fluids inpeople with hepatic encephalopathy must be established.Because it is unlikely that mammals could synthesiseheterocyclic molecules containing chlorine atoms,18 themost probable source is natural benzodiazepines19 whichenter the body in their native form from food or generatedfrom dietary precursors in the gut lumen. We are carryingout experiments to evaluate these hypotheses. If ingestion infood is established, the designation of "endogenous"benzodiazepine activity may have to be changed.This work was supported by National Institutes of Health grants R29MH43524-01Al and R01-DK-39527-01, and grants from the MetroHealthMedical Foundation and Case Western Reserve University biomedicalresearch support grant RR-05410-26. K. D. M. is an AGA/Industry MarionScholar.

REFERENCES

1. Mullen KD, Martin JV, Mendelson WB, Bassett ML, Jones EA. Couldan endogenous benzodiazepine ligand contribute to hepaticencephalopathy? Lancet 1988; i: 457-59.

2. Mullen KD, Szauter KM, Kaminsky K, Tolentino PD, McCullough AJ.Detection and characterization of endogenous benzodiazepine activityin both animal models and humans with hepatic encephalopathy. In:Butterworth RF, Pomier Layrargues G, eds. Hepatic encephalopathy.Clifton, New Jersey: Humana Press Inc, 1989: 287-94.

3. Bassett ML, Mullen KD, Skolnick P, Jones EA. Amelioration of hepaticencephalopathy by pharmacological antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminanthepatic failure. Gastroenterology 1987; 93: 1069-77.

4. Basile AS, Gammal SH, Jones EA, Skolnick P. The GABAA receptorcomplex in an experimental model of hepatic encephalopathy.Evidence for elevated levels of an endogenous benzodiazepine ligand.J Neurochem 1989; 53: 1057-63.

5. Mullen KD, Martin JV, Mendelson WB, Kaminsky-Russ K, Jones EA.Evidence for the presence of a benzodiazepine receptor bindingsubstance in cerebrospinal fluids of a rabbit model of hepaticencephalopathy. Metab Brain Dis 1989; 4: 253-60.

6. Mullen KD. Evidence for an endogenous benzodiazepine ligend incerebrospinal fluid. In: Jones EA, moderator. The gamma-

aminobutyric acid (GABA) receptor complex and hepaticencephalopathy: some recent advances. Ann Intern Med 1989; 110:541-42.

7. Olasmaa M, Guidotti A, Costa E, et al. Endogenous benzodiazepines inhepatic encephalopathy. Lancet 1989; i: 481-82.

8. Conn HO, Lieberthal MM. The hepatic coma syndrome and lactulose.Baltimore: Williams and Wilkins, 1978.

9. Skolnick P, Goodwin FK, Paul SM. A rapid and sensitive radioreceptorassay for benzodiazepine in plasma. Arch Gen Psychiatry 1979; 36:78-80.

10. Mullen KD, Martin JV, Mendelson WB, Jones EA. Further evidencethat hepatic encephalopathy in the galactosamine rabbit model may bemediated by an endogenous benzodiazepine compound. In: SoetersPB, Wilson JMP, Meijer AJ, Holm E, eds. Advances in ammoniametabolism and hepatic encephalopathy. Amsterdam: Elsevier, 1988:333-37.

11. Pedersen C, Ward C, Gaff S, Usategue M. Abuscreen RIA for detectionof benzodiazepines and their metabolites. Clin Chem 1987; 33: 973.

12. Jones EA, Basile AS, Mullen KD, Gammal SH. Flumazenil: potentialimplications for hepatic encephalopathy. Pharmacol Ther 1990; 45:331-43.

13. Wildmann J, Mohler H, Vetler W, Ranalder V, Schmidt K, Maurer R.Diazepam and N-desmethyldiazepam are found in rat brain andadrenal and may be of plant origin. J Neural Transmitters 1987; 70:383-88.

14. Wildmann J, Ranalder U. Presence of lorazepam in the blood plasma ofdrug free rats. Life Sci 1988; 43: 1257-60.

15. Wildmann J. Increase of natural benzodiazepines in wheat and potatoduring germination. Biochem Biophys Res Commun 1988; 157: 1436-43.

16. Sangemeswaran L, Fales HM, Friedrick P, DeBlas AL. Purification ofbenzodiazepine-like immunoreactivity in human brain. Proc Natl AcadSci USA 1986; 83: 9236-40.

17. DeBlas AL, Park D, Friedrich P. Endogenous benzodiazepine-likemolecules in the human, rat and bovine brains studied with a

monoclonal antibody to benzodiazepines. Brain Res 1987; 413: 275-84.18. Medina JH, Pena C, Piva M, Paladini AC, DeRobertis E. Presence of

benzodiazepine-like molecules in mammalian brain and milk. BiochemBiophys Res Commun 1988; 152: 534-39.

19. Wildmann J, Vetter W, Ranalder UB, Schmidt K, Maurer R, Mohlel H.Occurrence of pharmacologically active benzodiazepines in trace

amounts in wheat and potato. Biochem Pharmacol 1988; 37: 3549-59.20. Unseld E, Krishna DR, Fischer C, Klotz U. Detection of

desmethyldiazepam and diazepam in brain of different species andplants. Biochem Phamacol 1989; 38: 2473-78.

21. Klotz V, Antonin LH, Brugel H, Bieck PR. Disposition of diazepam andits major metabolite desmethyldiazepam in patients with liver disease.Clin Pharmacol Ther 1977; 21: 430-36.

22. Van der Ritt CCD, Schalm SW, Meulstee J, Stijren TH. Flumazeniltherapy for hepatic encephalopathy: a double blind cross-over study.Hepatology 1989; 10: 590.

From The Lancet

The disease amongst horned cattle

Just when we were becoming sensible in the increasing value andscarcity of the "nitrogenous forms of food"-to wit, meat and milk,and anxiously casting about for some substitutes for them, an eventhas happened calculated greatly to strengthen the impression thatwe are inconveniently and dangerously dependent upon cattle. Avery fatal epidemic has broken out in certain dairies of London, andhas already occasioned great ravages. Its first appearance wouldseem to have been about the 27th of June in a dairy in Islington,where, we are informed, 110 cows have died. It originated here withsix cows that had been recently imported, and bought in theMetropolitan Cattle Market. They were kept in a quarantine-shedfor some time, but other cows were admitted to this, and the diseasespread to the healthy stock of the owner. It is the price we pay for nothaving a paternal government, that a great evil like this may stealinto the land, radiate from a centre in all directions, and impress theauthorities with its presence only when it has become impracticablygreat and extensive. We have said that it appeared first in Londonabout the 27th of June, and not till a month after, or about the 27thof July, was any notice taken of it by the Government. Meantime, ofcourse, it had spread in various directions. Owners of doubtful ordiseased cattle, seeing that their only chance of saving themselvesfrom the probable loss of all their stock was to sell, took such cattle tothe market, and sold them. Accordingly the disease has already beentraced in various places ... 2000 head of cattle have already beendestroyed.... The cowkeepers are in great consternation, for thedisease is at once most fatal and most contagious. The public are notless interested in the malady than the cowkeepers, for, if not

checked, it will cause a great rise in the value of meat, which is alwaysapt, indirectly, to lead to typhus and other epidemics. The diseasedoes not affect the human subject, though it can be transmitted byus from animals affected by it to healthy ones. The veterinaryfaculty, which is becoming more and more scientific every year,feels that its utility is being subjected to a great test. And last, but notleast, the Government feels that the evil existing and threatening istoo serious to be left entirely to itself, or to parties directly concernedin it.

(Aug 5, 1865)