Therapeutic Drug Monitoring TDM

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Rational bromide treatment. New methods for its control.


A new coupling component for sulfanilamide determination.


The estimation of Atabrine in biological fluids and tissues.


9. Smith, T. W., Butler, V. P. and Haber, E. (1969)

Determination of therapeutic and toxic serum digoxin concentrations by radioimmunoassay.


10. Thompson, R. D., Nagasawa, H. T. and Jenne, J. W. (1974)

Determination of theophylline and its metabolites in human urine and serum by high-pressure liquid chromatography.

This page is intentionally left blank page 67 6. Wuth, O. (1927)

COMMENTARY TO Rational Bromide Treatment. New Methods for its Control. Journal of the

American Medical Association 88(26): 2013-2017.

Starting in the 1850s and for the next 150 years, bromide salts were the main ingredient in most over-the-counter and patent medicine sedatives. The half-life of bromide in humans is 12 to 15 days. Toxicity from abuse progresses from delirium, delusions and hallucinations to deep sedation followed by coma. Evelyn Waugh vividly described bromide psychosis in 1957 in his autobiographical novella The Ordeal of Gilbert Pinfold (1). It has been estimated that 2% of all admissions to mental hospitals were once due to bromide psychosis (2). McDanal et al. (3) reported on six cases of bromide psychosis from over-the-counter sedatives in San Diego County, California between 1970 and 1972. By the mid-1970s bromide was removed from all over-the-counter drugs. Miles Pharmaceutical stopped selling Nervine® and Emerson Drug took bromide out of Bromo Seltzer®. In 1990 the incidence of bromide toxicity was very low (4). Occasional reports of toxicity from imported herbal medicines that contain bromide continue to appear in the current literature (5).

In addition to over-the-counter use, prescription bromides have a long history that also dates back to the 1850s. Bromide was the only effective drug for the treatment of epilepsy until the introduction of phenobarbital and phenytoin (6,7). The paper by Wuth presented here is noteworthy for two reasons. First, he described a rapid gold chloride method for the determination of bromide in urine and serum to screen for cases of bromide overdose. In the method, a sample of a protein free filtrate of serum is mixed with a colloidal gold chloride solution. The reaction between colloidal gold and bromide ions shifts the color of the solution from red to a red-brown. His gold chloride method is still in use today (8). Wuth and Faupel (9) in 1927 had previously described the preparation of a stable colloidal gold solution for use in the Lange protein spinal fluid test. With the bromide assay, Wuth found that 21% of 238 admissions to the psychiatric unit at Johns Hopkins in a six-month period had detectable levels of this drug in their serum. In 1929, the LaMotte Chemical Products Company of Baltimore, Maryland produced the "Wuth Bromide Comparator" test kit for serum bromide levels according to Wuth's colloidal gold procedure (10). A sample of a protein free filtrate of serum was added to a colloidal gold solution and the color read against test tubes containing known calibrators. The test kit was claimed to be accurate up to 19 mmol/L (1 500 mg/L), took only 15 minute to perform and cost $12.50.

Secondly, Wuth described the therapeutic and toxic serum levels found in patients on bromide therapy for epilepsy. Based on clinical information he established 15 mmol/L (1 200 mg/L) as the upper limit of therapeutic and results over 19 mmol/L (1 500 mg/L) as toxic. He further recommended that patient's on bromide therapy for the control of epilepsy be routinely monitored with serum levels. Wuth demonstrated with his case studies that the blood levels of bromide correlate with therapeutic efficacy and not with the dose administered. This fundamental principal in therapeutic drug monitoring (TDM) was advocated by Wuth almost 50 years before it became standard practice in clinical medicine (11).


(1) Hurst, D.L. and Hurst, M.J. (1984) Bromide psychosis: a literary case. Clinical Neuropharmacology. 7(3):259-264.

(2) Walter, J.J. (1989) Halogens in Manual of Toxicologic Emergencies. Noji, E.K. and Kelen, G.D. (eds), Year Book Medical Publishers, Chicago, pgs 684-702.

(3) McDanal, C.E., Owens, D., and Bolman, W.M. (1974) Bromide abuse: a continuing problem. American Journal of Psychiatry. 131(8):913-915.

(4) Bowers, G.N. and Onoroski, M. (1990) Hyperchloremia and the incidence of bromism in 1990. Clinical Chemistry. 36(8):1399-1403.

(5) Boyer, E.W., Kearney, S., Shannon, M.W., Quang, L., Woolf, A., and Kemper, K. (2005) Poisoning from a dietary supplement administered during hospitalization. Pediatrics. 109(3), E49 (electronics pages) March [ content/full/109/3/e49] (Accessed January 2005).

(6) Joynt, R.J. (1974) The use of bromides for epilepsy. American Journal of the Diseases of Children. 128(3):362-363.

(7) Steinhoff, B.J. (1992) Antiepileptic therapy with bromides-historical and actual importance. Journal of the History of Neuroscience. 1(2):119-123.

(8) Bradley, C.A. (1986) Bromide in serum by spectrophotometry, in Selected Methods of Emergency Toxicology, Selected Methods of Clinical Chemistry, Vol 11, Frings, C.S. and Faulkner, W.R. (eds), American Association of Clinical Chemists Press, Washington, DC, pgs 51-52.

(9) Wuth, O. and Faupel, M. (1927) The significance of the H-ion concentration for the colloidal gold test. Bulletin of the Johns Hopkins Hospital. 40:297-303.

(10) [Anonymous] (1929) LaMotte Blood Chemistry Outfits for the General Practitioner's Routine Tests. (Product Catalog). LaMotte Chemical Products Company, Baltimore, MD, pg 11.

(11) Koch-Weser, J. (1972) Drug therapy. Serum drug concentrations as therapeutic guides. New England Journal of Medicine. 287(5):227-231.

JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1927, VOLUME 88; PAGES 2013-2017. Copyrighted © 1927 American Medical Association. All Rights reserved.

Volume 88 Number 26

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