Edward J. Schantz

Botulinum toxin therapy, immunologic resistance, and problems with available materials

Botulinum toxin is a valuable technology for the treatment of regional movement disease. High-dose applications ( > 100 LD50 units per injection cycle) have been associated with sensitization that renders further therapeutic injections ineffective. The true incidence of sensitization is probably underestimated by the mouse bioassay. Other immunotypes of botulinum toxin have been effective in producing some therapeutic benefit; however, duration of action (botulinum toxin type F) and lower potencies may make these less attractive alternatives than botulinum type A. Increased specific activity botulinum toxin may be a method to reduce antigen exposure and mitigate against immunoresistance associated with dystonia therapy. Limiting the dose to < or = 100 LD50 units per injection cycle may limit this complication in the interim.

Botulinum Toxin: The Story of Its Development for the Treatment of Human Disease

In 1885 the eminent physiologist Claude Bernard wrote in his classic work Experimental Sciences Poisons can be employed as a means for the destruction of life or as an agent for the treatment of the sick [1] . In line with his prediction for medical uses of natural poisons and toxins, over a century later, in 1989, the Food and Drug Administration (FDA) licensed botulinum toxin type A as an orphan drug for the treatment of persons who suffer from the involuntary muscle disorders strabismus, blepharospasm, and hemifacial spasm. The successful use of the toxin for these conditions soon led to its use for the treatment of many other diseases caused by involuntary muscle contractions, particularly focal and segmental muscle movements. Diseases treated have included spasmodic torticollis, limb dystonias, vocal disorders, tremors, cerebral palsy in children, gastrointestinal disorders, spasticity in adults, and various pain syndromes [2] . The nerve impulses causing these involuntary muscle contractions originate in the brain or basal ganglia of persons affected with these diseases, the cause ofwhich is unknown. Many of these diseases are defined as dystonias, disorders characterized by involuntary movements of muscle groups. In 1911, Oppenheim introduced the term dystonia musculorum deformans to describe children who had involuntary movement disorders [3] . In many diseases in adults such as spasmodic torticollis and hemifacial spasm, the contractions cause severe pain and bodily distortions, particularly in the

Chemistry and Biology of Saxitoxin and Related Toxins

Our present knowledge of the highly lethal neurotoxin known as paralytic shellfish poison or mussel poison, and now called saxitoxin, has had a long and interesting development. This paper is a summary of some work on the paralytic shellfish poisons (PSP) that I have carried out during the past 40 years in collaboration with many of my colleagues. Its purposes are (1) to review briefly the clinical history and aspects of human paralytic shellfish poisoning, and (2) to review in some detail the development of the chemical and physical aspects of saxitoxin that may be related to its biological function of reducing the permeability a t the sodium channel of nerve and muscle membranes. A thorough knowledge of the structural aspects of saxitoxin and its derivatives is essential in this respect.

Neurotoxins of gonyaulax excavata and bay of fundy scallops

Abstract Neurotoxins isolated and characterized from cultured G. excavata cells and from scallops are described and their relative abundance in both sources is compared.

Quality of Botulinum Toxin for Human Treatment

The crystallized botulinum toxin type A now used in treatment, Batch 79-11 prepared in November 1979 and licensed as an Orphan drug by the FDA in December 1989, has served well for treatment of many human dystonias and other involuntary muscle movement disorders. The continued production of high quality botulinum toxin presents some important problems that must be investigated. In this presentation we wish to make some proposals that should improve the quality of the toxin as a pharmaceutical.

Distribution of paralytic toxins in California shellfish.

Samples of Saxidomus nuttali and Mytilus californianus collected during the 1981 dinoflagellate bloom at Bodega Bay, California, were analyzed for the presence of paralytic toxins. Neck tissue of S. nuttali contained saxitoxin (STX) and neoSTX (95% of the total toxicity), whereas the bodies contained neoSTX and a mixture of the gonyautoxins. In a sample of M. californianus the presence of neoSTX and the gonyautoxins was demonstrated, whereas a second sample, collected at a different site, contained almost exclusively neoSTX.

Mechanism of Action of a New Toxin from Gonyaulax Tamarensis on Nerve Membranes

The toxin from the dinoflagellate Gonyaulax tamarensis blocks nervous conduction through a selective inhibition of the mechanism whereby the membrane undergoes an increase in permeability to sodium ions. The effect is exerted only from outside of the nerve membrane. These effects are exactly the same as those exerted by tetrodotoxin or saxitoxin.

The Amino Acid Sequence of the Staphylococcal Enterotoxins

The staphylococci produce many biologically active substances among which are the staphylococcal enterotoxins, the causative agents of staphylococcal food poisoning. The ingestion of these substances by humans produces a variety of symptoms, the most common being vomiting and diarrhea in 2–6 hr. Although this illness is not a reportable disease in the United States, a large percentage of food-borne illnesses that are reported are caused by the ingestion of staphylococcal enterotoxins.

Poisons Produced by Dinoflagellates - A Review

Many of the so-called red tides are caused by excessive blooms of dinoflagellates. Out of about 1200 species of dinoflagellates only a few (8 or 10) are known to produce poisonous substances that cause shellfish and fish to become poisonous or cause fish to die. When persons eat shellfish that have consumed the poisonous dinoflagellates Gonyaulax oatenella or Gonyaulax tamarensis, a disease known as shellfish poisoning results which is often fatal. Although shellfish poisonings have been reported as long as medical records have been kept, the relationship between a poisonous dinoflagellate and shellfish poisoning was not known before D. Hermann Sommer and his colleagues at the University of California reported it in 1937. Japanese investigators have recent evidence that a dinoflagellate found in the South Pacific produces the poison found in certain fish that causes the disease in humans known as ciguatera. Another, Exuviaella marie-lebouriae occurring in areas around Japan has caused short-necked clams to become poisonous. People eating them came down with a disease resulting in fatty degeneration of liver and kidney tissue. Other dinoflagellates, Gyrrmodinium breve and Gonyaulax monilata, found in the Gulf of Mexico produce poisons that kill fish and cause severe environmental problems due to decaying fish and polluted waters in these areas.

Characterization of 11-hydroxysaxitoxin sulphate, a major toxin in scallops exposed to blooms of the poisonous dinoflagellate Gonyaulax tamarensis

The major neurotoxin isolated from scallops collected from the Bay of Fundy during a local bloom of the marine dinoflagellate Gonyaulax tamarensis has been identified as the sulphate ester of 11-hydroxysaxitoxin (2).