A Young Child with Eosinophilia,Rash, and Multisystem Illness: Drug Rash,Eosinophilia, and Systemic Symptoms Syndrome After Receipt of Fluoxetine

Drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome is a severe systemic hypersensitivity reaction that usually occurs within 6 weeks of exposure to the offending drug. Diagnosis is usually straightforward in patients with pyrexia, skin rash, hepatitis, and eosinophilia with a preceding history of exposure to agents often associated with DRESS syndrome, such as aromatic anticonvulsants and sulfa drugs, but diagnosis of DRESS may still be a challenge. We report a 4‐year‐old child with probable DRESS syndrome complicated by multiple hematologic complications that developed 1 month after exposure to fluoxetine, a drug not known to be associated with such severe reactions.     

Bound to shock: protection from lethal endotoxemic shock by a novel, nontoxic, alkylpolyamine lipopolysaccharide sequestrant

Lipopolysaccharide (LPS), or endotoxin, a structural component of gram-negative bacterial outer membranes, plays a key role in the pathogenesis of septic shock, a syndrome of severe systemic inflammation which leads to multiple-system organ failure. Despite advances in antimicrobial chemotherapy, sepsis continues to be the commonest cause of death in the critically ill patient. This is attributable to the lack of therapeutic options that aim at limiting the exposure to the toxin and the prevention of subsequent downstream inflammatory processes. Polymyxin B (PMB), a peptide antibiotic, is a prototype small molecule that binds and neutralizes LPS toxicity. However, the antibiotic is too toxic for systemic use as an LPS sequestrant. Based on a nuclear magnetic resonance-derived model of polymyxin B-LPS complex, we had earlier identified the pharmacophore necessary for optimal recognition and neutralization of the toxin. Iterative cycles of pharmacophore-based ligand design and evaluation have yielded a synthetically easily accessible N(1),mono-alkyl-mono-homologated spermine derivative, DS-96. We have found that DS-96 binds LPS and neutralizes its toxicity with a potency indistinguishable from that of PMB in a wide range of in vitro assays, affords complete protection in a murine model of LPS-induced lethality, and is apparently nontoxic in vertebrate animal models.     

Development of an anti-core lipopolysaccharide vaccine for the prevention and treatment of sepsis

Sepsis continues to be a leading cause of death among hospitalized patients. Despite advances in supportive care and the availability of potent antimicrobials, the mortality exceeds 20%. The passive infusion of antibodies directed against a conserved region of the lipopolysaccharide (LPS) of Gram-negative bacteria was highly protective in an early study (NEJM 307 [1982] 1225). When this and similar preparations were unable to show consistent efficacy, efforts were directed towards other strategies, including cytokine modulation. Our group found that a whole bacterial vaccine made from the Escherichia coli O111:B4, J5 (Rc chemotype) mutant induced protective antibodies when given passively as treatment for sepsis in a neutropenic rat model. A subunit vaccine, composed of detoxified J5 LPS complexed to group B meningococcal outer membrane protein (OMP), provided similar protection when antibodies were given passively, or induced actively in both the neutropenic and cecal ligation/puncture models of sepsis. A phase I study in 24 subjects (at 5, 10 and 25 microg doses [based on LPS] for each group of 8) revealed the vaccine to be well-tolerated with no systemic endotoxin-like effects. Although a two to three-fold increase in antibody levels over baseline (by ELISA assay) was observed at the 10 and 25 microg doses, the plasma from both high and low responders reduced LPS-induced cytokine generation in whole blood. Reimmunization of six subjects at 12 months did not convert low responders to high responders or boost the still elevated anti-J5 LPS levels of high responders. If functional assays of anti-LPS antibodies are better predictors of vaccine efficacy than ELISA antibody levels, then it will be necessary to determine which of many potential assays best correlates with protection in animal models. We are currently comparing a panel of functional assays with protective efficacy in animal models of sepsis, as well as the ability of adjuvants to enhance vaccine efficacy. The availability of an effective anti-endotoxin vaccine will provide additional therapeutic options for the prevention and/or treatment of sepsis.     

The medicinal chemistry of botulinum, ricin and anthrax toxins

The potential use of weapons of mass destruction (nuclear, biological or chemical) by terrorist organizations represents a major threat to world peace and safety. Only a limited number of vaccines are available to protect the general population from the medical consequences of these weapons. In addition there are major health concerns associated with a pre-exposure mass vaccination of the general population. To reduce or eliminate the impact of these terrible threats, new drugs must be developed to safely treat individuals exposed to these agents. A review of all therapeutic agents under development for the treatment of the illnesses and injuries that result from exposure to nuclear, biological or chemical warfare agents is beyond the scope of any single article. The intent here is to provide a focused review for medicinal and organic chemists of three widely discussed and easily deployed biological warfare agents, botulinum neurotoxin and ricin toxins and the bacteria Bacillus anthracis. Anthrax will be addressed because of its similarity in both structure and mechanism of catalytic activity with botulinum toxin. The common feature of these three agents is that they exhibit their biological activity via toxin enzymatic hydrolysis of a specific bond in their respective substrate molecules. A brief introduction to the history of each of the biological warfare agents is presented followed by a discussion on the mechanisms of action of each at the molecular level, and a review of current potential inhibitors under investigation.