John B. Sullivan

Amitriptyline plasma protein binding: Effect of plasma pH and relevance to clinical overdose☆

Reversing ventricular ectopy with plasma alkalinization following acute tricyclic antidepressant overdose is a recognized mode of therapy. The mechanism responsible for this effect is unclear. Changes in plasma protein binding of free drug, effects of the sodium ion on the myocardium, and alterations of plasma concentrations of alpha-1-acid glycoprotein may all interact to alter toxicity of tricyclics in overdose. An in vitro investigation using equilibrium dialysis was designed to examine the effect of altering plasma pH on percentage of free amitriptyline at clinical overdose plasma concentrations. A 1973 report on this effect lacked adequate controls and was faulty in experimental protocol. The current investigation used plasma concentrations typically present in amitriptyline overdose, a sensitive gas liquid chromatographic assay to detect total and free drug, and adequate control of plasma pH. The results of two separate experiments demonstrated a significant decrease in percentage of free amitriptyline of 20% over a pH range of 7.0-7.4 (P less than 0.05) and 42% over a pH range of 7.4-7.8 (P less than 0.05). The rate of change in slope in both experiments was not significantly different (P less than 0.01) indicating similar effects of pH change on plasma protein binding of amitriptyline within the two groups.

Lead Toxicity in a 14-Year-Old Female With Retained Bullet Fragments

In the past 3 decades, lead levels in North American children have been declining. Despite the decline in lead exposure, lead toxicity remains a significant childhood environmental health hazard. The usual route of lead exposure is through ingestion, but lead toxicity secondary to retained bullet fragments has been well documented in the adult literature. The diagnosis of lead toxicity is often difficult and delayed secondary to vague and transient symptoms. Recognizing high-risk characteristics of bullet fragments can improve clinician awareness to the possibility of lead toxicity. The primary management of patients with continued lead exposure is to remove the source of exposure. However, in the case of retained bullet fragments, initiation of chelation therapy before surgical removal may be essential in preventing systemic toxicity. We present the case of a 14-year-old female with lead toxicity who presented with an 18-month course of chronic abdominal pain, vomiting, and anorexia 2 years after sustaining a gunshot wound to the right leg. The patient was treated with oral succimer and operative removal of bullet fragments.

Past, present, and future immunotherapy of snake venom poisoning

Management of snake venom poisoning with antivenin has been the time-proven and medically accepted standard in virtually every country, including the United States. All antivenins are equine in source, and administration to patients exposes them to all the adverse effects of heterologous antisera. The purity and specificity of neutralizing antibody titers in antivenin products vary among manufacturers. Research in the early 1980s demonstrated that immunosorbent affinity chromatography could purify a highly specific IgG(T) from equine hyperimmune antisera. This IgG(T) provided superior efficacy and reduced adverse effects as compared to commercial antivenin. The advent of newer biotechnical processes has now opened the doors for novel antibody and antibody fragment treatment of snake venom poisoning.

Lack of Observable Intoxication in Humans with High Plasma Alcohol Concentrations

Judging the degree of human alcohol intoxication is an important clinical, social, and medicolegal matter. Assessing the degree of intoxication is not always easy by direct patient observation. Observational instruments have been used in forensic science, medical, and social situations in an endeavor to measure alcohol intoxication. The validity of these observational instruments must be questioned. In this study, twenty-one patients with alcohol related complaints presenting to major city emergency departments were studied using one such observational instrument, the Alcohol Symptom Checklist (ASC). Three independent emergency medicine physicians applied the criteria of ASC to the twenty-one patients and obtained a plasma alcohol concentration (PAC) for correlation purposes. Individual correlation coefficients (r = 0.182, r = 0.202, r = 0.200) and a composite correlation coefficient (r = 0.235) demonstrated lack of correlation between PAC and ASC. This lack of correlation is supported by clinical observations of experienced emergency department personnel.

Immunological alterations and chemical exposure

The complex nature of the immune system with its multiple humoral and cellular components makes it an easy target for many drugs and chemicals. Immunotoxicology is defined as an adverse response of the immune system to a chemical or drug which may result in disease such as autoimmunity, immune suppression, allergy or other hypersensitivity states. Occasionally, immune enhancement is the end result. Because many of the immune systems cellular and humoral components can be isolated and studied in vitro, assays have been developed to study the immunotoxic effects of chemicals. Further refinement of these in vitro studies is required along with clinical investigations into the effects of chemicals on the immune system of humans. Extrapolating from the animal data to human effects has proven to be unsuccessful in many circumstances. Further definition and study of immunotoxic responses as contrasted with normal immune responses to neo-antigens are required to investigate actual disease causation.

Immunotherapy in the Poisoned Patient

Immunotherapy for reversal of toxicity due to poisons and drugs is not new. However, refinements in antibody isolation and purification as well as the advancement of hybridoma technology and recombinant DNA biotechnology has led to a new generation of immunotherapeutic and diagnostic agents.SummaryImmunotherapy for reversal of toxicity due to poisons and drugs is not new. However, refinements in antibody isolation and purification as well as the advancement of hybridoma technology and recombinant DNA biotechnology has led to a new generation of immunotherapeutic and diagnostic agents.The advent of monoclonal antibody technology in 1975 heralded the new age of immunopharmacology and immunotoxicology. Monoclonal antibodies designed for a specific antigen resolved the problem of polyclonality and cross-reactivity of traditional antibodies. Along with the production and isolation of active antibody fragments from both polyclonal and human monoclonal sources, as well as the ability to tailor-make chimeric antibodies by recombinant biotechnology, the development of novel immunotherapeutic agents has taken place. Two immunotherapeutic modalities, digoxin-specific antibody fragments (Fab) and snake antivenin, have been available for the clinician’s armamentarium for years. Along the same lines of anti-digoxin Fab development, application of newer antibody isolation technology has led to a purified IgG(T) antibody for snake venom poisoning which is still in the developmental stages.Potential future developments in immunotherapeutics must overcome the clinical problems of immunogenicity and adverse reactions to the antibodies. Human monoclonal sources, active antibody fragments, and chimeric antibodies from transfectomas are all potential resolutions to these problems.