Showing papers in "Annual Review of Pharmacology and Toxicology in 1981"

Organophosphorus ester-induced delayed neurotoxicity.

Abstract: In certain animals, including humans, exposure to some organophosphorus esters causes delayed neurotoxicity (OPIDN). The clinical condition becomes manifest after a delay period, first as ataxia, followed by paralysis. Lesions are characterized by degeneration of axons with subsequent secondary degeneration of myelin in the peripheral and central nervous systems. Recovery is only likely in mild cases, whereas more severe cases show symptoms of an upper motor neuron lesion in the lower limbs. The risk of use of these chemicals is related not only to human sensitivity to this syndrome, but also to the fact that in most disasters involving OPIDN, humans were the prime victims. Therefore, the neurotoxic action of a chemical is of great significance, since pesticides with this property are not recommended for use. Although OPIDN has been recognized for over a half a century, its mechanism of action is still unknown. It is believed, however, that the initial target in OPIDN is the phosphorylation of a neurotoxicity target protein in the nervous system. Study of the relationship between the chemical structure of organophosphorus esters and their neurotoxic potencies suggests that two hydrophobic areas may be present in the vicinity of the active site of the neurotoxicity protein. This article attempts to present an up-to-date overview of OPIDN. Despite the difficulties attributed to experimental variations of the reported studies, I feel that several significant points have come forth from the data.

The Pharmacology of Memory: A Neurobiological Perspective

Abstract: What is of interest in an area of scientific inquiry depends on one's perspec­ tive. If one looks primarily to find a drug that can improve memory in the healthy subject or retard the decline of memory in neurological disease, then any enhancing effect of a drug can hold promise. Further, a better memory test score occurring together with a wide spectrum of other drug actions might mean only that memory enhancement will inevitably be accompanied by side effects. Alternatively, if one wishes to know how the brain accom­ plishes memory storage, then drugs can be viewed as tools to dissect the neural machinery involved in memory and to reveal as much as possible about the neurotransmitter systems and biochemical steps involved. Drugs may also be viewed as tools to reveal structural principles of memory, such as how memory changes over time and how many processes are involved.

Receptor Adaptations to Centrally Acting Drugs

Abstract: Although most psychoactive drugs are used chronically in patients, the majority of preclinical psychopharmacological investigations utilize acute treatments. However, over the past few years it has generally been realized that the chronic effects of drugs may differ quite considerably from their acute influences. There is thus obvious clinical importance to gaining a biochemical understanding of the phenomena of tolerance, addiction, and withdrawal. These phenomena may result in part from changes in the number and affinity of eNS neurotransmitter and drug receptors (1). This review focuses on studies of eNS receptors identified by radioligand binding techniques and the influences of chronic drug treatments upon their number and affinity. Behavioral, biochemical, and electrophysiological studies are referred to when they enhance our understanding of the underlying receptor processes but these areas of research are not the main focus of this review. Many of the studies to be discussed were instigated as the result of clinical or behavioral observations. It is, however, important to emphasize that apparent changes in physiological responsivity may result from processes either proximal or distal to the neurotransmitter receptor. It is also attrac­ tive to assume that an increase in receptor number will be associated with an increased physiological responsiveness of the system under study. How­ ever, it is unclear as yet whether this is a necessary sequela of such change. For example, an increase in the number of presynaptic autoreceptors that regulate the release of neurotransmitter could result in a diminished synap­ tic response. This is an important consideration as the locations of many

Mechanism of Action of Barbiturates

Abstract: Despite the widespread use of barbiturates and their clear potential for abuse, little is known of their neurochemical mechanisms of action. Our purpose is to review the neurochemical effects of acute and chronic barbitu­ rate administration, with particular emphasis on the relationship between neurochemical changes and the development of tolerance and dependence. The electrophysiological effects of barbiturates have been reviewed recently (1-3), and Okamoto (4) has compared the neurophysiological and neuro­ chemical effects of barbiturates to the effects of alcohol. The clinical charac­ �eristics of barbiturate abuse have been reported by Wesson & Smith (5), and the membrane actions of barbiturates and other anesthetics have been reviewed by Seeman (6) and Roth (7).

Screening for Teratogenic Hazards: Nature of the Problems

Abstract: State of the art teratology is sufficient to develop a screening system of teratogenic hazard potential if one remembers the basic developmental biology underlying teratogenesis. Understanding of teratogenic mechanisms may provide better systems but such knowledge is not yet available. The system described is an interim step and may not prove valid. Hopefully Karnofsky's law will remain in our attention thereby permitting our realization that the question, "Is table salt teratogenic?" is naive and largely irrelevant. The answer is "Yes" from the viewpoint of total well-being of the conceptus. What the question is really asking is: "What is the developmental hazard potential of table salt?" This question can be answered quantitatively and it is, "No, it is not a developmental hazard because it is a coeffective teratogen with a developmental hazard index of less than 0.1." If we could all understand these basics, we could realistically proceed to safeguard your grandchildren and mine.

The pharmacological control of immediate hypersensitivity.

Abstract: Immediate hypersensitivity is a reaction to a foreign substance and is im­ munological in nature. Initial challenge with the foreign material stimu­ lates, by interaction with T lymphocytes and macrophages, the immune system. The response is the generation of B lymphocytes which recognize the antigenic determinants of the foreign material; these B cells then differentiate into plasma cells which elaborate IgE-class antibodies directed against the antigens. The IgE antibodies so formed become fixed to tissue mast cells or circulating basophil leucocytes. In man, rat, and mouse the antibody which fixes to mast cells and basophils is of the IgE class whereas in other species such as guinea pig it appears to be a subclass of IgG antibodies. In either case the production of antibody which specifically binds to mast cells and basophils is fundamental to the immediate hypersen­ sitivity reaction. Second and subsequent challenges with foreign antigen lead to an antigen-antibody reaction on the mast cell and basophil mem­ brane. The immunological and the pharmacological control of IgE produc­ tion has been the subject of earlier reviews (1-4). Stimulation of the mast cell and basophil membranes initiates a sequence of cellular events leading to the release of the mediators of the immediate hypersensitivity reaction. The mediators have long been known to include histamine, slow reacting substance (SRS), and, in some species, 5-hydroxy­ tryptamine. Other putative mediators include prostaglandins, kinins, chemotactic factors, and platelet activating factor. The smooth muscle contraction, glandular secretion, cell accumulation, increased capillary

Pharmacology of migraine.

Abstract: Some thirty years ago, methysergide was introduced as the first drug capable of preventing migraine attacks and proved to be remarkably effective [1,2]. Because many peripheral actions of serotonin were found to be antagonized by methysergide, attention was focused on circulating serotonin as a potentially important substance in the generation of headaches. However, over the years, interest in the humoral actions of serotonin waned because of a lack of supportive evidence. Today, there is an explosion of renewed interest in serotonin and headache, this time in its neurotransmitter role in the central nervous system (CNS) [3]. This progress report will focus on the lines of evidence that have led to perturbed serotonergic neurotransmission as a putative mechanism of migraine. It appears likely that the mode of action of the antimigraine drugs is stabilization of such perturbation by enhancing serotonergic neurotransmission [4].

Structure-Activity Relationships and Drug Disposition

Abstract: Drug disposition is of prime concern to pharmacologists, toxicologists, and clinicians. In many cases the variation in absorption, distribution, metabolism, and excretion of a series of congeners is governed by the molecular structure and the physicochemical properties of the drug molecule. When reproducible results of sufficient spread are available, these data can be analyzed in quantitative terms. In order to achieve a high degree of selective toxicity in designing better and safer therapeutic agents, the multifacet effects of molecular modification on drug disposition must be thoroughly investigated. It is hoped that more systematic effort will be directed toward the correlation of various pharmacokinetic parameters and therapeutic and toxicological effects of drugs with their physicochemical properties and molecular structures.

Host and Environmental Factors Enhancing Carcinogenesis in the Respiratory Tract

Abstract: Particularly in deaing with occupational lung cancer, it is often difficult to identify the major causative agent(s) or cofactor(s) in the complex work environment. The problem is further compounded by various factors that may predispose individuals or groups of individuals to the development of cancer. Among the factors that have to be considered are the genetic control of drug metabolism, and a number of genetic aberrations. Similarly, various acquired diseases and physiological or nutritional states have been implicated in certain types of cancer, though precise interrelationships have not been defined. Over the past 10 years, our laboratory has been engaged in studies concerned with the pathogenesis of lung cancer, with particular attention given to the possible interaction of multiple endogenous and exogenous factors. Those studies and major contributions made by other investigators which might have a bearing on the problem of the multifactor etiology of lung cancer are reviewed. Experiments relating to modification of host susceptibility and studies concerned with the interaction of environmental or occupational agents are discussed.

Stereology: applications to pharmacology

Abstract: The trend in pharmacological problem solving is clearly moving in the direction of collecting more and more detailed information, which in tum is being called upon to evaluate the effectiveness and safety of drugs. Any information

Genetic Investigation of Adenylate Cyclase: Mutations in Mouse and Man

Abstract: As a pivotal control point in cardiovascular, neural, endocrine, and meta­ bolic regulation, hormone-sensitive adenylate cyclase serves as the target for drugs used in treating disorders of almost every organ system. How do drugs and hormones stimulate adenylate cyclase? The methods of molecu­ lar pharmacology and biochemistry have provided most of the experimental facts: Radioligand binding studies have allowed characterization of the molecular properties of membrane receptors and established that recep­ tors are physically separable from the catalytic unit that synthesizes cyclic adenosine 3',5'-monophosphate (cAMP) from ATP (1-5). Purifica­ tion of plasma membranes has allowed precise kinetic studies of regu­ lation of cAMP synthesis, and has led to the discovery that guanine nucleotides regulate both cAMP synthesis and binding of agonists to recep­ tors (6-10). For detailed accounts of the biochemical characterization of adenylate cyclase and possible interactions of its components in membranes, we refer the reader to several recent reviews (11-13). Here we review results of an experimental approach, based on the concepts and techniques of somatic genetics, that has contributed significantly to our current understanding of adenylate cyclase. This approach has helped to define a membrane protein,

Recent Approaches to the Treatment of Acute Lymphocytic Leukemia in Childhood

Abstract: Acute lymphocytic leukemia (ALL) is the most common malignancy in childhood accounting for 35--40% of cancers in this age group. At the time of diagnosis approximately a trillion ( 1012) leukemic cells are present throughout the body (1). The bone marrow has been replaced and sup­ pressed by leukemic cells causing a cessation of normal blood cell produc­ tion. Previously both physicians and parents equated a diagnosis of acute lymphocytic leukemia with a certainty of rapid death. This dire prognosis has changed dramatically in the last 20 yeats. Now a complete bone marrow remission can be induced in 95% of children with ALL. Moreover, one half of these children will have a prolonged leukemia-free survival and probable cure. This chapter reviews the therapeutic advances that have led to this great improvement in survival, the current problems associated with this treat­ ment, and approaches to achieve more specific and effective therapy. Recent articles have summarized the first two topics (1-7), so we concentrate on new directions for therapy. Innovative new approaches are needed since the percentage of patients who achieve long-term leukemia·free survival has not increased appreciably in the last 10 years.