In this review the drugs capable of increasing or lowering the serum urate concentration are considered with regard to mechanism of action and significance of the effect, where known. Several hypouricemic agents, probenecid, sulfinpyrazone, and allopurinol, are considered in further detail because of their major clinical importance. No effort has been made, however, to summarize the relative clinical indications for each agent. In addition, in those cases where specific details could not be included because of limitation of space, the appropiate reference has been given.
Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Evidence has been adduced for the view that the morphiness receptor or receptors in the myenteric plexus of guinea pig ileum are very similar to the brain receptors that mediate the analgesic action of the narcotic alagesics. Such an in vitro model is very suitable for the study of structure-activity relationships because the angonist and antagonist activities of compounds can readily be assessed. One example is the investigation of the effects of changes at the N atom. Another point of interest is the role of substitutions at the C14 atom in morphine and morphinans. Such alterations in structure may have a profound effect on the relative agonist and antagonist activities and may convert a drug with dual agonist and antagonist actions into an antagonist devoid of agonist action.
The results of experimental studies on the relationship of estrogens and oral contraceptives to mammary lesions demonstrate that the type of response obtained depends largely on the species and strain of animal that is employed. A variety of clinical studies has failed to demonstrate that estrogen can cause mammary cancer, this lack of effort correlates with the results obtained in various studies in animals. Similar relationships exist for oral contraceptives, and the clinical data show good agreement in demonstrating that the contraceptive steroids do not have a tumorigenic effect on the human mammary gland. Estrogen can increase the occurrence of cervical cancer in certain strains of mice, but apparently this effect is not observed in other species of animals, including man. The preponderance of data shows that oral contraceptives do not adversely affect the occurence of abnormal Papanicolaou smears, cervical dysplasia, cervical cancer in situ, or invasive cervical cancer.
It is only in recent years that there has been concern with cadmium as an environmental contaminant. A very large literature on cadmium has appeared in the past few years. Much of it has appeared in abstract form, in conference reports, or project reports. Several comprehensive reviews have appeared in the past three years covering virtually all aspects of the subject. One of the objectives of this review is to direct the uninformed reader to these sources of information. Another will be to discuss a few selected aspects of current research on cadmium, especially as it relates to sources in the environment. 85 references.
The role of Se in biology appears from the evidence now at hand to be as a catalyst par excellence. As unique prosthetic group of a variety of enzymes, presumably as Se(2-), Se functions with tocopherol to protect cell and organelle membranes from oxidative damage, to facilitate the union between oxygen and hydrogen at the end of the metabolic chain, and to transfer ions across cell membranes, in protein synthesis in erythrocytes and in liver organelles, in immunoglobulin synthesis, and in ubiquinone syntheses. As perhaps the most versatile and rapid nucleophile, Se is thought to amplify and orient SH in equilibrium -S-S-interactions involving glutathione and proteins. Its toxicity appears to be due to overaccumulation of selenite ions, which act as oxidants to inhibit SH interactions. Such toxicity is readily avoided or reversed in many ways. Although not yet recognized as essential for man, Se is clearly essential for many animal species and some microorganisms. As the active selenide, Se emerged as the target for many heavy metal toxicities; contrariwise, as a specific antidote against heavy metal toxicities. Despite all this, its unusual toxicity and the many preconceived notions about Se continue to confuse attitudes toward the safe uses of selenicals. From a suspected cause of cancer, Se metamorphosed, via evidence over many years, into something of possible anticancer value. Interrelations between Se, Vitamin E, the ubiquinones, and various chronic diseases appear as beckoning research areas. The reported veterinary values of Se-tocopherol combinations in animals, together with clinical evidence, plus human and animal evidence for safety, offer promise for intensive medical investigation. The historical confusion and misunderstandings regarding Se must be corrected, however, before advantage can be taken of its potential for human welfare. The many misjudgments about Se, ever since 1900 and more obviously since the 1930s, have involved other trace elements. Unrealistic regulations stemming from these misunderstandings prevail worldwide. Evidence suggests that, once the nutrition biochemistry and toxicology of Se is sufficiently understood and appreciated, major breakthroughs in agriculture, medicine, and public health can result. Much has been accomplished along these lines in New Zealand in animal agriculture, in the US and other countries in veterinary medicine, and in Mexico in human medicine.
In the striated muscle of the upper esophageal sphincter, tonic maintenance of closure is probably mediated via tonic central excitation of the extrinsic motor innervation; relaxation represents central inhibition of this mechanism. The motor nerves are probably cholinergic and act through nicotinic receptors like those of somatic striated muscle. In the striated muscle of the esophageal body, swallowing-induced contraction is also probably a cholinergic and nicotinic response. In the smooth muscle of the esophageal body, the control of contractions is cholinergic and muscarinic in part, but there is evidence for a nonadrenergic and noncholinergic component as well. The muscarinic component may arise from the cholinergic innervation of the longitudinal muscle layer. The other component may lie in the cryptic innervation of the circular muscular layer. In the smooth-muscled lower esophageal sphincter, resting closure tension appears to reflect a variety of possible control mechanisms. No single control system predominates. The evidence for muscarinic excitation is equivocal. An excitatory adrenergic alpha mechanism and inhibitory adrenergic beta receptors may contribute. A role for the polypeptide hormones from the gastrointestinal tract seems unlikely. Relaxation of the lower sphincter with swallowing seems not to involve any of these mechanisms, but is apparently accomplished by nonadrenergic noncholinergic inhibitory nerves like those present elsewhere in the gut (87). The possibility that the transmitter of these nerves is an adenine nucleotide has been raised from studies of other parts of the gut, but that hypothesis has not yet been examined critically in the lower esophageal sphincter.
After a traumatic childhood in Europe during the Second World War, I found that scientific research in Israel was a pleasure beyond my expectations. Over the last 65 year, I have worked on the chemistry and pharmacology of natural products. During the ...Read More
Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Human nasal polyps from three ragweed-sensitive atopic patients released three chemical mediators: histamine, slow reacting substance of anaphylaxis, and eosinophil chemotactic factor of anaphylaxis on challenge with ragweed antigen. Polyps from four non-ragweed-sensitive subjects passively sensitized in vitro released the same chemical mediators. In a patient with chronic sinusitis and one with cystic fibrosis, dibutyryl cyclic adenosine 3′,5′-monophosphate and the beta adrenergic agent isoproterenol both produced dose-dependent suppression of the immunologic release of mediators. Cholera toxin after a 30-minute lag period induced a marked increase in the tissue concentrations of cyclic adenosine monophosphate in a patient with chronic sinusitis and at the same time suppressed the immunologic release of mediators; each of these effects persisted through three hours of incubation. Alpha-adrenergic stimulation as achieved by combining phenylephrine with propranolol and cholinergic stimulation with carbachol enhanced the antigen-induced release of histamine and slow reacting substance in two patients with chronic sinusitis. Thus, the antigen-activated release of mediators from nasal polyps is modulated by agents affecting the intracellular concentrations of cyclic nucleotides. (N Engl J Med 289:277–281, 1973)
This review critiques the scientific literature reporting the effects of carbon monox ide (CO) upon humans, examining those exposure situations that result in blood saturation of carboxyhemoglobin (COHb) below 18%, saturations which generally do not result in signs or symptoms of overt intoxication. A reappraisal of the CO literature is desirable for several reasons: 1. A recently reported national survey disclosed that 45% of the nonsmoking blood donors in 18 sections of the country, each one of which included metropolitan and rural areas, had COHb saturations greater than 1.5%, which indicated that exposure to CO in' excess of that permitted by the quality standards of the Clean Air Act of 1971 was widespread and occurring regularly (1-3). If the air quality standard for CO is judged to be scientifically sound, the decision not to enforce it but to relax the standard because of the national energy crisis could place the health of some citizenry in jeopardy. 2. A series of air quality standards for CO for various civilian populations, indus trial operations, and special military groups has been promulgated (Appendix A). In several instances these have been based upon scientific observations currently held to be of questionable validity. 3. The administration of certain drugs has been observed to accelerate the catabol ism of hepatic heme, doubling the endogenous CO production (4-6). In certain individuals with compromised cardiovascular systems, such an increase could pose a significant toxic stress. 4. Diseases manifesting increased hemolysis feature elevated COHb saturations that could be toxic to individuals with already compromised cardiovascular systems (7). This literature review itemizes the expected and unexpected source� elf CO, summarizes the basic pathophysiology of the gas, and then scrutinizes the effects of CO on human cognitive performance and cardiovascular system.
