Showing papers in "Advances in pharmacology in 1969"

Antineoplastic principles in plants: recent developments in the field.

Abstract: Publisher Summary Recent developments in the field of antineoplastic principles in plants can be summarized in terms of specific compounds that have been isolated, certain generalizations that can be made, and fringe benefits in phytochemistry. This chapter discusses such recent progress in this field. For this purpose, the chapter restricts its discussion by defining the limits by “plants” meant those that are commonly called higher plants and ferns or, more properly, spermatophytes (phanerogams) and pteridophytes. The chapter excludes lower forms of plants, except in a few cases where appropriate substances obtained from these forms serve to contribute to the discussion. Antineoplastic activity discussed implies activity in experimental tumors only. The chapter has adopted such restriction, as it has a certain advantage— namely, that all the screening results reported have been obtained under generally uniform experimental procedures. From the chapter, it is apparent that one of the main hopes originally held for this work is being realized— namely, that higher plants are yielding chemical compounds of a wide variety of types: alkaloids, sesquiterpene lactones, saponins, digitaloid glycosides, quinones, and proteins among others, active against many different experimental tumor systems. Furthermore, most of these compounds would have been inaccessible until their isolation from natural sources, because not only would there be no particular reason for attempted synthesis but also many of them could be synthesized only with severe difficulty. As these compounds are subjected to extensive pharmacological testing designed to select out those that have clinical promise, most of them are eliminated as is to be expected. However, a sufficient proportion of them passes the criteria and reaches the level of clinical trial as to justify the large effort involved in the whole process.

A Pharmacological Analysis of Aspirin

Abstract: Publisher Summary The salicylates are age old drug that in the form of willow bark and other herbal preparations have been used for long and their therapeutic effects have been reported in man first rather than in animals. It is suggested that salicylic acid was first used clinically in place of carbolic acid to disinfect wounds. When aspirin was introduced, as a more palatable and less topically toxic form of salicylic acid, the therapeutic properties of the parent compound were already well known. Because aspirin is probably the most widely used medicinal drug in the world, it is the mainstay of several pharmaceutical manufacturers. Interest lies in areas like what are the pharmacologic relatives of aspirin, where do the boundaries of this group of drugs lie, and does aspirin differ from sodium salicylate in its quantitative profile of actions. In view that aspirin is effective in its own right, this chapter explains the pharmacology of aspirin rather than that of salicylate in general. Results obtained with salicylates other than aspirin is only included, insofar, as they help to throw light on the pharmacology of aspirin. The chapter in the analysis of the antidefensive action of aspirin, considers the responses to noxae under various heads— namely, antipyresis, antinociception, anti-inflammation, antagonism of smooth muscle responses, and antihemostasis. The chapter also considers the other effects of aspirin that might be deemed antidefensive, such as damage to epithelia. When these pharmacologic effects of aspirin have been considered separately, how aspirin exerts these effects and to what extent a common mechanism underlying defensive responses may be identified as the target of this drug is assessed.

The combination of gas chromatography and mass spectrometry in the identification of drugs and metabolites.

Abstract: Publisher Summary It is likely that the world is now entering a period wherein physicochemical techniques will greatly influence progress in drug research. The techniques described in this chapter allows to determine infinitely smaller quantities of drugs in body fluids with a much greater power of separation than ever achieved with earlier methods. The correct choice of a sensitive and appropriate gas chromatographic technique nowadays can achieve rapid separation of components in complex mixtures, such as biologic extracts. However, in qualitative analysis the identification of an unknown compound cannot be based entirely upon its relative retention time on different stationary phases. Recently, an instrument, combining gas chromatography, with mass spectrometry, has been successfully applied to the identification of many naturally occurring body constituents. This instrument, with a number of accessories, has been used for the characterization of drugs and their metabolites. Other methods of chemical identification, such as infrared spectrometry (IR), ultraviolet spectrometry (UV), and nuclear magnetic resonance spectrometry (NMR) can be utilized for additional information. To obtain an IR or an NMR spectrum the compound has to be isolated in rather large quantities. This is a disadvantage, and in most cases makes drug analyses impossible in body fluids where only small amounts of compounds are available for chemical identification. In such cases, advantage cannot be taken of the techniques, but it is possible to further improve the sensitivity of gas chromatography (GC) by the additional dimension of a direct combination with mass spectrometry (MS). The main interest, in recent times, has been the application of the combined GC-MS method to the study of drugs and their metabolites.

Chemotherapy of chlamydial infections.

Abstract: Publisher Summary Chlamydiae are obligate intracellular parasites, related to Gram-negative bacteria but quite distinct from viruses. They produce a variety of human and animal infections that are characterized by strong chronicity and latency. Chlamydiae are susceptible to a variety of antibacterial drugs in laboratory models. This chapter discusses the efficacy of drugs that are acceptable for general use. While acute infections in animals or man can sometimes be cured by the administration of certain drugs, treatment of chronic infection is difficult. Usually drug administration results in the suppression of signs and symptoms of disease, but fails to eradicate the infectious agent. Prolonged administration of relative large doses of drugs is advisable in treating chronic chlamydial infections. However, more commonly, the administration of antimicrobial drugs suppresses active replication of chlamydiae, and thereby aids in clinical recovery, but fails to eliminate the infectious agent. Ultimately, the eradication of infection is a function of host responses. It is in this general framework that chemotherapy of chlamydial infections must be considered. Many different experimental infections have been employed in attempts to quantify and compare the activity of antimicrobial drugs on chlamydiae. The infected mouse, embryonated egg, and cell culture have been used most widely. Each of the models has its own peculiarities and no model entirely mirrors the treatment of infection in the natural host. The greatest weight must, therefore, be given to controlled therapeutic studies in natural hosts. Regrettably, only few adequately controlled treatment trials are available and most clinical reports rely on the anecdotal method. The greatest hazard in attributing therapeutic significance to a drug is the failure to acknowledge that spontaneous, sometimes dramatic, recovery is a part of the natural history of infectious diseases. This is a particular problem in chlamydial infections, because they exhibit a very wide spectrum of clinical severity.

Recent Progress in Pharmacogenetics

Abstract: Publisher Summary This chapter discusses the hereditary factors causing clinically significant variations in human responsiveness to drugs and the substantial advances made in pharmacogenetics. Along with past much recent work that has been reviewed in the chapter is devoted to these genetically transmitted conditions, but only a few new examples have been described. In the chapter, the term pharmacogenetics is applied to clinically significant consequences of hereditary variations in the handling of drugs. The chapter deals mainly with an increasing body of data on the defects in human and only tangentially with the very large literature, concerning animal experiments. Search for hereditary variations, affecting the way the body handles drugs, has until recently turned up almost exclusively traits inherited as single factors— that is, traits produced by point mutations at a single genetic locus and transmitted, either as Mendelian dominants or recessives. Investigation of the responsiveness of the general population to a drug in terms of the amount of a drug required to produce a given effect may take the form of a continuous unimodal distribution curve or of a discontinuous polymodal curve. Until recently, studies of drug responses that yield a normal or continuous distribution curve have been almost entirely ignored in pharmacogenetic investigations. To construct unimodal, Gaussian distribution curves large populations are required. Furthermore, genotypes are hard to deduce from such curves. In contrast, discontinuous, bimodal, or trimodal curves of response obtained from disorders transmitted as Mendelian dominants or recessives are more easily analyzed because each discrete curve generally corresponds to a different genotype.

The evaluation of present antileprosy compounds.

Abstract: Publisher Summary The state of leprosy control and treatment in the world as a whole, while less bleak than in the presulfone era remains greatly unsatisfactory. Progress in the chemotherapy of human leprosy infections has hitherto been seriously hampered by two facts: first, notwithstanding numerous unconfirmed claims, the presumably causative organism, Mycobacterium leprae (M. leprae), could not be definitely and reproducibly cultivated on or in any laboratory medium, second, it was not possible by injecting this organism to reproduce in any laboratory animal a generalized and progressive bacilliferous granulomatous disease resembling human leprosy. The application of existing knowledge of mycobactericidal drugs in mass treatment campaigns could conceivably break the cycle of transmission of viable intracellular host-dependent M. leprae from the disseminator to the susceptible recipient. The absence until recently of any experimental basis for the demonstration and evaluation of the mycobactericidal properties of a drug supposedly active against M. leprae goes far to explain the confusions and contradictions. Such an application, however, is generally proving too costly in precisely those countries where leprosy is a problem of medical and economic importance.

Composition of bacterial cell walls in relation to antibiotic action.

Abstract: Publisher Summary The cell walls of bacteria are composed of several chemically distinct types of component and separate layers, making up the wall, can sometimes be recognized in electron micrographs. As the integrity of the cell wall is necessary to the survival of the organism in its usual vegetative form, it is not surprising that several antibiotics have been found either to interfere with its synthesis or to promote its breakdown. Such antibiotics are selectively toxic for bacteria as opposed to their mammalian hosts, because the bacterial wall contains building blocks, such as muramic acid, diaminopimelic acid, and D-amino acids that are not found as constituents of the mammalian tissues. Furthermore, these components are linked together to form a dual polymer of polysaccharide and polypeptide—the murein, mucopeptide, or peptidoglycan—the synthesis of which is as specific to bacteria as the polymer itself. There is no doubt that if murein synthesis is interrupted or its dissolution promoted, then the bacteria cannot continue to reproduce unchecked. The antibiotics that are considered in this chapter interfere in some way or other with one of these processes. The chapter first discusses briefly what is known about murein synthesis and breakdown. The chapter also suggests that three important groups of antibiotics exert their specific action against bacteria through some involvement with the D-alanyl-D-alanine sequence that is first synthesized and then broken down during the build-up of the cross-linked murein of the bacterial cell walls.

Advances in the chemotherapy of viral diseases.

Abstract: Publisher Summary This chapter discusses the real achievements till date in antiviral chemotherapy and chemoprophylaxis in human This will permit to make an assessment of the practical outcome of the laboratory work A comparison of the results obtained in human with those in the laboratory will also enable the laboratory tests to be evaluated The chapter examines the possible reasons for the failure to make available to the physicians larger numbers of useful drugs from the apparent wealth of active substances The chapter defines, from existing knowledge, the avenues of approach that are likely to offer the greatest chance of success The activity of idoxuridine against herpes simplex virus has demonstrated that a topical therapeutic approach in viral disease is possible The activity of methisazone against the complications of vaccination has shown that a systemic therapeutic approach is also possible The activity of methisazone, in preventing variola major and variola minor in contacts, has demonstrated the feasibility of a systemic chemoprophylactic approach These are all contributions in their own right in this field, but they are small achievements compared to the vast morbidity and mortality, caused by viruses in man and in animals The chapter discusses the frequent meetings held to discuss the subject of antiviral chemotherapy, and from the more recent of these it can be said that there is reason to believe that important new developments are on its way

Drugs and the mechanism of insulin secretion.

Abstract: Publisher Summary Although it is commonly observed that there is an absolute insulin deficiency in the late diabetic, much confusion, concerning the status of the insulin secretory mechanism of the early diabetic, has resulted from the reports of an augmented insulin response to a standard glucose tolerance test in early maturity onset diabetes. This insulin response is so characteristic of all the stages of diabetes mellitus that it is proposed that the primary lesion of diabetes is a “biochemical inertia of the pancreatic β-cell.” As it is well established, therefore, that whatever else if anything the diabetic disease state encompasses, a primary defect in the continued storage and secretion of insulin by the diabetic pancreas must be included, it is the intent of this chapter to extensively review these agents that have been found to stimulate the secretion of insulin and to discuss the possible mechanism of its normal release in the nondiabetic and abnormal release in the diabetic. Although infusions of metacholine or benthanecol induce an elevation of plasma glucose, this elevation follows the hyperinsulinemia. In vitro, cholinergic drugs stimulate insulin release from the slices of rat pancreas, an effect that is suppressed by simultaneous administration of atropine. Of additional importance is the independence of this stimulatory effect on the concentration of glucose in the medium.