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PubMed1990

Future prospects for adjunctive therapy: pharmacologic and nutritional approaches to immune system modulation.

An increasingly large number of dietary components have been found to alter immune system function and, therefore, may be considered to have a pharmacologic effect (pharmacologic nutrition). Those dietary factors which have already been shown to influence outcome by producing a pharmacologic effect rather than correcting or preventing a simple deficiency include proteins (both type and amount), arginine, glutamine, omega-6 and omega-3 fatty acids, short-chain fatty acids, the metals iron and zinc, and the vitamins E, C, and A. Therapeutic outcome has already been influenced by dietary therapy (pharmacologic nutrition) in patients after burn injury or who have vascular diseases, and in experimental animals for the prevention of gut origin sepsis, the prevention and treatment of infection, prevention and development of secondary lesions in autoimmune diseases, augmentation of immunosuppression in transplantation, and in the treatment of cancer. Nutritional therapy using disease-specific formulations or supplements is an old idea now undergoing rapid evolution to increasing importance for successful therapeutic outcome.

Animals↗
PubMed1989

Development of pharmacological sensitivity to adenosine analogs in embryonic chick heart: role of A1 adenosine receptors and adenylyl cyclase inhibition.

The developing chick heart was employed as a model system to explore temporal correlations between the onset of pharmacological sensitivity to adenosine analogs and the appearance of A1 adenosine receptors coupled to adenylyl cyclase. A characterization of the developmental profile for adenosine analog-induced negative chronotropic response revealed that isolated atria from 5- and 6-day embryos were unresponsive to adenosine analogs. The onset of pharmacological sensitivity occurred on embryonic day 7, as evidenced by a 27% reduction in atrial beating rate in the presence of 2-chloradenosine (2-CIA) (30 microM). The sensitivity of embryonic atria to 2-CIA increased continuously from day 7 to day 12 in ovo, when the atria became fully responsive to the negative chronotropic effect of this adenosine analog. In order to evaluate whether the developmental increase in pharmacological sensitivity to 2-CIA reflected changes in the number of A1 adenosine receptors, the ontogenesis of A1 adenosine receptors was assessed using the antagonist radioligand 8-cyclopentyl-1,3-[3H]dipropylxanthine as a probe. Cardiac membranes from day 5 and day 6 embryos possessed approximately one third of the maximum number of A1 adenosine receptors expressed at later embryonic ages. Additionally, agonist/[3H] DPCPX competition curves revealed that the high affinity state receptors comprised a larger proportion of the total receptor population in membranes from day 6 as compared with day 12 embryos. These results suggest that there are pharmacologically inactive A1 receptors in hearts from day 5 and day 6 embryos. The developmental change in A1 receptor-mediated negative chronotropic response paralleled the increase in [3H]DPCPX binding sites from embryonic day 7 to day 10. Thus, a large fractional occupancy of A1 adenosine receptors is required to express negative chronotropy during this period of embryonic development. Studies of the sensitivity of adenylyl cyclase to inhibition by cyclopentyladenosine as a function of ontogenesis revealed that cyclopentyladenosine inhibited basal adenylyl cyclase activity to a similar maximal extent from embryonic day 5 through day 16. The efficacy of cyclopentyladenosine as an inhibitor of adenylyl cyclase activity was, therefore, stable during a developmental period when A1 receptor density increased approximately 3-fold. Hence, only a fraction of the A1 receptors present during embryogenesis need to be coupled to produce a maximum response with respect to adenylyl cyclase inhibition, which is an indication of the presence of spare receptors. receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

2-Chloroadenosine↗
PubMed1989

Clinical pharmacology of sedatives and opioid analgesics, Part I.

This two-part article reviews the human pharmacology of two classes of pharmacologic agents: sedative-hypnotics and opioid (narcotic) analgesics. The major emphasis is on the injectable drugs that play a central role in contemporary anesthesiology. In this issue, Part I addresses the pharmacokinetics of intravenous anesthetics and the clinical pharmacology of sedative-hypnotics. In the next issue, Part II will discuss the clinical pharmacology of opioid agonists.

Anesthesia, Intravenous↗
PubMed1988

Estimation of the affinities of allosteric ligands using radioligand binding and pharmacological null methods.

The theoretical basis for using radioligand binding and pharmacological techniques to estimate the dissociation constants of drugs which interact allosterically with receptors is described. This theory predicts that an allosteric ligand changes the affinity of another ligand which binds at the primary recognition site on the receptor complex without affecting the binding capacity of the primary ligand. The magnitude of this effect depends on the amount of cooperativity (positive or negative) between the binding of ligands at the allosteric and primary recognition sites. It is possible to estimate the dissociation constant of an allosteric ligand by measuring its effect on the binding of a radioligand at a fixed concentration. In this situation, the dissociation constant of the allosteric ligand can be calculated from the concentration of ligand which causes half of its maximal effect on radioligand binding. The effects of an allosteric ligand on the pharmacological responses to an agonist can be attributed to changes in affinity and intrinsic efficacy of the agonist-receptor complex. If the agonist used in the pharmacological experiments has a large receptor reserve, or if the allosteric ligand only influences the affinity of the agonist, then the dissociation constant of the allosteric ligand can be calculated from the results of experiments in which the concentration of agonist required for half-maximal response (EC50) is measured in the presence of various concentrations of the allosteric ligand. If the agonist used in the pharmacological experiments is a partial agonist with little receptor reserve, then the shift in the EC50 of the agonist caused by the allosteric ligand may be dependent on the affinity of the agonist.

Allosteric Regulation↗
PubMedDate not supplied

Effects of cognitive and pharmacologic strategies on analogued labor pain.

Using an analogued labor pain procedure, the efficacy of combinations of five cognitive and one pharmacologic approach to pain management was examined. Nulliparous undergraduates (N = 120) were randomly assigned to 1 of 12 groups. Cognitive groups included: systematic desensitization (SYS DENS); sensory description (SEN DESC); sensory transformation (ST); modeling (M); and relaxation (R); combined groups: SYS DENS, SEN DESC, and ST; SEN DESC, ST, and R; SEN DESC, R, ST, and Demerol. Pharmacologic groups included expected Demerol, did not expect Demerol, placebo, and no treatment control. Subjects assigned to a cognitive group received two 1-hour training sessions 1 week apart. Remaining subjects were given the assigned pharmacologic treatment one-half hour prior to the exposure to the painful stimulus. Assessment of the cognitive and pharmacologic approaches were made in a 1-hour session involving twenty 80-second exposures to a laboratory pain stimulus patterned to resemble labor contractions. Dependent variables included self-reported pain, blood pressure, frontalis electromyograph, heart rate, and respiratory rate. Significant treatment by trials and treatment effects were found for self-reported pain. No other effects achieved statistical significance.

Adult↗
PubMed1988

Pharmacological and therapeutic properties of an ideal beta-blocker.

With hindsight it is now possible to define some of the additional pharmacological characteristics which enhance the pharmacodynamic and therapeutic efficacy of a drug whose primary purpose is to antagonize competitively sympathetic stimulation of the heart. The ideal pharmacokinetic profile for a beta-blocker includes ready and unimpeded absorption; a predominantly hydrophilic distribution; a relatively long duration of pharmacological activity and alternative routes of elimination. The ideal pharmacodynamic activity of such a drug involves a number of factors, including the essential element of beta 1-adrenoceptor selectivity. In addition, moderate beta 2-adrenoceptor agonist activity and mild stimulation of myocardial contractibility afford enhanced haemodynamic efficacy. The intrinsic ability to relax vascular and bronchial smooth muscle are also highly desirable ancillary pharmacodynamic properties. From the therapeutic aspect, a drug administered with the primary objective of reducing myocardial ischaemia in patients with a coronary heart disease, or of lowering blood pressure in patients with hypertension, should not only prove effective in clinical practice, but should also be shown to have beneficial haemodynamic properties and a minimum of undesirable pharmacological effects. The unique pharmacological profile of celiprolol appears to allow fulfillment of many of these desirable objectives.

Adrenergic beta-Antagonists↗
PubMed1987

Pharmacologic effects of atrial natriuretic peptide.

ANP harbors truly remarkable properties in having demonstrable interactions at several key loci of the systems that control blood pressure and extracellular fluid volume. The discovery of ANP by deBold and colleagues succeeded in bringing together neighboring scientists (that is, nephrologists, endocrinologists, cardiologists, and vascularologists), whose research efforts do not often coalesce, in attempts to define the pharmacology and physiology of this peptide. Although we have witnessed a tremendous explosion of interest and work over the past 6 years, several areas of research need to be pursued to obtain these goals. ANP appears to lower blood pressure by reducing either afterload or preload, with the sympathetic state of the individual having an important modulating effect. ANP causes an increased renal secretion of electrolytes, although there is yet to be uniform agreement on the underlying mechanism(s). The depressor and natriuretic effects of ANP act in harmony with an inhibitory effect on the release of aldosterone, renin, and vasopressin. Although this intriguing pharmacologic foundation of ANP has been laid, the physiologic role or importance is still in question. Nonetheless, as we gain further insight into the pharmacology, we stand to advance our knowledge of, and hopefully develop more useful regimens for, cardiovascular and renal pathologic states. As would be expected of an agent that may interact at multiple regulatory sites for control of hemodynamics and fluid volume, differences will most likely exist among species in the pharmacology of ANP, not only as a function of structure-activity relationships but also as a consequence of phylogenic differences in the integration of cardiovascular control.

Animals↗
PubMed1987

Pharmacology of vitamin E in the newborn.

The use of pharmacologic doses of vitamin E is distinctly different from nutritional vitamin E in regards to issues of efficacy and safety. Repeated administration of pharmacologic doses of vitamin E results in increasing concentrations of vitamin E in all tissues examined. The emergence of a toxic clinical syndrome associated with vitamin E therapy, the effects of vitamin E on important physiologic systems such as granulocyte function and the arachidonic acid cascade, the theoretic possibility of vitamin E becoming a prooxidant at high concentrations, and the continuing controversy regarding the efficacy of pharmacologic doses of vitamin E mandate further study of the dose-response nature of pharmacologic vitamin E therapy from both an efficacy and toxicity perspective.

Animals↗
PubMedDate not supplied

Integrating behavioral and pharmacological therapeutic modalities.

Fear of dental procedures and associated anxiety are widely accepted as important deterents to optimal oral health. Such health care-related fears and anxieties are also common in many areas of medicine. For both medical and dental care a large body of psychologically derived therapeutic modalities have evolved. These methods have been shown to interact positively with pharmacological therapies also designed to help patients better tolerate medical and dental treatment. Despite these findings, behavioral interventions have not found widespread acceptance in medical and dental practice. A multidimensional model which emphasizes the simultaneous consideration of pharmacologic, psychologic, and clinical dental factors is suggested in order to arrive at therapeutic decisions. Further research could address more powerful behavioral modalities, safer pharmacologic methods, and behavioral and pharmacologic combinations which interact optimally for particular clinical conditions.

Adult↗
PubMed1986

Potential roles for preclinical pharmacology in phase I clinical trials.

Concepts elucidated from preclinical pharmacology studies have made a substantial impact on the clinical use of anticancer drugs. However, the majority of animal pharmacology results have not been available until after drugs have entered clinical trials. Since clinical pharmacokinetic measurements are already part of many phase I trials, human data could be directly compared with mouse data if mouse pharmacology studies were completed before clinical trials were initiated. Once the starting dose in a phase I clinical trial has been evaluated, subsequent doses are escalated until the maximum tolerated dose is reached. The rate of escalation is empirically defined by a modified Fibonacci series. This universal escalation scheme is applied to all drugs, with no modifications based upon pharmacology or other factors. If the starting dose is far removed from the maximum tolerated dose, a large number of dose escalations are required. Consequently, most patients receive subtherapeutic doses, and the amount of resources allocated to each drug increases. We are exploring potential strategies for controlling the rate of dose escalation based upon pharmacokinetic determinations in mouse and man. Retrospective analyses indicate that 20%-50% savings in the total number of dose escalations are possible.

Aminoacridines↗
PubMed1982

Prevention of physostigmine-induced lethality in rats. A pharmacological analysis.

A systematic study of a large number of compounds from various pharmacological classes was performed to better define their interaction with the cholinergic nervous system. An 'in vivo' test procedure called 'physostigmine antagonism' in rats was used; it involved the administration of the test compounds, measurement of the pupil diameter and recording of the survival time after injection of a lethal dose of physostigmine. Known peripherally acting anticholinergics, such as isopropamide and methylscopolamine did not protect from physostigmine lethality at doses up to more than 150 times the mydriatic dose. Known centrally acting anticholinergics, such as dexetimide and benztropine, protected from lethality at doses equal to or slightly higher than the mydriatic dose. Penetration into the brain of a muscarinic blocking agent thus appeared to be a sufficient condition to significantly reduce the cholinergic overstimulation of the CNS that results from inhibition of acetylcholine hydrolysis. Drugs of other pharmacological classes that are known to have anticholinergic activity in addition to their more characteristic action, were also active in the physostigmine test. They include most of the tricyclic antidepressants, some antihistamines such as diphenhydramine and cyproheptadine, some ganglion blocking agents such as mecamylamine and the neuroleptic clozapine. Drugs with hypnotic or anticonvulsant properties, sedative neuroleptics and high doses of some members of other pharmacological classes protected from physostigmine-induced lethality by a mechanism not based on anticholinergic activity. The results further show that a number of pharmacological actions: dopamine, histamine H1 and serotonin S2 antagonism, MAO-inhibition, alpha-adrenergic blockade etc. are all insufficient to produce physostigmine antagonism.

Animals↗
PubMed1983

Pharmacology of opioids.

The concept of multiple opioid receptors reconciles a large body of clinical and pharmacological data. Recent studies have shown that there are also multiple opioid binding sites. It would appear that there is considerable variability between species in both the specificity and selectivity of opioid receptors. This issue has not been explored systematically regarding opioid binding sites. Better characterization of the pharmacological profiles and receptor binding specificity for different species may help resolve some of the apparent disparities. The number of putative receptors now number nearly a dozen. Already subspecies of mu, kappa, and sigma receptors are being postulated. Both pharmacological and neurochemical methods may reveal even more. Some of the newer kappa agonists differ in their pharmacology from the prototypic kappa agonist ethylketazocine.

Analgesia↗
PubMedDate not supplied

[Radioreceptor assay: principles and applications to pharmacology].

The aim of the first part of this work is to present the theory of the radioreceptor assay and to compare it to the other techniques of radioanalysis (radioimmunoassay, competitive protein binding assays). The technology of the radioreceptor assay is then presented and its components (preparation of the receptors, radioligand, incubation medium) are described. The analytical characteristics of the radioreceptor assay (specificity, sensitivity, reproducibility, accuracy) and the pharmacological significance of the results are discussed. The second part is devoted to the description of the radioreceptor assays of some pharmacological classes (neuroleptics, tricyclic antidepressants, benzodiazepines, beta-blockers, anticholinergic drugs) and to their use in therapeutic drug monitoring. In conclusion, by their nature, radioreceptor assays are highly sensitive, reliable, precise, accurate and simple to perform. Their chief disadvantage relates to specificity, since any substance having an appreciable affinity to the receptor site will displace the specifically bound radioligand. Paradoxically in some cases, this lack of specificity may be advantageous in that it allows for the detection of not only the apparent compound but of active metabolites and endogenous receptor agonists as well and in that radioreceptors assays can be devised for a whole pharmacological class and not only for one drug as it is the case for classical physico-chemical techniques. For all these reasons future of radioreceptor assay in pharmacology appears promising.

Adrenergic beta-Antagonists↗
PubMed1978

A kinetic and pharmacologic analysis of 5-hydroxytryptamine transport by human platelets and platelet storage granules: comparison with central serotonergic neurons.

The mechanisms whereby human platelets transport serotonin (5-HT) were explored by determining the initial velocity of 5-HT uptake over a wide range of 5-HT concentrations. Total 5-HT transport could be resolved into a saturable high affinity-low capacity active transport system plus nonsaturable passive diffusion. Previous kinetic analyses of 5-HT transport into platelets and brain slices have been found to be in error and the correct kinetic constants have been recalculated here. The saturable active uptake of 5-HT into human platelets is directly susceptible to inhibition by several pharmacologic agents (ouabain, metabolic inhibitors and tricyclic antidepressants) which do not inhibit the nonsaturable passive diffusion nor the nonsaturable granular transport of 5-HT. On the other hand, granular binding of 5-HT is directly susceptible to inhibition by pharmacologic agents (reserpine, tetrabenazine and N-ethylmaleimide) which do not directly inhibit saturable active uptake nor nonsaturable passive diffusion of 5-HT. Quantitative studies of platelet 5-HT transport have shown that at low concentrations of 5-HT, the pharmacologic and biochemical properties of total 5-HT transport are determined mostly by the saturable high affinity active membrane transport system for 5-HT; at high concentrations of 5-HT, the properties of 5-HT accumulation by platelets are determined mostly by the granular storage mechanism. Detailed comparisons of the kinetic, biochemical and pharmacologic characteristics of 5-HT transport in platelets and brain support the notion that the platelet can serve as a model for 5-HT transport by central nervous system neurons.

Adolescent↗
PubMed1995

Pharmacological effects of oral enzyme combinations.

Combinations of hydrolytic enzymes have been used for therapy of variety of diseases for a long time, their pharmacology, however, is being recognized only in the course of last decades. In the article, the following pharmacological effects of combinations of oral hydrolytic enzymes are reviewed: fibrinolytic, hemorheologic, anti-edematous, anti-inflammatory, activation of macrophages and NK cells, modulation of adhesion molecules, cytokines and immune complexes. Pharmacological effects are classified on four levels: biochemical, physiological, medical, and immunological. A spectrum of indications of enzyme therapy is inferred from the pharmacological effects: inflammations, traumatological events, surgical interventions, autoimmune and immune complex diseases, rheumatological diseases, viral infections and malignant tumors.

Administration, Oral↗
PubMed1993

[The pharmacological problems of searching for and using antimutagens].

To design protectants of human genomic structures against mutagenic effects is defined as a new pharmacological problem; the perspectives of its solution are outlined. The experimental evidence that formed the biological basis for searching for pharmacological correctors of the mutagenic effects produced by xenobiotics is analysed, the basic principles for designing pharmacological protectants of genetic structures are formulated. Great emphasis is laid on the antimutagenic properties of antiradical agents. Evidence is provided for that there are no prospects of searching for pharmacological protectants among natural and synthetic phenol compounds. It is noted that the informative value of microbiological tests is poor. To design a corrector of the damaging action of each particular mutagen is shown to be an independent scientific problem which can be solved only by employing eukaryotic test systems. The areas of possible application of antimutagens are defined and some known examples of their use to protect human genetic structures are presented.

Antimutagenic Agents↗
PubMedDate not supplied

Non-pharmacologic therapy in the management of hypertension: an update.

At the Canadian consensus conference on non-pharmacologic approaches to the management of high blood pressure in 1989 the evidence on the role of salt, body weight (obesity), alcohol, physical exercise, calcium and potassium supplementation, and stress management was reviewed, and recommendations were made. Most of the recommendations are still valid in 1994, although it is worth reviewing some of the data published since 1989. The evidence linking body weight or obesity to hypertension is strong, and weight reduction should be part of non-pharmacologic therapy for hypertension. The data on physical exercise are stronger now, such that further recommendations may be worth considering. There are new data on the management of patients who have borderline blood pressure elevation or are predisposed to develop hypertension. The roles of weight loss, salt restriction and mineral replacement are reviewed. The management of mild hypertension can involve a choice between non-pharmacologic and pharmacologic therapy; however, a combination of both is usually necessary. Public education may have a growing role in the prevention of hypertension in selected population groups.

Age Factors↗
PubMed1995

Cloning and pharmacological characterization of human alpha-1 adrenergic receptors: sequence corrections and direct comparison with other species homologues.

We have cloned cDNAs encoding three human alpha-1 adrenergic receptor (AR) subtypes and characterized pharmacological properties of the expressed receptor protein. A number of significant sequence corrections have been identified and compared with previously published data, at both nucleotide and amino acid levels; the most major differences occur for the human alpha-1a/dAR. Pharmacological characterization was performed simultaneously using six cloned alpha-1AR subtypes (human and rat alpha-1a/d, human and hamster alpha-1b, human and bovine alpha-1c) stably expressed in rat-1 fibroblasts at approximately equal receptor concentrations (1-2 pmol/mg of total protein). In general, human alpha-1AR subtypes have similar pharmacology compared to their rat, hamster and bovine homologs, although a few minor species differences important for alpha-1AR classification are noted. In addition, much lower inactivation (approximately 20%) by the alkylating agent chloroethylclonidine is noted in this study compared to previous reports for both human and bovine alpha-1cAR membrane preparations. All six alpha-1AR subtypes couple to phosphoinositide hydrolysis in a pertussis toxin-insensitive manner, including the cloned human alpha-1a/dAR which had not been expressed previously. In spite of significant sequence differences between human alpha-1ARs and their other species counterparts, previously established ligand selectivity remains fairly comparable. In summary, these data represent the first side-by-side comparison of pharmacological properties between species homologs of alpha-1AR subtypes and should facilitate the development of alpha-1AR subtype selective drugs for clinical use.

Amino Acid Sequence↗