Effects Of Individual Drugs Research Articles

Enalapril & nifedipine in essential hypertension; synergism of the hypotensive effects in combination.

Twelve male hypertensive patients who had required enalapril and nifedipine to control their blood pressure were entered into a study of modified 2 x 2 factorial design (3 week study periods) to determine the effect of each drug separately and in combination. Factorial analysis indicated that enalapril alone (20 mg/d) lowered supine blood pressure by 10 +/- 2/8 +/- 1 mmHg, nifedipine alone (30 mg/d) lowered supine blood pressure by 11 +/- 2/8 +/- 1 mmHg and there was a positive interactive effect of 10 +/- 3/7 +/- 2 mmHg (P less than 0.001) such that the combination lowered supine blood pressure by 32 +/- 3/24 +/- 2 mmHg. The effects of the individual drugs were both significant (P less than 0.001) but did not differ from each other. Enalapril and nifedipine are both effective antihypertensive drugs and in some hypertensive patients their effects appear to be synergistic.

Modification of visual orientation illusions by drugs which influence dopamine and GABA neurones: differential effects on simultaneous and successive illusions.

The effects of haloperidol, nomifensine and lorazepam on the visual tilt illusion were studied in normal volunteers. Haloperidol and nomifensine produced no significant changes in the illusion, although in previous work they had been found to reduce and enhance, respectively, a closely related illusion, the tilt aftereffect. By contrast, lorazepam produced a dose-related increment in the size of the tilt illusion, but had no effect on the tilt aftereffect. The results are discussed in relation to proposed mechanisms which may underlie the two kinds of illusion. The differential effects of individual drugs on the two illusions may reflect their differing actions on two processes: lateral inhibition and adaptation in visual channels.

Mechanisms of depressant drug action/interaction.

Whereas the effects of individual psychotropic drugs depend upon drug type, route of administration, dose, and frequency of use, as well as unique subject (patient) variables, the actions achieved by two or more psychotropics taken concurrently are complicated by their influence upon each other. Interactions may be antagonistic, additive, or synergistic and are frequently predictable, given a basic understanding of the kinetic and dynamic characteristics for each drug. This knowledge should enable rational interpretation, therapeutic intervention, and possible prevention of polydrug toxicity. Classically, pharmacodynamic drug interaction is described in terms of common receptor activation or antagonism. This limited view is inadequate in the present context and should be broadened to encompass all of the mechanistic elements that initiate, transduce, and amplify neuronal membrane action. Thus, although psychotropic drugs may compete for a limited number of specific binding sites, as the opiates do, they may also interact through allosteric mechanisms and nonspecific modulation of the receptor environment or subsequent effector cell mechanisms. Drugs in the depressant class often act synergistically in these ways. Through consideration of nonreceptor mediated interaction, we can more fully appreciate the potentiation that occurs between seemingly unrelated substances (e.g., antihistamines and ethanol) and the ability or lack thereof to medically treat such interactions specifically. The pharmacokinetic determinants of drug action provide many opportunities for synergy between psychotropic drugs. Each process is a fertile substrate. Absorption from the gastrointestinal tract is sensitive to drugs that alter peristaltic motility and glandular secretion. Those that inhibit motility tend to delay the rate, if not the extent, of absorption and consequently reduce peak intensity and prolong duration of the psychotropic effect. Serum albumin binding can be a vital point of interaction for drugs with high intrinsic binding affinity (e.g., 98% for methadone); displacement of a small amount of bound drug by a competing substance may increase the free drug concentration severalfold and thereby potentiate its actions(s). Psychotropic drug effects would last for days and even weeks, were it not for the body's ability to synthetically alter drug molecule configuration. This process takes place primarily in the liver where oxidative reactions are frequently catalyzed by the mixed function oxidase system.(ABSTRACT TRUNCATED AT 400 WORDS)

Modulating effects of drugs on cell cycle kinetics

The effects of individual drugs on cell cycle progression can often be determined by analyzing the DNA distribution of cultured cells at appropriate times after drug administration. In addition, to cell counts, RNA and/or protein content, the alterations in cell cycle distribution of drug-treated cells can yield information on the potential cell cycle phase specificity of the drug. However single parameter DNA analysis, as currently used, can give inaccurate information when drug effects are associated with cytokinesis perturbations, in spite of various statistical and mathematical analyses. Scanning flow cytometry could be an interesting alternative for the detection of binucleate cells.

The cellular mechanisms of cardiac antiarrhythmic drug action.

In the preceding pages we have considered a number of mechanisms whereby drugs may modify arrhythmias and we also have demonstrated that certain types of action are specific to individual drugs. In addition, through the description of the use-dependence of drug effects, we have shown that the specificity of a drug's action often is attributable to its interactions with specific channels. As we learn more about the specificity of individual drug effects we should be better able not only to understand the actions of presently available drugs, but also to discover compounds that promise to be of use in the future.

Adverse Effects of Antiepileptic Drugs

Anticonvulsant therapy requires a commitment of one to many years. Multiple-drug administration is also not uncommon. Therefore, complications of treatment are pertinent considerations. Recent techniques in monitoring plasma concentrations have been helpful, yet adverse effects of anticonvulsants are frequent. Schmidt has divided this book into three segments. The first describes the mechanisms of adverse effects; the second, adverse effects on organ systems; and the third, side effects of individual drugs or genera of drugs. In the first chapter, the division of pharmacologic and clinical factors is helpful, and the mechanisms of production of side effects are mentioned. This chapter eases the reader into the descriptions of complications affecting specific organ systems. While some organ systems are treated almost entirely, the descriptions of others suffer from excessive brevity. Later in the text, in a repetitious manner, the drugs are described independently with listings of complications. Here again, brevity is a disadvantage

A Benzodiazepine—Anticholinergic Drug Synergism in the Prevention of Stress‐Induced Gastric Mucosal Erosion in Mice

Chlordiazepoxide and clidinium each, as a function of dose, prevent stress-induced gastric mucosal erosion in mice. Clidinium was 2.5 times more potent than chlordiazepoxide. When used in a combination of 2 parts chlordiazepoxide and 1 part clidinium, the protective effect was nearly five times greater than that produced by clidinium alone. Furthermore, the combination dosing proved nearly three times more potent than the potency that was predicted from simple additivity of the individual drug effects. This potentiation appears related to the number of ways in which the combination treatment can decrease autonomic input to the gastric mucosa. Thus, the peripheral cholinergic blockade by clidinium may be potentiated by a central chlordiazepoxide suppression of both sympathetic and parasympathetic activities. Therefore, the combined use of these drugs in the therapy of stress-induced gastric disorder appears to have a rational pharmacologic basis.

In Vitro Studies on the Radioresistance of Oxic and Hypoxic Cells in the Presence of Both Radioprotective and Radiosensitizing Drugs

In vitro studies, involving CHO monolayers, have demonstrated that the oxygenation status of the cells determines whether radioprotection or radiosensitization will be observed when both Ro-07-0582 (6 mM) and cysteine (8 mM) are present in the medium. This combination sensitizes hypoxic cells yet protects well-oxygenated ones. A comparison of individual drug effects on radiation resistance with those of the combination indicates that the latter can yield a larger therapeutic gain than either alone through reduction of drug toxicity and/or by improving relative tumor response.

“Wirkung von Psychopharmaka und zugrundeliegende theoretische Vorstellungen”: Theoretische und methodische Aspekte der Wirkungsprüfung psychiatrischer Psychopharmaka bei gesunden Probanden

The paper points out that the current theories about the effects of psychiatric drugs in healthy human individuals is primarily a function of the methodological approaches applied in psychopharmacological research. Three approaches are distinguished: the diagnostic, the differential-psychological and the experimental-psychological approach. Within the diagnostic approach psychological-diagnostic instruments (e.g. tests) are considered to be able to measure specific effects of drugs (e.g. concentration). The differential-psychological approach takes into account inter- and intraindividual differences in psychological and psychophysiological variables (e.g. personality traits, actual state variables), which are responsible for the kind of drug effect on certain variables. The experimental-psychological approach typically studies drugs from the viewpoint of psychological theories concerning those psychological variables supposed to be affected by the drug (e.g. anxiety, attention). For each of these approaches the theoretical concept, the data gathering procedure, the kind of data interpretation, and the empirical adequacy are discussed. Meaning and usefulness of such terms as "Eigenwirkung", primary and secondary effect, main and side effect, and paradoxical effect are considered.

Methodological issues in psychopharmacological research: chlorpromazine--a case in point.

Past research on the relative efficacy of powerful psychotropic agents has generally relied on group designs, which may mask critical individual differences in drug response. This and other methodological inadequacies raise questions about much of the vast literature in support of the clinical efficacy of chlorpromazine and similar drugs. A research strategy employing within-subJect designs, using a single subject as his own control, is suggested as advantageous in assessing individual drug effects at specific dosage levels.

Synergistic action of amphotericin B and rifampin against Candida species.

Amphotericin B and rifampin act synergistically against certain yeasts in vitro. Whether this synergism is a general phenomenon or whether the effect has strict species and strain requirements was studied. Included in a survey of the genus Candida were eight human isolates of Candida albicans and one strain each of Candida krusei, Candida tropicalis, Candida pseudotropicalis, Candida parapsilosis, Candida guilliermodnii, and Candida stellatoidea. Cultures in both control and drug-containing liquid medium were incubated at 37 C with aeration. Effects of the drugs were determined from viability assays performed at zero-time and at 17 hr. Amphotericin C and rifampin were judged to be synergistic if any one of three different sets of criteria was met. Combined activity greater than the sums of individual drug effects was required in each set of criteria. Partially inhibitory or fungistatic levels of amphotericin B and noninhibitory concentrations of rifampin acted synergistically against all strains of Candida examined. Within the genus Candida, synergism of amphotericin B and rifampin appears to be a rather general phenomenon.

Interactions between the effects of methamphetamine and pentobarbital on operant behavior in the pigeon.

This study investigated the effects of methamphetamine and pentobarbital on the performance of pigeons trained to peck a key on two alternating schedules of food reinforcement. In the presence of a blue key-light, every 31st response was reinforced (FR 31); in the presence of a red key-light, a single response was reinforced when 5 min had elapsed (FI 5). In control studies, methamphetamine (1–3 mg/kg, i.m.) alone decreased rates of responding on FR 31, but increased rates of responding on FI 5. Pentobarbital (1–10 mg/kg, i.m.) alone increased rates of responding on both FI 5 and FR 31; maximal effects occurred at 10 mg/kg. Combinations of methamphetamine and pentobarbital produced FR 31 response rates between those produced by the individual drugs. In contrast, the combination markedly increased FI 5 response rates. The maximal increase in FI 5 response rates occurred with the combination of 1 mg/kg of methamphetamine and 10 mg/kg of pentobarbital, and it was greater than the sum of the maximal increases produced by either drug alone. Thus, combined doses of methamphetamine and pentobarbital can either antagonize or enhance the effects of the individual drugs on operant behavior; the type of interaction that occurs is dependent upon the schedule of reinforcement.

Peptic Ulcer Associated with Corticosteroid Therapy: Serial Roentgenographic Studies

During a period of two and one-half years, 77 patients who were candidates for or were receiving steroid therapy, were observed for peptic ulcer. Most of them were examined roentgenologically at three-month intervals. This made it possible to correlate ulcer incidence with dose, duration of therapy, and effect of individual drugs, as well as to add to the very sparse information upon the behavior of ulcers during continuous steroid administration. Almost all of the patients had systemic lupus erythematosus and required large amounts of steroids. The incidence of peptic ulcer in this treated group was compared with the incidence in a similar group of patients not receiving these hormones. Since there are relatively few reports of roentgenologic surveys of patients treated with steroids, and none with such extensive serial studies while on high dosage, it was thought that presentation of our findings and comparison with previous data would be of interest. Up to 1954, Sandweiss (1) and Wollaeger (2) were abl...

Concerning the influence of antipyretics on the acuity of hearing

In connection with an extensive pharmacological and psychological study of antipyretic drugs, the effect of same was tried on the acuity of hearing. Experiments were performed on normal human subjects, and in a few cases on persons suffering with mild deafness. The tests were made, by means of a watch, in a quiet room, with the subject in a sitting position; and all necessary controls were carried out for the elimination of error. In every experiment the normal limit of hearing was first determined; the drug to be studied was then administered by mouth; and the acuity was afterwards tested at definite intervals of time. Only therapeutic doses of the drugs were administered. The following substances were studied: acetanilid, acetphenetidin, antipyrin, pyramidon, lactophenin, salol, aspirin, quinin, sodium salicylate, and “melubrin.” After studying the effects of individual drugs, certain combinations were administered. The following were among the combinations studied: acetanilid plus sodium bicarbonate, a...