Primary Action Of Drug Research Articles

Homeopathic use of modern drugs: therapeutic application of the organism paradoxical reaction or rebound effect

When Samuel Hahnemann systematized homeopathy and the effects of drugs on the state of human health, he described the primary action of drugs and the following secondary and opposite reaction of the organism. Seeking to apply this secondary action or vital reaction of the organism as therapeutic method, he postulated the principle of similitude, i.e. the prescription to ill individuals of drugs that cause similar symptoms in the healthy (similia similibus curentur). In modern pharmacology, secondary action (vital reaction) of drugs is known as rebound effect or paradoxical reaction of the organism. It has been observed after discontinuation of several classes of palliative (enantiopathic) drugs, namely those that act according to the principle of contraries (contraria contrariis curentur). Although in this case it is associated with severe and fatal iatrogenic events, rebound effect might awaken a healing reaction when the very same drug is employed according to the principle of similitude. The validity of the principle of similitude is proved by scientific evidence on rebound effect, whereas conventional drugs primary (therapeutic, adverse and side) effects might be equated to pathogenetic manifestations and thus be homeopathically applied. For this purpose a homeopathic materia medica and repertory comprising 1,251 modern drugs was elaborated using the monographs described in The United States Pharmacopeia Dispensing Information as source (www.newhomeopathicmedicines.com). Thus, the therapeutic range of homeopathy is broadened through the addition of hundreds of new medicines that might be employed in every kind of disease including countless modern clinical syndromes.

Ketamine and neuroticism: a double-hit hypothesis of internalizing disorders.

Psychiatric disorders can often be viewed as extremes of personality traits. The primary action of drugs that ameliorate these disorders may, thus, be to alter the patient's position on a relevant trait dimension. Here, we suggest that interactions between such trait dimensions may also be important for disorder. Internalizing disorders show important differences in terms of range of activity and speed of response of medications. Established antidepressant and anxiolytic medications are slow in onset and have differing effects across different internalizing disorders. In contrast, low-dose ketamine is rapidly effective and improves symptom ratings in all internalizing disorders. To account for this, we propose a "double hit" model for internalizing disorders: generation (and maintenance) require two distinct forms of neural dysfunction to coincide. One hit, sensitive to ketamine, is disorder-general: dysfunction of a neural system linked to high levels of the personality trait of neuroticism. The other hit is disorder-specific: dysfunction of one of a set of disorder-specific neural modules, each with its own particular pattern of sensitivity to conventional drugs. Our hypothesis applies only to internalizing disorders. So, we predict that ketamine will be effective in simple phobia and (perhaps partially) in anorexia nervosa, but would make no such prediction about other disorders where neuroticism might also be important secondarily (e.g. attention deficit hyperactivity disorder and schizophrenia).

P-1113 - How do psychotropic drugs work?

The theory of “action-reaction” in living systems was used for studying the mechanism of action of psychotropic drugs. Primary action (PA) is the direct/immediate effect of drug. It consists of therapeutic and side effect profile of drug. The PA of each drug was compared with symptoms of the illness that it is used for. Also long term patterns of behaviour of drugs and response of body were extracted from National British Formulary (BNF) too. Findings could be summarized into two main groups: Consists of drugs which their PA counteracts the symptoms of illness e.g. drowsiness as PA of hypnotics when they are used for treatment of insomnia. 1. PA of drug is therapeutic therefore improvement starts quickly. 2. Tolerance develops in long term use. Consists of drugs which their PA simulates the symptoms of illness e.g. anxiety and palpitation as PA of Citalopram used for Panic disorder. 1. There is possibility of initial paradoxical worsening due to PA of drug. It can be minimized by reducing the initial dose. 2. Unlike above, here the reaction of body (we call it as secondary action) seems to provide the therapeutic effect and therefore improvement starts with delay. 3. They can be used long term without developing tolerance. Show that 10% of psychotropic drugs work in contrary based and 47% in simulation based mode. Information in BNF has not been conclusive for 43% of drugs, like Benperidol for antisocial behaviour. Confirmation of clinical value requires further studies.

Global gene expression profiling of Plasmodium falciparum in response to the anti-malarial drug pyronaridine.

BackgroundPyronaridine (PN) and chloroquine (CQ) are structurally related anti-malarial drugs with primarily the same mode of action. However, PN is effective against several multidrug-resistant lines of Plasmodium falciparum, including CQ resistant lines, suggestive of important operational differences between the two drugs.MethodsSynchronized trophozoite stage cultures of P. falciparum strain K1 (CQ resistant) were exposed to 50% inhibitory concentrations (IC50) of PN and CQ, and parasites were harvested from culture after 4 and 24 hours exposure. Global transcriptional changes effected by drug treatment were investigated using DNA microarrays.ResultsAfter a 4 h drug exposure, PN induced a greater degree of transcriptional perturbation (61 differentially expressed features) than CQ (10 features). More genes were found to respond to 24 h treatments with both drugs, and 461 features were found to be significantly responsive to one or both drugs across all treatment conditions.Filtering was employed to remove features unrelated to primary drug action, specifically features representing genes developmentally regulated, secondary stress/death related processes and sexual stage development. The only significant gene ontologies represented among the 46 remaining features after filtering relate to host exported proteins from multi-gene families.ConclusionsThe malaria parasite's molecular responses to PN and CQ treatment are similar in terms of the genes and pathways affected. However, PN appears to exert a more rapid response than CQ. The faster action of PN may explain why PN is more efficacious than CQ, particularly against CQ resistant isolates. In agreement with several other microarray studies of drug action on the parasite, it is not possible, however, to discern mechanism of drug action from the drug-responsive genes.

Second messenger-regulated protein kinases in the brain: their functional role and the action of antidepressant drugs.

Depression has been treated pharmacologically for over three decades, but the views regarding the mechanism of action of antidepressant drugs have registered recently a major change. It was increasingly appreciated that adaptive changes in postreceptor signaling pathways, rather than primary action of drugs on monoamine transporters, metabolic enzymes, and receptors, are connected to therapeutic effect. For some of the various signaling pathways affected by antidepressant treatment, it was shown that protein phosphorylation, which represents an obligate step for most pathways, is markedly affected by long-term treatment. Changes were reported to be induced in the function of protein kinase C, cyclic AMP-dependent protein kinase, and calcium/calmodulin-dependent protein kinase. For two of these kinases (cyclic AMP- and calcium/calmodulin-dependent), the changes have been studied in isolated neuronal compartments (microtubules and presynaptic terminals). Antidepressant treatment activates the two kinases and increases the endogenous phosphorylation of selected substrates (microtubule-associated protein 2 and synaptotagmin). These modifications may be partly responsible for the changes induced by antidepressants in neurotransmission. The changes in protein phosphorylation induced by long-term antidepressant treatment may contribute to explain the therapeutic action of antidepressants and suggest new strategies of pharmacological intervention.

Intensive Care Unit Neuromuscular Syndrome?

Intensive Care Unit Neuromuscular Syndrome?

The molecular mode of action of the Ca agonist (?) BAY K 8644 on the cardiac Ca channel

The primary drug action of (-) BAY K 8644 on whole-cell Ca current in atrial myocytes was measured under conditions where secondary Ca-mediated changes of Ca channel activity were minimized. The most direct action of (-) BAY K 8644 is the change of gating kinetics which results in a strictly voltage-dependent increase of the peak current in the voltage range between -40 and 0 mV. Peak currents were increased dose dependently in the concentration range from 1 to 30 nM. Analysis of peak current/voltage relations revealed a linear shift of the current activation by approximately 23 mV to more negative membrane potentials, without any change in its voltage dependence and in the current reversal potential or the maximum whole-cell conductance. Measurement of Ca current activation and deactivation time constants suggests that (-) BAY K 8644 prolongs the single-channel open time without affecting the closed time. From the shift of the open time function to more negative voltages by about 50 mV the energy transferred to the gating process is calculated to be 5.4 kJ/mol (1.3 kcal/mol). The drug-induced slow component of tail current has been used to estimate the true dose/response relation for (-) BAY K 8644. A KD value of 4.3 nM and a Hill coefficient of 1.25 were determined. Flash-induced competition experiments with the Ca antagonist nifedipine allowed the measurement of binding kinetics of (-) BAY K 8644. The association rate constant is estimated to about 5 x 10(6) mol-1.s-1 and dissociation time constant is approximately 50-70 s; both are in close agreement with receptor binding studies. Results are discussed in relation to models for drug action of dihydropyridine-type compounds and to implications for the structure of the Ca channel protein.

Chronic exposure of human cells in culture to the tricyclic antidepressant desipramine reduces the number of beta-adrenoceptors

The effects of the antidepressant drug desipramine (DMI) on the density of beta-drenoceptor sites were studied on intact cultured human cells: skin fibroblasts, lung fibroblasts and macrophages. Direct binding studies were performed with the radioligand 3H-CGP 12177, a hydrophilic beta-adrenergic antagonist. The confluent cell cultures were exposed to DMI and all three cell types showed a dose-dependent decrease in the number of beta-adrenergic binding sites. This receptor desensitisation was only seen after chronic exposure of the cells to DMI. The extent of desensitisation was comparable to that seen in brain following chronic treatment of rats with DMI. The affinity of the binding sites to the radioligand was not affected by the antidepressant drug action. From these results we suggest that the in vivo effect of antidepressant drugs on postsynaptic beta-adrenoceptor density, at least in part, reflects a primary drug action and not only an adaptive change to presynaptic events.

Measurement of fasciculations as motor nerve ending discharges in the rat: a dose related effect of neostigmine.

The muscle fasciculations caused by neostigmine and similar agents are the result of a primary drug action on motor nerve endings. Asynchronous, repetitive firing of action potentials are evoked at motor nerve endings which are then transmitted to muscle. A dose-response relationship between neostigmine dose and the rate of/or total neural activity has been established in the rat. This fasciculatory response to neostigmine can serve as an index of motor nerve ending excitability and may be useful in assessing the effects of certain pathological states or drug actions at the neuromuscular junction.

Determinants of response in cancer chemotherapy and modulation of anticancer activity

The Symposium on Determinants of Response in Cancer Chemotherapy and Modulation of Anticancer ActiviQ was focused on a discussion of selective biochemical pharmacological and biological parameters which may affect the response of individual patients to drugs and may provide a basis for the design of new treatments. Elucidation of the biochemical and pharmacological determinants of drug action in tumor and normal tissues is a well recognized goal in any attempt to improve the design of chemotherapy. During the last ten years, however, it has become increasingly evident that primary drug action in a cell population is determined by a multiplicity of factors and, in addition, that in many cases a new metabolic equilibrium is established in a target cell as a result of a cascade of effects following the proximal action of a drug. Thus knowledge of the secondary metabolic consequences of a primary effect is essential in developing optimal treatments with a drug alone or in combination with other drugs. The well known heterogeneity of tumor cell populations and the consequences of the relative genetic instability of tumor cells are additional complicating factors in the rational design of cancer chemotherapy (5). The potential utility of stem cell assays and cell kinetics in assessing sensitivity of cell subpopulations to agents and treatments was stressed by Stephens (6) and the difficulties and uncertainties related to clonogenic stem cell assays recognized; it was emphasized, however, that these studies are important in order to clarify fundamental phenomena regulating the biology of neoplastic cell populations. Kinetics of tumor cell repopulation repair of ‘potentially lethal damage’, cloning of human tumors and characterization of drug resistance were particularly emphasized. Studies of the type described are leading to a more detailed understanding of heterogeneous populations of tumour cells. A basic problem in cancer therapy is that tumors that initially are successfully treated have the ability to adapt by generating resistant variants. It is the instability and heterogeneity of tumor cell populations that confers on them the ability to react in this way. A major advantage of cell cloning assays is that they allow one to detect growth from individual tumor cells and to explore their clonal heterogeneity.

Dissociations between the behavioral effects of LSD and tolerance development during ontogeny in cats: A novel approach to the study of tolerance mechanisms

The characteristic behavioral effects of d-lysergic acid diethylamide (LSD) in cats first appeared at approximately 25 days of age and increased rapidly in magnitude over the next 10 days. However, 25 day old kittens showed no tolerance to the repeated administration of the drug. While the behavioral response to the initial dose of LSD remained relatively constant between 35 and 112 days of age, the tolerance gradually became more pronounced throughout this time period, reaching an adult level of virtually complete tolerance at 112 days. These findings provide new insight into the nature of the relationship between the primary drug action and the development of tolerance, and suggest a new strategy for investigating the neural bases of tolerance, i.e., examining the neurochemical effects of repeated LSD administration in kittens during various stages of tolerance development.

Effects of cytochalasin B on polymorphonuclear leucocyte locomotion, phagocytosis and glycolysis

Observations have been made on the inhibitory action of cytochalasin B (CB) on locomotion, phagocytosis and glycolysis in human, horse, and rabbit polymorphonuclear leucocytes (PMNs). Locomotion in all three species was suppressed by as little as 0.3 μg/ml CB and completely blocked by 3 μg/ml, as judged by direct observation or by a Millipore filter assay system. Phagocytosis was evaluated morphologically as well as in a bactericidal system. Three μg/ml CB suppressed, but did not completely block, phagocytosis by horse and human cells; increasing the concentration of CB to 40 μg/ml exerted little additional suppression of phagocytic capacity. Rabbit exudate cells ingested and killed certain species of bacteria Staph. aureus or Salmonella less effectively than did horse or human cells; in these instances CB did not alter the killing rate significantly CB did inhibit the killing of E. coli by rabbit cells. Three μg/ml CB resulted in a partial inhibition of several glycolytic parameters, i.e., glucose utilization, lactate production, and CO 2 production from C-1 or C-6 labeled glucose. These parameters were inhibited more than 75 % by 10 μg/ml CB. Studies made thus far indicate that CB probably suppresses glycolysis by interfering with glucose transport or phosphorylation. Comparison of the inhibition of various parameters by CB and by other metabolic inhibitors suggests that the glycolytic inhibition by CB is probably not the primary drug action responsible for the altered locomotion and phagocytosis.

HEPARIN REACTIONS IN PATIENTS WITH VASCULAR DISEASE.

ADVERSE reactions to heparin are uncommon and poorly understood. Toxic effects varying from alopecia 1,2 to severe anaphylaxis with death 3 have been described in the medical literature. The incidence of heparin reactions, as evidenced by the paucity of reports in recent years, has been decreasing. This has been attributed to the greater purity of commercial heparin which contains much less animal protein contaminant than older preparations. Despite the wide use of heparin in cardiovascular operations heparin sensitivity has not been emphasized in the surgical literature. Unwanted effects of drugs are usually divided into six classes 4 : (1) overdosage, (2) intolerance, defined as lower threshold to the normal pharmacological action, (3) undesirable side effects, (4) secondary effects defined as indirect consequences of primary drug action, (5) idiosyncrasy, and (6) hypersensitivity. Most authors have assumed that heparin reactions represent a hypersensitivity to the drug. This implies that an immunologic response accounts