Main Pharmacological Action Research Articles

Cellular Immunobiology and Molecular Mechanisms in Alloimmunity-Pathways of Immunosuppression.

Current maintenance immunosuppression commonly comprises a synergistic combination of tacrolimus as calcineurin inhibitor (CNI), mycophenolic acid, and glucocorticoids. Therapy is often individualized by steroid withdrawal or addition of belatacept or inhibitors of the mechanistic target of rapamycin. This review provides a comprehensive overview of their mode of action, focusing on the cellular immune system. The main pharmacological action of CNIs is suppression of the interleukin-2 pathway that leads to inhibition of T cell activation. Mycophenolic acid inhibits the purine pathway and subsequently diminishes T and B cell proliferation but also exerts a variety of effects on almost all immune cells, including inhibition of plasma cell activity. Glucocorticoids exert complex regulation via genomic and nongenomic mechanisms, acting mainly by downregulating proinflammatory cytokine signatures and cell signaling. Belatacept is potent in inhibiting B/T cell interaction, preventing formation of antibodies; however, it lacks the potency of CNIs in preventing T cell-mediated rejections. Mechanistic target of rapamycin inhibitors have strong antiproliferative activity on all cell types interfering with multiple metabolic pathways, partly explaining poor tolerability, whereas their superior effector T cell function might explain their benefits in the case of viral infections. Over the past decades, clinical and experimental studies provided a good overview on the underlying mechanisms of immunosuppressants. However, more data are needed to delineate the interaction between innate and adaptive immunity to better achieve tolerance and control of rejection. A better and more comprehensive understanding of the mechanistic reasons for failure of immunosuppressants, including individual risk/benefit assessments, may permit improved patient stratification.

Role of Danggui Buxue Decoction for the prevention and treatment of cardiovascular and pulmonary diseases.

Cardiovascular and pulmonary diseases have become the major disease endangering people's physical and mental health because of its high morbidity and mortality. Danggui Buxue Decoction, a noteworthy classical prescription, is composed of astragali radix and angelicae sinensis radix at a ratio of 5꞉1. It is a prescription for tonifying both vital energy and blood and has the effect of dredging collaterals. Its main active components, such as polysaccharides, saponins, flavonoids and volatile oils, have good effects on antioxidation, inflammation regulation, immune regulation and promotion of blood circulation. Danggui Buxue Decoction can improve myocardial ischemia-reperfusion injury and heart failure, relieve the symptoms of diabetic cardiomyopathy, inhibit pulmonary fibrosis, protect lung injury and fight against lung cancer and other cardiopulmonary diseases. Preclinical studies have showed that this prescription can inhibit inflammation and oxidative stress, regulate autophagy and enhance immune function through multi-target pathways. Reviewing the main effective components, pharmacological action and mechanism, and clinical application of Danggui Buxue Decoction are helpful to provide comprehensive information for the clinical application of Danggui Buxue Decoction in prevention and treatment of cardiovascular and pulmonary diseases.

Structure-Activity Assessment and In-Depth Analysis of Biased Agonism in a Set of Phenylalkylamine 5-HT2A Receptor Agonists.

Serotonergic psychedelics are described to have activation of the serotonin 2A receptor (5-HT2A) as their main pharmacological action. Despite their relevance, the molecular mechanisms underlying the psychedelic effects induced by certain 5-HT2A agonists remain elusive. One of the proposed hypotheses is the occurrence of biased agonism, defined as the preferential activation of certain signaling pathways over others. This study comparatively monitored the efficiency of a diverse panel of 4-position-substituted (and N-benzyl-derived) phenylalkylamines to induce recruitment of β-arrestin2 (βarr2) or miniGαq to the 5-HT2A, allowing us to assess structure-activity relationships and biased agonism. All test compounds exhibited agonist properties with a relatively large range of both EC50 and Emax values. Interestingly, the lipophilicity of the 2C-X phenethylamines was correlated with their efficacy in both assays but yielded a stronger correlation in the miniGαq- than in the βarr2-assay. Molecular docking suggested that accommodation of the 4-substituent of the 2C-X analogues in a hydrophobic pocket between transmembrane helices 4 and 5 of 5-HT2A may contribute to this differential effect. Aside from previously used standard conditions (lysergic acid diethylamide (LSD) as a reference agonist and a 2 h activation profile to assess a compound's activity), serotonin was included as a second reference agonist, and the compounds' activities were also assessed using the first 30 min of the activation profile. Under all assessed circumstances, the qualitative structure-activity relationships remained unchanged. Furthermore, the use of two reference agonists allowed for the estimation of both "benchmark bias" (relative to LSD) and "physiology bias" (relative to serotonin).

Telmisartan and losartan: The marked differences between their chemical and pharmacological properties may explain the difference in therapeutic efficacy in hospitalized patients with COVID‐19

Telmisartan and losartan: The marked differences between their chemical and pharmacological properties may explain the difference in therapeutic efficacy in hospitalized patients with COVID‐19

Efficacy of computational predictions of the functional effect of idiosyncratic pharmacogenetic variants.

BackgroundPharmacogenetic variation is important to drug responses through diverse and complex mechanisms. Predictions of the functional impact of missense pharmacogenetic variants primarily rely on the degree of sequence conservation between species as a primary discriminator. However, idiosyncratic or off-target drug-variant interactions sometimes involve effects that are peripheral or accessory to the central systems in which a gene functions. Given the importance of sequence conservation to functional prediction tools—these idiosyncratic pharmacogenetic variants may violate the assumptions of predictive software commonly used to infer their effect.MethodsHere we exhaustively assess the effectiveness of eleven missense mutation functional inference tools on all known pharmacogenetic missense variants contained in the Pharmacogenomics Knowledgebase (PharmGKB) repository. We categorize PharmGKB entries into sub-classes to catalog likely off-target interactions, such that we may compare predictions across different variant annotations.ResultsAs previously demonstrated, functional inference tools perform variably across the complete set of PharmGKB variants, with large numbers of variants incorrectly classified as ‘benign’. However, we find substantial differences amongst PharmGKB variant sub-classes, particularly in variants known to cause off-target, type B adverse drug reactions, that are largely unrelated to the main pharmacological action of the drug. Specifically, variants associated with off-target effects (hence referred to as off-target variants) were most often incorrectly classified as ‘benign’. These results highlight the importance of understanding the underlying mechanism of pharmacogenetic variants and how variants associated with off-target effects will ultimately require new predictive algorithms.ConclusionIn this work we demonstrate that functional inference tools perform poorly on pharmacogenetic variants, particularly on subsets enriched for variants causing off-target, type B adverse drug reactions. We describe how to identify variants associated with off-target effects within PharmGKB in order to generate a training set of variants that is needed to develop new algorithms specifically for this class of variant. Development of such tools will lead to more accurate functional predictions and pave the way for the increased wide-spread adoption of pharmacogenetics in clinical practice.

Study on the molecular mechanism of BuShenHuoXue capsule in treatment of steroid-induced osteonecrosis of the femoral head.

BackgroundSteroid-induced osteonecrosis of the femoral head (SONFH) is the pathological process caused by the death of the active components of the head of the femur due to the high dose of hormones, which has become a common public health problem. BuShenHuoXue capsule (BSHXC) has been clinically proven to be effective against the SONFH, the main pharmacological action of BSHXC is tonifying kidney and promoting blood circulation, but the mechanism remains to be explored.MethodsWe established a rat SONFH model by injecting Methylprednisolone (MPS) into the right gluteus muscle 30 mg/kg/d, 3 days of continuous injection every week, 4 weeks in total. According to the clinical dosage of BSHXC (Herba epimedium 3 g, Eucommia ulmoides 15 g, Salvia miltiorrhizae 30 g, Chuanxiong 15 g, Paeonia lactiflora Pall 15 g, Poria cocos 12 g, Achyranthes bidentata 12 g, antler gum 10 g, Cyperus rotundus L. Nine g and Radix Glycyrrhizae 9 g), it was converted into the equivalent dose of rats, and gavage was performed at the weight of 10 mL/kg, once per day. The BSHXC was subjected to experiments in vivo, SONFH pharmacodynamics, bioinformatics, and network of pharmacology to determine the active ingredients, and its protective role against SONFH, Enrichment analysis was performed to explore the possible mechanism of BSHXC, and cell experiments were undertaken to analyze the impact of BSHXC on the hormones associated with bone marrow mesenchymal stem cells (BMSCs) between osteogenesis and apoptosis.ResultsExperiments confirmed that BSHXC could effectively reduce bone loss in SONFH rat models. From bioinformatics and a network constructed from 10 drugs-208 pharmacology-126 targets, the enrichment analysis showed that the core targets were inflammatory reaction, steroid hormones, estrogen receptors, osteoporosis, and adjustment of osteogenesis and osteoclast differentiation, among others. The cell proliferation and staining supported that the mechanism of BSHXC promoted osteogenesis and intervening in apoptosis.ConclusionsThe BSHXC reduced the inflammatory response, changed steroid response, regulated estrogen receptors, delayed osteoporosis, regulated osteoblast and osteoclast differentiation by regulating related targets, and improved the local microenvironment by a multi-component, multi-target, and multi-link process to delay or reverse the progression of SONFH.

Comparative quantitative study of the Total anthracen derivatives in combined preparations of Rheum palmatum

This paper presents the results of spectrophotometric quantitative determination of total anthracen derivatives in biologically active additives to food of American origin, containing in its composition roots of Rheum palmatum L. The roots of Rheum palmatum contain a sufficient amount of anthracen derivatives (from 2% to 6%), among which dominate: frangula-emodin, rheum-emodin, chrysophanol and rhein. It is the content of these representatives of anthracen derivatives that causes the laxative pharmacological effect of the roots of Rheum palmatum and preparations based on it. In the Russian Federation there are no registered complex drugs of roots Rheum palmatum. Therefore, foreign drugs can serve as a prototype for the development of new laxative combined dosage forms. Quantitative determination of anthracen derivatives in complex preparations of Rheum palmatum was carried out calculated on one of the dominant substances of Rheum palmatum roots-frangulaemodin. The content of anthracen derivatives in the combined preparations of Rheum palmatum roots was from 3.97 to 6% in one tablet or capsule, depending on the indications for the use of the studied drugs. Laxative effect of the drug Colon herbal cleanser manufacturer Mason Natural is due to a high single dose-more than 20 mg of anthracen derivatives per reception, while the drug Herbs and prunes manufacturer Nature's Life has a lower dosage-6 mg, however, the pharmacological effect is achieved through a combination with prunes. Capsules Ojibwa Herbal Extract 450mg manufacturer Now Foods contain an average amount of anthracenes, because the laxative effect is not the main pharmacological action of this drug, but only complements the main anticancer action.

Evaluation of clinical efficacy of Derinat® in form of spray in practice of district therapist

The widespread worldwide spread of acute respiratory diseases is an urgent problem in health care. Expressed polyetiology of respiratory diseases does not allow to limit the use of specific vaccine preparations and dictates the need to use to combat them a variety of non-specific means that stimulate the natural resistance of the human body. The main pharmacological action of sodium deoxyribonucleate is the stimulation of phagocytic activity of T-helpers and T-killers, increasing the functional activity of neutrophils and monocytes/ macrophages, providing regeneration and repair processes in the epithelial component of antiviral protection of the body. Based on the above, the study of the clinical efficacy of Derinat® in the form of spray in the treatment of acute respiratory viral infections is relevant.

Monitoring drug safety in Astrakhan, Russia

The problem of drug safety will never disappear as new drugs are delivered in increasing numbers. They have high biological activity and adverse drug reactions (ADR) [1]. Currently, adverse drug reactions are the fourth leading cause of death for patients.There are databases of ADRs (Vigibase, Eudravigilance), but we know that ADR manifestations may vary in different countries and regions, due to the demographic, genetic characteristics of the population and the quality of manufactured drugs [2]. In this regard, the study of the ADR at the regional level is very relevant. We aimed to optimize the work on monitoring drug safety in Astrakhan region through pharmacoepidemiological research and development of computer database for analysis of information coming to the center for drug safety monitoring (CDSM). 1. To study the rates of ADR reporting and the structure in the Astrakhan region at the regional center for drug safety monitoring.2. To analyze the outcomes of registered adverse drug reactions.3. To determine the causality of adverse drug reactions.4. To identify reports on the ineffectiveness of drugs.5. To analyze the rates and structure of ADR reporting for drugs prescribed off-label. We studied spontaneous adverse event reporting. The adverse event reports received by the regional CDSM for the period of 2010 to 2014 was analyzed. The groups of drugs were categorized according by Anatomical Therapeutic Chemical classification system. The data were analyzed using Microsoft Office Excel. The likelihood of whether an ADR was actually due to the drugs was assessed with the Naranjo algorithm. The analysis of the results showed that the establishment of the CDSM in September 2010, contributed to improvement of drug safety monitoring in health facilities of the region. Noteworthy was the increasing the number of adverse event reports in 2011 and 2012, compared with the beginning of the year 2010, when the CDSM was not yet functioning.The decrease of adverse event reporting in 2013 and 2014 was due to the fact that doctors in the region had access to better ADR drug information. Along with the increasing number of adverse event reporting we also noted the increase in the number of health facilities that monitored drug safety. The number of health facilities that reported, doubled from 2010 to 2014. We observed the increase in the number of adverse event reports submitted by pharmaceutical companies. General anti-infective drugs for systemic use (class J) were the most common cause of all registered ADRs (44%). Drugs for treatment of tuberculosis (group J04A) were the cause of adverse drug reactions in 34% of reports. ADRs associated with drugs used for treating diseases of cardiovascular system accounted for 16% of case-reports; drugs belonging to the group of Alimentary tract and metabolism (class A) and to the group of Nervous System (class A) were reported to cause ADRs in 10% of cases each. Type A adverse drug reactions, which are usually a consequence of a drug's primary pharmacological effect, were detected in 45% of cases. These reactions were often registered for drugs affecting cardiovascular system (class C), nervous system (class N), dlood and blood forming organs (class B). Type B ADRs were reported in 54% of cases. These were "idiosyncratic" reactions, which could not be predicted on the basis of the drug's main pharmacological action, were not dose-related and were severe [3]. The most frequent cause of type B adverse drug reactions was the General anti-infective medicines for systemic use (Class J). The fatality rate associated with ADRs was 0.3%. Type A adverse drug reactions resulted in death in 38% of cases. Type B ADR (anaphylactic shock) accounted for 62% of the patient's deaths. The Naranjo scale determined the causality of ADRs. The "definite" ADRs were detected in 14% of reports, "probable" - in 47%, and "possible" - in 39% of cases. The rate of reporting associated with ineffectiveness of drugs amounted to 1%. Most often the lack of therapeutic effect was reported in patients receiving drugs of class C (Cardiovascular system, 31% of all cases of inefficiency of drugs). These drugs were used in accordance with their official instructions for use. The proportion of ADR reports for drugs prescribed off-label was 1.4%. The results substantiate the need to continue drug safety monitoring in the Astrakhan region. We plan to further improve the software for ADR analysis.

A PK–PD model of ketamine-induced high-frequency oscillations

Objective. Ketamine is a widely used drug with clinical and research applications, and also known to be used as a recreational drug. Ketamine produces conspicuous changes in the electrocorticographic (ECoG) signals observed both in humans and rodents. In rodents, the intracranial ECoG displays a high-frequency oscillation (HFO) which power is modulated nonlinearly by ketamine dose. Despite the widespread use of ketamine there is no model description of the relationship between the pharmacokinetic–pharmacodynamics (PK–PDs) of ketamine and the observed HFO power. Approach. In the present study, we developed a PK–PD model based on estimated ketamine concentration, its known pharmacological actions, and observed ECoG effects. The main pharmacological action of ketamine is antagonism of the NMDA receptor (NMDAR), which in rodents is accompanied by an HFO observed in the ECoG. At high doses, however, ketamine also acts at non-NMDAR sites, produces loss of consciousness, and the transient disappearance of the HFO. We propose a two-compartment PK model that represents the concentration of ketamine, and a PD model based in opposing effects of the NMDAR and non-NMDAR actions on the HFO power. Main results. We recorded ECoG from the cortex of rats after two doses of ketamine, and extracted the HFO power from the ECoG spectrograms. We fit the PK–PD model to the time course of the HFO power, and showed that the model reproduces the dose-dependent profile of the HFO power. The model provides good fits even in the presence of high variability in HFO power across animals. As expected, the model does not provide good fits to the HFO power after dosing the pure NMDAR antagonist MK-801. Significance. Our study provides a simple model to relate the observed electrophysiological effects of ketamine to its actions at the molecular level at different concentrations. This will improve the study of ketamine and rodent models of schizophrenia to better understand the wide and divergent range of effects that ketamine has.

Pharmacological research of wild and cultivated Atractylodes lancea

To explore the differences of the main pharmacological action in wild and cultivated Atractylodes lancea. Study the effect of the 70% ethanol extracts from the wild and the culticated A. lancea on the mice with gastriculcer induced by absolute ethyl alcohol or HCl. Stdudy the effect on intestinal propulsive function in mice by measuring the length of intestine and distance of Indian ink. Observe anti-bacteria effect in vitro of the A. lancea by determining the minimum inhibitory concentrations. The pharmacological action, which made a little difference in the sane productive places, and made significant differences in different productive places. Compared to Jurong, it has better actions in Luotian on small intestinal propulsive function and bacteriostatic action. There was not an obvious difference in protective effect on gastric ulcer induced by absolute ethyl alcohol and 0.6 mol x L(-1) HC1 between different locations. To the main effect, cultvated A. lancea had no significant difference on the whole but having better result in some respects, which can provide the pharmacodynamics evidence of cultivated A. lancea being used instead of the wild.

Azelaic acid 15% gel in the treatment of rosacea

Rosacea represents a chronic inflammatory dermatosis of uncertain pathophysiology. There are several associated risk factors and the need for long-term treatment is well recognized. This diverse disease is frequently difficult to manage and has a significant impact on quality of life. There are several topical and oral treatments available, of which azelaic acid 15% gel (Finacea®) is the first new treatment for rosacea in more than a decade. Azelaic acid per se has multiple modes of action in rosacea, but an anti-inflammatory effect achieved by reducing reactive oxygen species appears to be the main pharmacological action. Clinical studies have shown that azelaic acid 15% gel is an effective and safe first-line topical therapeutic option in patients with mild-to-moderate papulopustular rosacea. Significant continuous improvement in the number of inflammatory lesions and in erythema has been shown over a period of 15 weeks. Adverse effects associated with azelaic acid 15% gel are mostly mild or transient and do not usually necessitate discontinuation of therapy.

Aminophylline for treating asthma and chronic obstructive pulmonary disease

Aminophylline is a complex of theophylline and ethylenediamine. Its main pharmacological action is relaxation of bronchial smooth muscle. Two meta-analyses examining the efficacy of aminophylline in acute asthma attacks in children and in adults have been reported by the Cochrane Collaboration. In the meta-analysis reporting results from studies in children, it was concluded that aminophylline does not add any benefit to standard care. Yet one study, which has the largest patient population, reports that aminophylline improves lung functions within 6–8 h and reduces the risk of intubation. The meta-analysis examining adult studies revealed that there is no outstanding difference between aminophylline and standard therapy in the management of adult acute asthma. In conclusion, aminophylline may be an alternative to intravenous infusion of β-agonists, heliox or magnesium sulfate administration in children in whom respiratory fatigue begins to develop and intensive-care unit admission and mechanical ventilation seems to be the next treatment in line. However, in adults, it is not recommended for use in the treatment of acute asthma owing to its possible adverse effects.

Minimising Harm: Human Variation and Adverse Drug Reactions (ADRs)

‘First, do no harm’ – great advice to aspiring physicians throughout most of human history, but with the discovery of effective drugs in the twentieth century, no longer tenable as it stands. We could not get to first base in treating leukaemias, infections, cardiovascular disease, diabetes and so on if we were not prepared to accept an element of risk. It is the balance between benefit and harm that is key, rather than an unachievable ideal of absolute safety. But quantifying the probability of harm is problematic – at least for Rumsfeld’s ‘unknown unknowns’. The slogan ‘Distaval – the safe hypnotic’ adorned the drug company calendar in my father’s consulting room: ‘safe’ in the sense that when taken in overdose it was less likely to prove fatal than barbiturates, which were the market-leading hypnotics in the nineteen fifties. Phocomelia had yet to be described, the epidemic of which jump-started drug regulation worldwide. Today’s drug regulators are concerned with a far wider spectrum, including topical issues such as the licensing of generic ‘biosimilar’ biological treatments [1]. The concept of biosimilars has a long way to go before it achieves even the present incomplete maturity of the concept of ‘bioequivalence’ between different preparations of conventional low molecular weight drugs. Meanwhile, drugs continue to be prescribed during pregnancy, and may cause harm to the unborn child that is more subtle (and hence harder to recognise as drug-related) than limb defects.The report in this issue by Bakker et al of an approximate doubling in the use of selective serotonin reuptake inhibitors among pregnant women over the past ten years [2], is surely cause for concern in this regard. Regulatory authorities appropriately remain highly sensitised to idiosyncratic drug reactions.Nevertheless, it is the less exotic but more predictable adverse effects that relate to the main pharmacological action of a drug that account for much of the harm that drugs do, and much of this should be quantifiable and predictable, and thus potentially avoidable. The size of the problem

Voltammetry of some catamphiphilic drugs with solvent polymeric membrane ion sensors

The transfer of some catamphiphilic drugs across a water–solvent polymeric membrane interface is researched using differential voltammetric techniques with a solvent polymeric membrane ion-sensor and a four-electrode potentiostat. The standard ion transfer potentials of the antiarrhythmic drugs procainamide and quinidine, the antimalarial quinine and the anesthetics bupivacaine, lidocaine, procaine and tetracaine have been determined. In addition to their main pharmacological action, these drugs are of interest as multidrug resistance reversers in the chemotherapy treatment for cancer. The relationship between the pharmacological potency of the different drugs and the corresponding standard ion transfer potentials obtained in the present work has been studied. The relationship between the sensitivity of an amperometric sensor based on the ion transfer across the water–solvent polymeric membrane interface towards the different catamphiphilic drugs and the standard ion transfer potentials has also been studied. A dependence between them was obtained when the applied potential of the sensor was set at a value previous to the diffusion controlled zone.

Loperamide-induced enhancement of moxidectin availability in cattle.

Moxidectin (MXD) is a milbemycin endectocide compound active at extremely low dosages against a wide variety of nematode and arthropod parasites. Different pharmacological approaches are currently being tested to delay the bile-faecal elimination and to obtain increased systemic availability for endectocide molecules in ruminants. Loperamide (LPM) is an opioid derivative, whose main pharmacological action is to abolish intestinal propulsive peristaltic waves. The influence of LPM on the pattern of faecal excretion of MXD and on its plasma disposition following intravenous (i.v.) and subcutaneous (s.c.) administrations to cattle was evaluated in the current work. Parasite-free calves were treated with MXD given either alone at 200 microg/kg by i.v. (Experiment 1) and s.c. (Experiment 2) administrations or coadministered with LPM subcutaneously injected at 0.4 mg/kg. Blood and faecal samples were collected over a period of 20 (Experiment 1) and 40 (Experiment 2) days post-treatment. The recovered plasma and faecal samples were extracted and analysed by high-performance liquid chromatography (HPLC) using fluorescence detection. Significantly higher MXD plasma concentrations were obtained after the coadministration of MXD + LPM compared with treatments with MXD alone by both routes. The higher MXD plasma concentration profiles measured after the coadministration with LPM accounted for the significantly higher AUC values obtained following the i.v. (> 46%) and s.c. (> 38%) treatments. A reduced MXD body clearance was observed in the presence of LPM. The appearance of MXD in faeces was significantly delayed after the i.v. and s.c. coadministrations of MXD with LPM (T(1/2app)=5.87 and 10.6 h, respectively) than that observed after the treatment with MXD alone (T(1/2app)=3.48 and 5.12 h). A delayed MXD peak concentration in faeces collected from MXD + LPM-treated animals compared with those receiving MXD alone, was observed. The delayed intestinal transit time caused by LPM and a potential competition between MXD and LPM for the P-glycoprotein-mediated bile/intestinal secretion processes, may account for the enhanced MXD systemic availability measured in cattle in the current work.

臭化ジスチグミンの血清コリンエステラーゼ値への影響 直腸癌患者に対して

The main pharmacological action of distigmine bromide is to bind with choline esterase to inactivate it and increase the activity of acetylcholine. However, few studies have previously described the extent of distigmine bromide' s effect on the living body. In this study, the effect of distigmine bromide on serum choline esterase was examined in 119 patients with rectal cancer.Neurogenic bladder developed in 40.3% of the patients who received surgery for rectal cancer, and 50.3% of them were treated with distigmine bromide. Although this treatment reduced the serum choline esterase levels by 30.1%, on average, the rate of reduction varied among the patients.When comparing the rate of reduction of choline esterase in patients aged 65years of age or older with those less than 65years of age, the rate was found to be higher in the older group. Diarrhea, which is one of the effects of excess distigmine bromide, was observed in 33.3%, and the rate of reduction for serum choline esterase was higher in those with diarrhea.Distigmine bromide should be carefully administered, particularly in old patients, while closely monitoring the serum choline esterase levels and the occurrence of possible digestive symptoms. Such observations are also important for preventing a cholinergic crisis

合成抗トロンビン剤ＭＤ‐８０５の第一相試験 単回および連続投与試験

The phase one study was performed by the use of the single and multiple intravenous administration of newly developed synthetic antithrombin agent: (2 R, 4 R)-4-methyl-l- [N2- [(3-methyl-1, 2, 3, 4-tetrahydro-8-quinolinesulfonyl)-Larginyl] -2-piperidinecarboxylic acid monohydrate; MD-805]As a single administration study, each one of groups consisting of six healthy volunteers was injected with one of 2.25mg, 4.5mg and 9mg of this agent by drip intravenous infusion taking 30 minutes and as a multiple administration study, 5 volunteers were injected with 9mg of the agent intravenously in three hours once a day for three days.The clinicopharmacological reactions of this agent were evaluated with many parameter tests and clinical manifestations.The evaluation from clinical symptom after the administration of this agent revealed no abnormality without spontaneous bleeding. However, the prolonga-tion of thrombin time, PTT and prothrombin time and the defect of platelet aggregation induced by thrombin were observed. These findings might be caused by main pharmacological action of this antithrombin agent.On the other parameter tests, serum LDH level was slightly decreased on the cases of both single and multiple administration of this agent and A/G ratio was increased within normal range on single administration with this agent. All others of the safety parameters were within permitable changes in the clinical point of view.On the basis of these results, we concluded that this agent can be applicable for phase two study.

The effect of prolonged treatment with oxyfedrine on intracellular potentials and on other features of cardiac function in rabbits and guinea-pigs.

1. Previous work in acute experiments has shown that the main pharmacological action of oxyfedrine is stimulation of beta-adrenoceptors, yet there have been clinical reports that the drug is beneficial in the treatment of angina pectoris.2. In the present experiments rabbits and guinea-pigs were treated for several weeks with daily i.p. injections of oxyfedrine.3. A daily dosage of 15 mg/kg oxyfedrine had no effect on growth rate for 4 weeks, but thereafter the growth rate of treated animals fell below that of controls.4. The heart weights of the treated animals, expressed as a percentage of body weight, were significantly lower than those of controls.5. Measurement of intracellular potentials in hearts taken from treated rabbits showed that the main effects were a reduction in the maximum rate of depolarization and a prolongation of the plateau of the action potential.6. Guinea-pigs treated for 6 weeks with 15 mg/kg oxyfedrine daily i.p. were protected to some extent from the toxic effect of ouabain infused intravenously.