Pharmacological activity of sanchi ginseng (Panax notoginseng)

The pharmacological activity and constituents of the sanchi ginseng Panax notoginseng have been reviewed. The bulk of pharmacological findings have been based on the saponins or steryl glycosides, although polysaccharides with immunopotentiating activity, proteins with antifungal, ribonuclease and xylanase activity, and a triacylglycerol (trilinolein) with antioxidant activity have been reported. Protective actions against cerebral ischaemia, beneficial effects on the cardiovascular system, and haemostatic, antioxidant, hypolipidaemic, hepatoprotective, renoprotective and estrogen-like activities have been described. Various methods for authentication of P. notoginseng are available.     

New approaches for antithrombotic antiplatelet therapies

Cardiovascular diseases are one of the major causes of mortality in the western world. As platelet dependent thrombosis is of central importance in their pathophysiology, several successful strategies, targeting a specific platelet function or interaction, have been developed to prevent or treat these disorders. However, as the current antiplatelet strategies are limited in efficacy and safety, and often influence normal haemostatic functions, new compounds are being developed with improved characteristics. This review deals with the development of novel antiplatelet compounds for which evidence is available on their antithrombotic action in vivo. In a first part, these compounds, their targets and their potential applicability are discussed. The second part of this review focuses on BT tests and bleeding models and their usefulness for determination and/or prediction of the safety of novel antiplatelet compounds.     

OECD test strategies and methods for endocrine disruptors

The question whether (man-made or natural) chemical substances may have an adverse effect on the endocrine system has gained high visibility in the public as well as in the scientific community. This relates to possible effects on the environment as well as on human health for chemicals with (anti)estrogenic, (anti)androgenic or (anti)thyroid activity. Taking into account the broad universe of chemicals to which humans or the environment may be exposed, a sound testing strategy and robust test methods are urgently needed. Both subjects have been addressed by a specific OECD working group (EDTA-Endocrine Disruptor Testing and Assessment Task Force) involving regulatory agencies, the scientific community, chemical industry and NGOs. Like other organizations the OECD has adopted a tiered-testing strategy with the first tier using screening assays as quick and inexpensive tools, providing a way of generating alerts to potential endocrine activity that can be used to prioritize substances for definitive tests that then can determine the toxicological consequences of endocrine toxicity. The efforts of the OECD have therefore concentrated on the validation of specific screening and testing guidelines, like the uterotrophic, the Hershberger, and the "enhanced TG 407" test. The experimental testing necessary for this validation procedure is completed for the uterotrophic and the "enhanced TG 407" tests and near completion for the Hershberger assay. The data obtained so far have been published (for the uterotrophic assay) or will be submitted to the EDTA working group for final evaluation. Overall, the validation program has been very successful and should be sufficient for setting up OECD test guidelines for these experimental procedures. This will add substantially to the "tool-box" of OECD test methods that is available internationally to regulatory agencies and chemical industry for the identification and assessment of possible endocrine disruptors. Despite this success it is well recognized that the methodological "tool-box" should be supplemented by further screening and testing procedures related to effects on human health and the environment.     

The estrogenic and androgenic potential of pyrethroids in vitro. Review

Synthetic pyrethroids are used worldwide as insecticides. Their metabolites are regularly detected in the urine of adults and children from the general population. There is increasing concern that they may induce sex-hormone disrupting effects. The present work reviews available published information on the (anti)estrogenic and (anti)androgenic activity of pyrethroids in in vitro screening tests.In recent years, a large number of pyrethroids have been evaluated using various common testing methods. In tests using recombinant yeast or mammalian cells, the pyrethroids were found to be essentially negative or weakly estrogenic. More inconsistent results were found regarding their estrogenic action in proliferation tests. Conflicting findings were also reported across studies and/or assays which evaluated their anti-estrogenic or anti-androgenic potential. Some studies have suggested that certain pyrethroids may have potential antagonist activity. However, no strong interaction with the estrogenic or androgenic pathway was reported. The present review confirms the interest in performing a screening battery and in adopting an integrative approach for identifying the potential of different compounds from a chemical family to interfere with the endocrine system.     

Considerations for safety pharmacogenetics in clinical practice

The focus of treating an individual patient is the identification of the individual's specific needs. The measurement of the patient's characteristics, such as blood pressure or body temperature, and also the measurement of biomarkers, such as cholesterol or hemoglobin A1C is part of the patient's health assessment. The deeper the insights into the phenotypic and molecular characteristics of the patient, the better we are positioned to treat a patient. Increasingly, this assessment includes testing for certain pharmacologically relevant genetic variations (pharmacogenetics). Evaluating how the patient's genetic makeup combined with the patient's exposure to environmental influences could impact disease and treatment decisions is becoming the cornerstone of personalized medicine. However, we often use such assessments for finding the most 'effective' treatment, but we might not always be as rigorous in our assessment of potential safety risks. This is particularly apparent when looking at how safety risks are communicated. Often this information is only available as general, population-based statements and a small amount of information is available to evaluate whether or not an individual patient is at risk. Although pharmacogenetic tests that can help to assess whether an individual patient's personal risk exist (safety pharmacogenetics), they are not always performed.     

Prescribing without evidence - pregnancy

Prescribing of medicines during pregnancy is common, and for some groups of women is essential for maintaining maternal and therefore fetal health. Pregnant women and prescribers are rightly concerned, however, about the potential adverse fetal effects of medicines. These may include fetal death or stillbirth, congenital malformations, developmental impairment, neonatal effects or late carcinogenesis. It is therefore essential that the risks and benefits for mother and fetus are considered carefully before prescribing in pregnancy. This is often challenging because of the paucity of information available. To complicate the issue further, drug pharmacokinetics are commonly altered in pregnancy, potentially affecting optimal dosing as well as interpretation of plasma concentration measurements, with specific information on individual drugs seldom available. Most drugs cross the placenta, especially lipophilic drugs and those with low plasma protein binding. Active membrane transporters also have an important role in enhancing or preventing drug transfer, although this is not yet clearly understood. Animal studies have limited applicability to humans because of species-specific effects, and clinical trials in pregnancy are only undertaken in special circumstances. Prescribers therefore need to rely on observational studies of fetal outcomes following drug exposure in human pregnancy. These often involve limited numbers, and data are also subject to confounding and bias, making interpretation difficult. It therefore remains essential that appropriate mechanisms for systematic data collection, including congenital malformation registries, teratology information services, pregnancy registers and linked population registries, are maintained and enhanced to increase the amount and quality of information available.     

Contribution of toxicology towards risk assessment of carcinogens

In the last decade many tests have been designed to detect possible carcinogenicity of compounds. Presently, many more or less simple and convenient systems are available to detect mutations, effects on chromosomes, DNA binding and damage and malignant transformation. These systems, which have been extensively refined during the last years, often show reasonably good relevance to carcinogenicity. Although inconsistencies in the patterns of response do indicate that their role as predictive indicators of carcinogenicity remains still uncertain, the use of such short-term tests in carcinogen risk assessment does seem feasible.Factors other than these tests should also be taken into consideration, since other characteristics like chemical structure, biotransformation, toxicokinetics, qualitative and quantitative physiological and/or morphological effects, species, strains, organ specificity, dose-response relation and information on studies in man, if available, are of importance too.In conjunction with the results of adequately performed carcinogenicity tests in mammals, one may attempt to classify carcinogens. Current knowledge does not permit a rigid classification, but may warrant a subclassification into carcinogens acting via a genetic or a non-genetic mechanism. It is emphasized that on theoretical and practical grounds a different extrapolation system should be used for the different types of carcinogens in risk assessment procedures. Evaluations on individual compounds should be made to decide whether such genotoxic or non-genotoxic compounds should be permitted in the human environment.Dedicated to Professor Dr. med. Herbert Remmer on the occasion of his 65th birthday     

Clinical application of a human-collagen fleece as haemostatic agent

Local haemostatic agents have been employed for years in all surgical fields. Collagen has proved superior to other materials in terms of its haemostatic effect and good tolerability. A human-collagen fleece (Beristypt) is now available for the first time. A special manufacturing process excludes the possibility of human-pathogenic viruses being transmitted. The good clinical efficacy of human-collagen fleece for the indication haemostasis and the fact that it is easy to use, have been demonstrated in 63 operations in four surgical fields. Human-collagen fleece was well tolerated; no adverse effects were reported. The use of human-collagen fleece is a promising adjuvant method for improvement of surgical haemostasis.     

Are there differential symptom profiles that improve in response to different pharmacological treatments of premenstrual syndrome/premenstrual dysphoric disorder?

Current evidence suggests that the accepted treatments for premenstrual syndrome (PMS)/premenstrual dysphoric disorder (PMDD) have similar overall efficacy. While these treatments are more effective than placebo, response rates associated with them are far from satisfactory (<60%), such that, irrespective of treatment modality, there remain a significant number of women who are unresponsive to current conventional pharmacological therapy. The available data on response rates of specific types of premenstrual symptoms to, or symptom profiles that are most amenable to, each treatment modality are limited and not well defined because most studies were not designed to assess specific symptom profiles. Those studies that have attempted to evaluate which symptom profiles respond to specific therapies have revealed variations within the individual modalities, as well as between the different modalities. It appears that suppression of ovulation ameliorates a broad range of behavioural as well as physical premenstrual symptoms. SSRIs are most effective for irritability and anxiety symptoms, with lesser efficacy for 'atypical' premenstrual symptoms. GABAergic compounds are most efficacious for anxiety and anxious/depressive symptoms, while dopamine agonists, particularly bromocriptine, are perhaps most efficacious for mastalgia. Overall treatment response rates may improve if treatments are targeted at well-defined subgroups of patients. Re-analysis of available datasets from randomised clinical trials may shed more light on the notion that targeting women with specific premenstrual symptom profiles for specific treatment modalities would improve response rates beyond the current ceiling of approximately 60%. Such information would also improve understanding of the putative pathophysiological mechanisms underlying PMS and PMDD, and may point to a more specific diagnosis of these conditions.     

Safety and tolerability of treatments for allergic rhinitis in children.

Allergic rhinitis is a common condition in adults and children and can have a large impact on patients' health and quality of life. The aim of current allergic rhinitis therapies is to treat the subjective symptoms and to improve objective measures of the disease. Of the available treatment options for paediatric allergic rhinitis, the newer oral antihistamines and intranasal corticosteroids are first-line treatments.First-generation antihistamines are associated with unwanted adverse effects such as cardiotoxicity, sedation and impairment of psychomotor function. Despite results from studies using first-generation antihistamines demonstrating impairment of cognitive and academic function in children, many of these agents are still commonly given to patients. The newer antihistamines, developed with the aim of being more specific for the histamine H(1) receptor and of overcoming these adverse effects, are the medication of choice in patients with mild intermittent allergic rhinitis. For children <12 years of age, three newer oral antihistamines are currently available: cetirizine, loratadine and fexofenadine. A lack of adverse effects with these antihistamines has been demonstrated in children using EEG and psychomotor performance tests, and in clinical studies. However, issues of receptor selectivity and the potential for CNS adverse effects still remain, and further studies are warranted.Intranasal corticosteroids are the most effective anti-inflammatory agents used for the treatment of paediatric allergic rhinitis; however, the safety of these compounds remains controversial. The safety implications associated with corticosteroids are long-term, dose-related systemic effects, such as suppression of adrenocortical function, growth and bone metabolism, and the extent of these effects is influenced by a number of factors including corticosteroid type, pharmacokinetic profile, mode of delivery and delivery device. Topical corticosteroids were introduced to reduce the systemic effects seen with the long-term use of oral agents. The intranasal corticosteroids currently available for the treatment of paediatric allergic rhinitis - beclometasone, budesonide, flunisolide, fluticasone propionate, mometasone and triamcinolone - have short half-lives and rapid first-pass hepatic metabolism; however, their pharmacokinetics vary in terms of systemic absorption, potency, binding affinity, lipophilicity, volume of distribution, and half-life. A number of studies - utilising hypothalamic-pituitary-adrenal axis function tests such as plasma cortisol levels, 24-hour urinary-free cortisol tests; stimulation tests with corticotropin (adrenocorticotropic hormone), lypressin, and corticotropin-releasing hormone; and growth assessment studies using knemometry and stadiometry - have indicated that these intranasal corticosteroids are well-tolerated in paediatric patients and do not significantly affect growth.The wealth of clinical data and the recommendations from evidence-based guidelines suggest that both antihistamines and intranasal corticosteroids have good safety profiles in children. Nevertheless, growth should be regularly monitored in children receiving intranasal corticosteroids. Other treatments such as immunotherapy, local chromones and decongestants can also be beneficial in managing paediatric allergic rhinitis, and therapies should be considered on an individual basis.     

Effects on haemostasis variables by second and third generation combined oral contraceptives: a review of directly comparative studies

Previous reports and reviews indicate differences in effects of second and third generation combined oral contraceptives (COCs) on haemostasis variables. This review analyses directly comparative studies on such effects. From the literature, 17 longitudinal comparative studies with parallel groups were retrieved, containing data on comparisons between COCs containing levonorgestrel (second generation COCs) and COCs containing desogestrel, gestodene or norgestimate (third generation COCs) with 30-35 ug ethinylestradiol. Six or more comparisons were available only for fibrinogen, platelet count, antithrombin III, factor VII, factor VIII and factor X. The comparisons reveal a consistently larger increase in factor VII with the third generation COCs compared to the second generation COCs. The effects on factor VII do not coincide in these comparative studies with effects on factor X and prothrombin, rendering a specific sensitivity of the vitamin K-dependent mechanisms for progestogens unlikely. Fibrinogen effects tend to be different for the different progestogens, suggesting a progestogen-specific dependence. Trends in antithrombin III are towards more reduction for the third generation COCs, but the effects are very minor. The effects on factor V suggest a possible progestogen specificity, which may be relevant to explain the difference in APC-resistance between second and third generation of COCs. In general, direct comparisons of effects of different types of COCs on haemostatic variables are available for only a very few factors, which hampers the drawing of general conclusions with respect to haemostatic consequences.     

Biological indicators of neurotoxicity in central and peripheral toxic neuropathies

This article reviews the biological indicators available for monitoring human neurotoxicity by exogenous chemicals with reference to the phases in which the neurotoxic process takes place, namely delivery, receptor-linkage, and toxicodynamic phase. Among the delivery phase tests, indicators are available for metals (lead, mercury) and some organic substances (CS2, n-hexane, DDT, etc.), but a correlation between neurotoxic effects and these indices is rather loose or not yet proved. The receptor-phase tests comprise well known enzymes, such as cholinesterase, less known but promising indicators, such as neuropathy target esterase (NTE), and new tools under study, such as acrylamide-hemoglobin adducts or 2,5-hexanedione-protein adducts. The toxicodynamic phase tests, which mainly consist of measuring substances released from the nervous system, have provided so far rather poor results, but more specific techniques of measurement (monoclonal antibodies) could offer new possibilities in the future.     

Pharmacogenetics of hypertension treatment: a structured review

The extent of blood pressure lowering by anti-hypertensive agents is difficult to predict for individual patients, even when evaluated in the context of biochemical or demographic information. Genetic predictors (mainly single nucleotide polymorphisms, SNPs) have been the focus of several recent studies and are gaining much attention. We have conducted a literature search for studies in which the lowering of ambient blood pressure by specific drugs or drug classes in humans was related to specific genotypes. Twenty-eight studies were identified, of which six had a single-dose design, and the remaining 22 studied drug effects after more than 4 weeks of drug administration. Virtually all were association studies. Prospective trials that compared the prognostic value of genetic methods to routine clinical practice were not identified. Almost all studies used a candidate-gene design, usually with a very small number of SNPs (typically one). Gene-gene and gene-environment interactions were studied only rarely. Only one study targeted genes involved in drug metabolism. Most candidate-genes were part of the renin-angiotensin system. By far the most extensively studied has been the angiotensin-converting enzyme insertion/deletion polymorphism (15 studies) but, to date, no clear picture has emerged for this or other genetic variants. Thus, the potential for utility of genetic characterization of individual patients as a predictor of anti-hypertensive response has yet to be realized.     

Animal models of depression: are there any?

Simple tests for antidepressant-like activity, such as 5-HTP-induced syndrome or reserpine-induced hypomotility, are often mechanism-based tests, pharmacologically specific for certain known classes of therapeutically successful antidepressant agents. Many of these behavioural assays have been superseded by neurochemical techniques such as in vivo microdialysis. In contrast to these mechanistic-based models, investigators have also endeavoured to reproduce in the laboratory, factors that are believed to precipitate depression in people. It is a strong assumption in this approach that depression is a response to stress. This strategy profiles the consequences of chronic stress particularly psychosocial stress or early life events, in order to reproduce in animals the behavioural signs and pathologies associated with depression. The advances in the social psychological, clinical pathological and new areas such as neuroimaging research offer the possibility of establishing more sophisticated models for depression in animals with a broader range of biomarkers from the immunological and endocrinological to neurochemical and behavioural. Combining these novel insights with more traditional tests of depression may not only increase our understanding of the neurobiology of depression but also afford more precise and predictive preclinical models of depression. The responsiveness of different strains or genetically modified animals to stress is likely to be a key area of study. Furthermore we must look to individual differences in subjects, even within the same strain, to more fully understand why some individuals show pathological responses to stress whereas others appear unaffected. Conversely in validating our models using currently available treatments we must include the concept of non-responders so as not to disregard models that may extend therapeutic possibilities in these patients.     

Methods for computer-aided chemical biology. Part 1: Design of a benchmark system for the evaluation of compound selectivity

Computational drug design and discovery methods have traditionally put much emphasis on the identification of novel active compounds and the optimization of their potency. For chemical genetics and genomics applications, an important task is the identification of small molecules that are selective against target families, subfamilies, or individual targets and can be used as molecular probes for specific functions. In order to develop or tune computational methods for such applications, there is a need for molecular benchmark systems that focus on compound selectivity, rather than biological activity (in qualitative terms) or potency. We have constructed a selectivity-oriented test system that consists of 26 compound selectivity sets against 13 individual targets belonging to three distinct families and contains a total of 558 selective compounds. The targets were chosen because of pharmaceutical relevance and the availability of suitable ligands, privileged structural motifs and/or target structure information. Compound selectivity sets were characterized by structural diversity, chemical scaffold and selectivity range analysis. The test system is made freely available and should be useful for the development of computational approaches in chemical biology.     

Toxicological comments to the discussion about REACH

It is the ultimate goal of the intended REACH process (Registration, Evaluation and Authorization of Chemicals) of the European Union to identify substances of hazardous properties and to evaluate the risks of human and environmental exposure. During the last few months there has been a controversial discussion as to what extent in vitro studies and consideration of structure activity relationship provide sufficient information to waive repeated exposure studies. Industry as well as certain regulatory agencies or NGOs support this approach and propose that repeated dose studies may only be required beyond 100 t/a. From a toxicological point of view it has to be stressed that this discussion primarily considers the cost reduction and protection of animals, whereas protection of human health and the environment are secondary. In vitro studies only allow identification of specific hazardous properties which can be detected by the specific test system. Moreover, appropriate information on the dose response of adverse effects, identification of thresholds and NOELs that are essential for risk characterization cannot be obtained from these studies. Consequently, identification of all relevant hazardous properties and endpoints of adverse effects can only be determined in the intact animal by repeated dose studies such as 28-day or 90-day studies. In the absence of such information the hazard identification is incomplete and there is no basis for appropriate risk assessment of human exposure. Thus, any waiving of repeated dose studies in animals bears the probability of unforeseen effects in case of acute or continuous human exposure. From this the undersigning European Toxicologists conclude: 1. The intention of REACH is to identify hazardous properties in order that a reliable risk assessment can be made and measures taken to deal with chemicals posing a significant risk. 2. The recent debate has centered on ways in which the well established in vivo methods for risk assessment can be bypassed. 3. The evidence that the available alternatives would support such replacement is weak. Progress to improve their value for risk assessment purposes is bound to be slow because the issues are very complex. As a group of European Toxicologists we strongly support the need for more research support in these areas, but we believe that over claims for progress is damaging their development. 4. Under the circumstances only two options are available: to reduce very substantially the estimation of hazard and risk with inevitable adverse consequences for human health and environmental protection, or to continue the existing methods until properly validated new methods are available.     

The triptan formulations : how to match patients and products

The 5-HT(1B/1D) receptor agonists (the 'triptans') are migraine-specific agents that have revolutionised the treatment of migraine. They are usually the drugs of choice to treat a migraine attack in progress. Different triptans are available in various strengths and formulations, including oral tablets, orally disintegrating tablets, nasal sprays and subcutaneous injections. In Europe, sumatriptan is also available as a suppository. Specific differences among the triptans exist, as evidenced by different pharmacological profiles including half-life, time to peak plasma concentrations, peak plasma concentrations, area under the concentration-time curve, metabolism and drug-drug interaction profiles. How or whether these differences translate to clinical efficacy and tolerability advantages for one agent over another is not well differentiated. However, delivery systems may play an important role in onset of action. Given that the clinical distinctions among these agents are subtle, identification of the most appropriate triptan for an individual patient requires consideration of the specific characteristics of the patient and knowledge of patient preference, an accurate history of the efficacy of previous acute-care medications and individual features of the drug being considered. The selection of an acute antimigraine drug also depends upon the stratification of the patient's migraine attack by peak intensity, time to peak intensity, level of associated symptoms such as nausea and vomiting, time to associated symptoms, comorbid diseases and concomitant treatments that might cause drug-drug interactions. Individual patient response to the triptans seems to be idiosyncratic and possibly genetically determined. Therefore, a set of specific questions can be used to determine whether a currently used triptan is optimally effective, whether the dose needs to be increased or whether another triptan should be tried. The clinician has in his/her armamentarium an ever-expanding variety of triptans, available in multiple formulations and dosages, which have good safety and tolerability profiles. Continued clinical use will yield familiarity with the various triptans, and it should become possible for the interested physician to match individual patient needs with the specific characteristics of a triptan to optimise therapeutic benefit. Use of the methods outlined in this review in choosing a triptan for an individual patient is probably more likely to lead to migraine relief than making an educated guess as to which triptan is most appropriate.     

Autoimmune Neuromuscular Disorders

Autoimmune neuromuscular disorders affecting peripheral nerves, neuromuscular junction or muscle have a wide clinical spectrum with diverse pathogenetic mechanisms. Peripheral nervous system may be targeted in the context of complex immune reactions involving different cytokines, antigen-presenting cells, B cells and different types of T cells. Various immunomodulating and cytotoxic treatments block proliferation or activation of immune cells by different mechanisms attempting to control the response of the immune system and limit target organ injury. Most treatment protocols for autoimmune neuromuscular disorders are based on the use of corticosteroids, intravenous immunoglobulins and plasmapheresis, with cytotoxic agents mostly used as steroid-sparing medications. More recently, development of specific monoclonal antibodies targeting individual cell types allowed a different approach targeting specific immune pathways, but these new treatments are also associated with various adverse effects and their long-term efficacy is still unknown.