Herb-drug,food-drug,nutrient-drug,and drug-drug interactions: mechanisms involved and their medical implications

Adverse drug reactions (ADRs) and iatrogenic diseases have been identified as significant factors responsible for patient morbidity and mortality. Significant studies on drug metabolism in humans have been published during the last few years, offering a deeper comprehension of the mechanisms underlying adverse drug reactions and interactions. More understanding of these mechanisms, and of recent advances in laboratory technology, can help to evaluate potential drug interactions when drugs are prescribed concurrently. Increasing knowledge of interindividual variation in drug breakdown capacity and recent findings concerning the influence of environment, diet, nutrients, and herbal products can be used to reduce ADRs and iatrogenic diseases. Reviewed data suggest that drug treatment should be increasingly custom tailored to suit the individual patient and that appropriately co-prescribed diet and herbal remedies, could increase drug efficacy and lessen drug toxicity. This review focuses mainly on recently published research material. The cytochrome p450 enzymes, their role in metabolism, and their mechanisms of action are reviewed, and their role in drug-drug interactions are discussed. Drug-food and drug-herb interactions have garnered attention. Interdisciplinary communication among medical herbalists, medical doctors, and dietetic experts needs to be improved and encouraged. Internet resources for obtaining current information regarding drug-drug, drug-herb, and drug-nutrient interactions are provided.     

Tenascin-C expression in human breast tumors

INTRODUCTION: Increased amounts of extracellular matrix proteins have been described in breast tumours, which are normally present in embryonal connective tissue, in adults however, these occur only in pathological conditions: one of which is tenascin. Within the tenascin family the most examined and most controversial member is tenascin-C. It has been suggested that tenascin-C decreases cell adhesion, promotes invasion and metastases, and may play role in pathological angiogenesis. MATERIAL AND METHODS: Authors investigated 62 primary breast carcinomas and in further 20 cases both the primary and the recurrent or second primary tumours were examined. In the latter group the main question was whether tenascin-C was of prognostic significance. The newly formed vessels were visualised using CD31 antibody. RESULTS AND CONCLUSIONS: Tenascin-C positivity in the tumour cells was shown in the 10 of the 62 primary carcinomas and in 7 from the second group of cases (20 patients). Of all cases examined, in five specimens tenascin-C positivity was present in normal ductal epithelial cells. In variable amount, in the stroma of invasive tumours, tenascin-C was present in every case. The presence of tenascin-C within tumour cells, at the periphery and also in the stroma of tumours, within the proliferating ducts, around tumour cell nests and in situ carcinomas, furthermore, in the epithelial cells of normal ducts suggests that tenascin-C may promote detachment and migration of carcinoma cells. There was no correlation, however, between tenascin-C expression and the occurrence of recurrences in this small group. Correlation was found between increased stromal tenascin-C expression and angiogenesis. Authors conclude that tenascin-C might have a role in angiogenesis.     

Hyponatremic encephalopathy--some experimental and clinical findings

Hyponatremia is a common electrolyte disturbance occurring in a broad spectrum of patients, from asymptomatic to critically ill. The disease is defined as a decrease in serum sodium concentration to a level below 136 mmol per liter. The brain damage from hyponatremia can be associated with either hyponatremic encephalopathy or improper therapy of symptomatic hyponatremia both in patients and in experimental models of hyponatremia in rats. This review covers the clinical symptoms of hyponatremia as well as the consequences of its correction. It also summarises the effects of experimental hyponatremia associated with vasopressin on some aspects of cerebral blood flow regulation and the morphology of cerebral tissue.     

Biological significance of the different erythropoietic factors secreted by normal human early erythroid cells

Evidence is accumulating that autocrine/paracrine regulatory mechanisms play an important role in regulating normal hematopoiesis. To support this, various growth factors, cytokines and chemokines are expressed and secreted by normal early and differentiated hematopoietic cells. In this review, we summarize recent advances in the identification and understanding of the role of autocrine/paracrine axes in normal human erythropoiesis. We will also address a biological significance of the secretion of (i) metalloproteinases which in addition to growth factors and cytokines are secreted by normal erythroid cells and (ii) membrane-derived microvesicles (MV), that are shed from the surface of maturating erythroblasts/reticulocytes, and as we postulate may also play a role in intercellular communication. We hypothesize that all these factors together play an important role in a crosstalk between erythroid cells and their environment. A better understanding of intercellular crosstalk operating in normal erythropoiesis and of the mechanisms regulating synthesis of these endogenously produced factors may allow us to develop more efficient therapeutic strategies to treat various erythropoietic disorders.     

Postprandial lipemia and coronary risk

A number of cross-sectional studies have demonstrated that the magnitude of postprandial lipemia or single postprandial triglyceride values predict asymptomatic and symptomatic atherosclerosis, independent of risk factors measured in the fasting state. Postprandial lipemia reflects an integrated measure of an individual’s triglyceride metabolic capacity. Numerous genetic and environmental factors that are known or suspected to affect triglyceride transport contribute to the magnitude of postprandial lipemia. In this article, mechanisms linking postprandial lipemia with the development and progression of atherosclerosis are described, and determinants of the extent and duration of postprandial lipemia are discussed.     

Limited usefulness of the PFA-100 for the monitoring of ADP receptor antagonists--in vitro experience.

We have evaluated the usefulness of the PFA-100 system (collagen/ADP and collagen/epinephrine cartridges) to assess the in vitro effects of a few platelet function inhibitors: Aspisol (60 microg/ml), 4-[4-[4-(aminoiminomethyl]-1-piperazinyl]-1-piperidineactetic acid, hydrochloride trihydrate (GR144053F, fibrinogen receptor antagonist, 100 nM), adenosine-3',5'-diphosphate (A3P5P, P2Y1 ADP receptor antagonist, 500 microM) and Bis[(adenosine-5'-O-phosphorodithioyl)methylene]-phosphinic acid (APTMPA, P2Y12 ADP receptor antagonist, 500 microM) on platelet function, as compared with the other commonly used diagnostic technique, a whole blood electrical aggregometry (20 microM ADP or 0.5 mM arachidonic acid). The in vitro studies were carried out on a group of 38 subjects. Whereas all the examined platelet antagonists and inhibitors almost completely blocked the 20 microM ADP- or 0.5 mM arachidonic acid-induced (in the case of acetylsalicylic acid) whole blood aggregation, only two inhibitors (Aspisol and GR144053F) remained effective in a significant prolongation of the PFA-100 occlusion time. Otherwise, using the PFA-100 system we were not able to detect the inhibitory actions of ADP receptor antagonists- P2Y1 and P2Y12. Our findings point to a limited usefulness of the PFA-100 system for the monitoring of the effectiveness of ADP receptor antagonists. The outcomes of this study show that platelet aggregometry in whole blood is characterised by the highest sensitivity in the monitoring of the investigated blood platelet inhibitors.     

Multiplex polymerase chain reaction on FTA cards vs. flow cytometry for B-lymphocyte clonality.

BACKGROUND: Two-colour flow cytometry was compared with multiplex PCR with capillary electrophoresis for clonality determination in specific categories of B-cell lymphoma. FTA cards were evaluated for preserving DNA from node imprints and expediting molecular analysis. METHODS: A single-tube multiplex PCR targeted IGH and lymphoma-specific translocations in DNA extracted from 180 frozen lymphoid tissues and DNA bound to FTA cards from 192 fresh tissues and 137 aspirates. PCR results were compared with flow cytometry in the extracted and aspirated samples. RESULTS: Overall, single-tube multiplex PCR sensitivity was equivalent in the sample groups (intergroup range 79%-91%). False negatives were associated with tumour origin in the follicle centre. Multiplex PCR and flow cytometry were equally sensitive and together detected 98% of B-cell lymphomas. Additional two-tube targeting of IGK suggested an overall molecular sensitivity >90%. False positive (pseudoclonal) single-tube multiplex PCR was associated with necrosis and sparse lymphocytes. CONCLUSIONS: Multiplex PCR using template DNA bound to an FTA card effectively detects B-lymphocyte clonality, obviates DNA extraction and refrigeration, and can be used without diminished sensitivity in fine needle aspirates or node imprints as a replacement for or complement to flow cytometry at any point in the diagnostic work-up.     

Effect of obesity and insulin sensitivity on adiponectin isoform distribution

Background Adiponectin is an insulin‐sensitizing, antiatherogenic and anti‐inflammatory adipocytokine that circulates in three isoforms: a trimer [low‐molecular weight (LMW)], a hexamer (trimer‐dimer) of medium molecular weight (MMW) and a multimeric high molecular weight (HMW) isoform. Evidence is accumulating that HMW adiponectin is the active isoform of the adipocytokine. We investigated the impact of adipose tissue and insulin sensitivity on adiponectin isoform distribution. Materials and methods One hundred and eighty‐seven normolipidaemic, non‐diabetic lean or obese subjects with or without insulin resistance participating in the Salzburg Atherosclerosis Prevention program in subjects at High Individual Risk (SAPHIR) were included in the study. Insulin sensitivity was determined by the short insulin tolerance test and the homeostasis model assessment (HOMA) index. Serum adiponectin isoform distribution was determined by an enzyme immunoassay. Results Total adiponectin as well as HMW/total adiponectin ratio was significantly increased in female subjects. Circulating total adiponectin levels were lowest in obese patients due to reduced concentrations of HMW adiponectin. As determined by stepwise regression analysis, besides age and high density lipoprotein (HDL) cholesterol, visceral fat area and waist‐to‐hip ratio predicted concentrations of HMW adiponectin, while insulin sensitivity had no influence on either total adiponectin or its isoforms. Conclusions Our results underline that determination of adiponectin isoforms are more useful than measurement of total adiponectin in clinical settings. Our data suggest that adiponectin concentrations are strongly associated with visceral fat area but not with insulin sensitivity. Thus, we hypothesize that insulin resistance is a consequence rather than the cause of hypoadiponectinaemia in obese subjects.     

Metabolic side effects of antipsychotic medication

The use of second-generation antipsychotics (SGAs) is associated with metabolic side effects including weight gain, diabetes mellitus and an atherogenic lipid profile. These adverse effects are not only the risk factors for cardiovascular disease, insulin resistance and diabetes mellitus leading to increased morbidity and mortality but may also impair the patient's adherence to treatment. SGAs in particular are associated with significant weight gain with clozapine and olanzapine carrying the highest risk, whereas newer agents, such as risperidone and aripiprazole, are considered to be less prone to cause weight gain. Consequently, a consensus development conference convened issuing recommendations on patient monitoring when treated with SGAs. The metabolic effects of antipsychotic drugs should be of concern when planning a patient's treatment strategy. Baseline screening and regular follow-up monitoring whose intervals should depend on the individual predisposition are advised. Possible therapeutical strategies for the management of drug-induced obesity include therapeutic approaches, such as life style change and pharmaceutical intervention. Drugs with a weight reducing effect become more important because of the lack of compliance with behavioural intervention. Topiramate, histamine-antagonists, dopaminergic- and serotoninergic agents have shown positive results in the management of psychotropic medication induced weight gain. However, further trials are required to support a specific therapeutical approach as well as studies to investigate the underlying mechanisms for future drug development.     

Role of insulin in lipoprotein secretion by cultured rat hepatocytes

To study the effect of insulin on lipoprotein synthesis and secretion by the liver, apoprotein and lipid levels were measured in primary rat liver cell cultures grown on fibronectin-coated dishes. Triglycerides, phospholipids, apoprotein (apo) B, apo-E, and apo-C-III3 all accumulated in culture media linearly for periods up to 20 h. During incubations, cellular triglyceride contents increased slightly, while cellular apoprotein and phospholipid contents remained constant. In the absence of insulin, rates of accumulation in media of triglycerides, apo-B, apo-C-III3, and apo-E were 2.5 +/- 0.3 micrograms/mg and 33 +/- 5, 24 +/- 3, and 162 +/- 32 ng/mg cell protein per h, respectively. On gel permeation chromatography and density gradient ultracentrifugation, the majority of apoproteins in media were found to be associated with very low density lipoproteins (VLDL) and very little eluted or sedimented with albumin. Incubations in the presence of 50-800 microU/ml of insulin resulted in dose-dependent decreases of triglyceride, phospholipid, apo-B, and apo-E accumulation in the media, paralleled by increases in the cellular contents of these lipoprotein components. The inhibitory effects of insulin on secretion were reversible. Levels of apo-C-III3 and albumin were not affected by insulin. In addition to decreasing secretory rates, the proportion of apo-B, apo-E, and apo-C-III3 associated with VLDL also decreased after the addition of insulin. Concomitantly, the proportion of apo-B eluting with LDL and apo-C-III3, and apo-E eluting near albumin increased. Control experiments, in which exogenous 125I-VLDL or endogenously labeled [14C]VLDL were added to cultures, revealed that the insulin-induced differences in VLDL accumulation and the lipid association of media apoproteins were not due to differences in the processing of VLDL by cells cultured in the presence or absence of insulin. Therefore, it appears that insulin may inhibit the secretion of VLDL perhaps by reducing the intracellular association of lipids and apoproteins.