Current Drug Targets - Volume 4, Issue 1, 2003

Adverse reactions to drugs are a major problem in pharmacotherapy. About 1 / 6 of all side-effects are thought to be drug-induced immune-mediated reactions. It is well established that T and B cells recognize a drug if it is bound as hapten to carrier molecules. However, the model does not explain many T cell-mediated reactions with chemically inert compounds. This review will first discuss the hapten-carrier concept of drug-presentation to T cells and the currently used methods to predict an allergenic potential of a drug. It then introduces our new model of drug-uptake- and processing-free HLA class II-restricted T-cell response termed “direct metabolism-independent T-cell stimulation”. This led us to an other new concept: the pharmacological interaction of drugs with immunological receptors, namely the MHC and T-cell receptors. Additionally, we focus on certain conditions of non-covalent drug presentation by antigen presenting cells and on the molecular recognition of MHC / peptide / drug complexes by specific T-cell receptors. Finally, we discuss the clinical relevance of drug-specific T cells, namely that T cells seem to exert a certain pathology (e.g. drug-induced exanthema or pustular eruptions) depending on their function. These findings, which are based on the analysis of clinical drug allergy, have major implications for our understanding of T-cell biology and on the concept how to test and predict the allergenic potential of a drug.

To provide an overview of the epidemiologic parameters of emerging adverse effects associated with antiretroviral therapy for human immunodeficiency virus (HIV) disease.All available antiretroviral agents are associated with significant adverse drug effects. Of particular interest are newly emerging suspected adverse drug effects which were not generally noted in pre-marketing trials nor captured under current standard clinical care practices. Suspected antiretroviral toxicities meeting these criteria include: HIV-associated lipodystrophy which can include peripheral lipoatrophy, lipohypertrophy and metabolic abnormalities, hyperlactatemia and lactic acidosis, and metabolic bone abnormalities such as decreased bone mineral density, osteoporosis and osteonecrosis. Results of prospective and observational studies reported to date suggest that these abnormalities, while aetiologically complex, are likely attributable to treatment factors and may be intricately interrelated. The medical management of these symptoms remains unsatisfactory given the unexplored efficacy of traditional approaches in the HIV positive population. While the pathogenic mechanism of these disorders remains obscure, a theory of tissue-specific mitochondrial toxicity has been proposed.With the continued introduction of novel therapies and standard treatment with combination therapy, new adverse events will continue to emerge among persons being treated for HIV disease. Beyond their immediate clinical implications, these events may contribute to changing patterns of antiretroviral utilisation including therapy initiation, adherence and cessation.

In this review we focus on the role of the membrane lipids in multidrug resistance and its modulation. Results of the research performed in recent years indicate the importance of lipid phase playing active role in many membrane processes. Along with the alterations of lipid membrane composition of cancer cells (with respect to the normal ones) the resulting changes of the biophysical membrane properties are discussed. Next we describe the general features of multidrug resistance phenomenon paying a special attention to the role of lipids and alterations of lipid membrane composition in MDR cells. Taking into account the phase separation properties of sphingolipids the importance of membrane heterogeneity (presence of caveole and lipid rafts) is emphasised. On the basis of vacuum cleaner hypothesis of drug transport proteins action we discuss the importance of lipid bilayer as medium in which diffusion of drugs takes place. Considering the membrane fluidity and its influence on the integral proteins activity, we underline the role of balance between the passive cellular influx and active efflux of the drug molecules. Finally the effects exerted on membranes by different kinds of multidrug resistance modulators (chemosensitizers) are described. In this part we discuss the influence of verapamil, phenothiazine derivatives, tamoxifen and chosen flavonoids on the biophysical properties of membrane lipids. Some further consequences of the alteration of membrane state are also considered.

Multidrug resistance (MDR) to antitumor agents represents a significant challenge to effective chemotherapy. The use of MDR modulators is a promising approach to overcome the undesired MDR phenotype. The more effective MDR modulators are urgently needed for clinical use. This review focuses on literatures published in 1998-2001.

Cancer chemoprevention is a new approach in the management of cancer. Traditional cytotoxic chemotherapeutic approaches cannot cure most advanced solid malignancies. Chemoprevention can be defined as the use of non-cytotoxic drugs and natural agents to block the progression to invasive cancer. Chemoprevention can either prevent DNA damage that initiates the neoplastic transformation process or reverses the progression of pre-invasive lesions. Epidemiological observations, experimental evidence from animal carcinogenesis models, knock-out models, cancer cell lines and clinical trials have shown the efficacy of this approach. Recent advances in our understanding of carcinogenesis have led to the synthesis of new drugs that target specific receptors. Non-steroidal anti-inflammatory drugs target the prostaglandin pathway. The identification of the role of cyclooxygenase-2 in epithelial carcinogenesis led to the synthesis of selective cyclooxygenase-2 inhibitors (Celecoxib). Celecoxib was subsequently approved for the prevention of colon polyps in familial adenomatous polyposis after the completion of a randomized clinical trial. The large chemoprevention clinical trial with the selective estrogen receptor modulator, tamoxifen, showed the benefit of tamoxifen in the prevention of breast cancer in high-risk women. Retinoids and rexinoids target the retinoid receptors and have a role in chemoprevention of aerodigestive, hepatic and cervical neoplasia. Selenium, an inhibitor of the glutathione peroxidase system, is being tested in the chemoprevention of prostate cancer and lung cancer. The different isoforms of vitamin E (tocopherols) may be chemopreventive. Recent evidence indicates that g-tocopherol may be a more powerful chemopreventive than the a-tocopherol. The review details the rationale, experimental and clinical evidence and the drug targets of the chemopreventive agents that are currently in various phases of clinical development.

A group of oxytocinergic neurons originating in the paraventricular nucleus of the hypothalamus and projecting to extrahypothalamic brain areas (e.g. hippocampus, medulla oblongata and spinal cord) control penile erection. Activation of these neurons by dopamine and dopamine agonists, excitatory amino acids (N-methyl-D-aspartic acid) or oxytocin itself, or by electrical stimulation leads to penile erection, while their inhibition by GABA and GABA agonists or by opioid peptides and opiate-like drugs inhibits this sexual response. The activation of oxytocinergic neurons in the paraventricular nucleus by dopamine, oxytocin and excitatory amino acids is apparently secondary to the activation of nitric oxide (NO) synthase. NO in turn activates, by a mechanism that is as yet unidentified, the release of oxytocin from oxytocinergic neurons in extrahypothalamic brain areas. Several peptide analogues of hexarelin, a growth hormone releasing peptide, also induce penile erection when injected into the paraventricular nucleus and, to a lesser extent, systemically, apparently by acting on a specific receptor to activate oxytocinergic neurons as shown for the above drugs and oxytocin. Paraventricular oxytocinergic neurons and mechanisms similar to those reported above are also involved in the expression of penile erection in physiological contexts, namely when penile erection is induced in the male by the presence of an inaccessible receptive female, which is considered a model for psychogenic impotence in man, as well as during copulation. These findings show that paraventricular oxytocinergic neurons projecting to extra-hypothalamic brain areas and to the spinal cord are a likely target for the treatment of erectile dysfunction of central origin.

There is increasing evidence that steroid hormones derived from vitamin D act through classical nuclear receptors (nVDR), as well as specific binding sites on the plasma membrane of target cells that are coupled to signal transduction systems. These sites are referred to as M embrane A ssociated, R apid R esponse S teroid (MARRS) binding proteins or complexes. In the case of the seco-steroid 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3], the two ‘receptors’ appear to be different proteins with distinct affinities for vitamin D analogs. These differences may be useful in a number of clinical situations. In treating leukemias, it would be useful to promote the actions of the nVDR for differentiation to macrophages while blocking the 1,25D3-MARRS in intestine, which might contribute to the undesirable side effect of hypercalcemia. In contrast, stimulation of the intestinal 1,25D3-MARRS would be desirable in the elderly, since this signalling system appears to decline with age in model systems, potentially contributing to diminished intestinal absorption of calcium and associated bone loss. Bone itself is known to have osteoblasts that respond to 1,25(OH)2 D3 through both nVDR and 1,25D3-MARRS mechanisms. Both systems are required for bone-building activities. Osteoclasts lack the nVDR, but may become activated through the 1,25D3-MARRS, offering another site of drug intervention in the treatment of osteoporosis. Finally, during tooth mineralization, immunohistochemical studies reveal an absence of the nVDR and a marked appearance of the 1,25D3-MARRS. In addition to our growing knowledge of 1,25(OH)2 D3, the physiological actions of a lesser studied metabolite of vitamin D, 24,25(OH)2 D3, are coming to light and may offer additional targets for pharmaceutical modulation.

Phytoestrogens exert different estrogen receptor-dependent and -independent pharmacological actions. They share with estrogens several structural features and show greater affinity for the newly described estrogen receptor-beta. Many hope that phytoestrogens can exert the cardioprotective, anti-osteoporotic and other beneficial effects of the estrogens used in hormone replacement therapy in postmenopausal women without adversely affecting the risk of thrombosis and the incidence of breast and uterine cancers.Although there are many positive indications that phytoestrogens can fulfil this role, it remains to be proven: controlled interventional studies are lacking, and many questions remain unanswered. This review analyzes, on the basis of available experimental and epidemiological studies, the pros and cons of phytoestrogen use and describes the potential tissue targets and mechanisms of action of phytoestrogens.