Current Medicinal Chemistry - Volume 9, Issue 8, 2002

A noninvasive DNA sampling method has been implemented collecting buccalmucosa cells by cotton wool swabs. An amount of 0.2-2 μg DNA per patient wasobtained after the phenol-extraction procedure and 0.2-2 ng DNA template wassufficient for PCR amplification of the polymorphic 48 basepair repeat region of dopaminereceptor D4 (DRD4) gene. PCR products were visualized during microfabricated electrophoretic separationby laser-induced fluorescent detection and automatic data registration. Initial data of genotyping drugdependentsubjects shows a relatively high ratio of heterozygotes, possessing either longer or shorter variantsbeside the common 4-repeat DRD4 allele.

Selective Serotonin reuptake inhibitors (SSRIs) have contributed to the major advances in the treatment of depression and other psychiatric diseases. This review summarises current knowledge concerning the SSRI class of drugs and discusses the importance of secondary pharmacology in the mechanism of action and effectiveness of these drugs. Particular attention is given to the emerging importance of the SSRI ‘plus’approach: where the serotonin reuptake receptor inhibition of a drug is supplemented by one or more other receptor interactions either by the same drug or by a combination therapy. This area of research has shed light on the pharmacological mechanisms of SSRI therapy and has the therapeutic usefulness of serotonin reuptake inhibition, especially in the area of depression. There are many new emerging SSRI ‘plus’ drugs, which address the pharmacological and pharmacokinetic issues of current therapies and these, are discussed in detail.

The use of peptidomimetics has emerged as a powerful means for overcoming the limitations inherent in the physical characteristics of peptides thus improving their therapeutic potential. A peptidomimetic approach that has emerged in recent years with significant potential, is the use of β-amino acids. β-Amino acids are similar to α-amino acids in that they contain an amino terminus and a carboxyl terminus. However, in β-amino acids two carbon atoms separate these functional termini. β-amino acids, with a specific side chain, can exist as the R or S isomers at either the α (C2) carbon or the β (C3) carbon. This results in a total of 4 possible diastereoisomers for any given side chain. The flexibility to generate a vast range of stereo- and regioisomers, together with the possibility of disubstitution, significantly expands the structural diversity of β-amino acids thereby providing enormous scope for molecular design. The incorporation of β-amino acids has been successful in creating peptidomimetics that not only have potent biological activity, but are also resistant to proteolysis. This article reviews the rapidly expanding applications of β-amino acids in the design of bioactive peptide analogues ranging from receptor agonists and antagonists, MHC-binding peptides, antimicrobial peptides and peptidase inhibitors. Given their structural diversity taken together with the ease of synthesis and incorporation into peptide sequences using standard solid-phase peptide synthesis techniques, β-amino acids have the potential to form a new platform technology for peptidomimetic design and synthesis.

Kidney toxicity comprises an important type of hospital admission with associated high costs. Large numbers of chemicals are involved comprising a wide variety of classes, both organic and inorganic. These include therapeutic drugs, radiocontrast agents, carcinogens, metals, abused drugs, and industrial chemicals. This review provides extensive evidence for participation of oxidative stress (OS) and electron transfer (ET) as a unifying framework. Application is made to all the main classes of nephrotoxins, in addition to many miscellaneous types. We believe it is not coincidental that the vast majority of these substances incorporate ET functionalities (quinone, metal complex, ArNO2, or conjugated iminium) either per se or in metabolites, potentially giving rise to reactive oxygen species (ROS) by redox cycling. Some categories, e.g., radiation, radiocontrast agents, and peroxides, appear to generate OS by non-ET routes. For completeness, other theories are also addressed a multifaceted approach appears the most logical. The ET-OS viewpoint should increase understanding and contribute to prevention, e.g., use of antioxidants.

Prostaglandin-H synthase exists in two isoforms, PGHS-1 and PGHS-2. PGHS-1 is present and is constitutively expressed in most cells and tissues, whereas PGHS-2 is mainly thought to mediate inflammation. Selective prostaglandin-H synthase-2 (or cyclooxygenase-2) inhibitors have been shown to be potent antiinflammatory agents with fewer side effects than currently marketed nonsteroidal antiinflammatory drugs (NSAIDs). This review addresses the main classes of the selective PGHS-2 inhibitors whose selectivity is documented by supporting PGHS-1 and PGHS-2 enzyme data. In addition, we also describe our experience in design, synthesis and pharmacological in vivo evaluation of new 1,2-benzodioxole derivatives as candidate of the selective PGHS-2 inhibitors, with special attention to molecular dynamics simulations of these derivatives attached to the active site of PGHS-2.

Docetaxel is a new semi-synthetic anticancer agent derived from bacatin III of the needles of the European yew Taxus baccata. Docetaxel has a novel mechanism of action since it binds to tubulin inducing its polymerization and promoting stable microtubule formation. Several differences exist between docetaxel and paclitaxel: (i) broader activity of docetaxel against freshly explanted human tumors than paclitaxel; (ii) a 2- fold higher affinity than paclitaxel (iii) 2.5-fold more potent than paclitaxel as an inhibitor of cell replication and (iv) docetaxel acts at the S-phase whereas paclitaxel at the G2 / M phases of the cell cycle.Preclinical and phase II studies revealed that docetaxel is active against NSCLC. In chemotherapy-naïve patients with NSCLC response rates ranged from 19% to 54% with a median duration of survival ranging from 6.3 months to 11 months, and 1-year survival ranging from 21% to 71%. Docetaxel as single agent provided a survival as well as a clinical benefit over BSC in untreated patients with NSCLC. Docetaxel has been efficiently combined with cisplatin (ORR 33%-46%), carboplatin (ORR 30%-48%), vinorelbine (ORR 20%-51%), gemcitabine (ORR 37%-47%), with a median survival ranging from 5-14 months. A preliminary analysis of a multicenter randomized trial comparing docetaxel / CDDP with docetaxel / gemcitabine revealed that the two regimens had comparable activity in terms, of response rates, duration of response, TTP and overall survival; however, the docetaxel / gemcitabine combination has a most favourable toxicity profile compared to docetaxel / CDDP.Docetaxel has also demonstrated radiosensitizing properties and encouraging results have been achieved in combination with irradiation. Finally, docetaxel has shown an important activity in previously-treated patients with NSCLC with ORR ranging from 16% to 25% with a median survival ranging from 7.2 months to 10.5 months. Randomized trials revealed that second-line docetaxel confers a survival benefit over either BSC or ifosfamide / vinorelbine in pretreated patients with NSCLC.

Non-small cell lung cancer (NSCLC) remains a fatal disease: the majority of patients are diagnosed as having metastases or advanced inoperable tumors. The activity of chemotherapy in NSCLC patients is low with objective response rarely complete and sustained. Cisplatin-based combinations are considered as the standard chemotherapy treatment. Recently., the introduction of new and less toxic chemotherapeutic agents., such as vinorelbine., has led investigators to research for active non-cisplatin-containing combinations to treat patients with advanced disease having as primary needs symptom relief and an acceptable quality of life. This review will focus on the pharmacological properties of vinorelbine and its role in adjuvant chemotherapy., in combined chemo-radiotherapy., in advanced disease and in the particular setting of the elderly. The oral use of vinorelbine will be among the future developments of this drug.

Non-small cell lung cancer (NSCLC) is a systemic illness. More than half of those patients who present with stage I-IIIA disease and are resected will experience distant relapse. Postoperative adjuvant chemotherapy has been evaluated in several randomized trials but the results of these trials have been inconclusive with increased survival reported in few trials. In resectable stage IIIA NSCLC the findings of three randomized trials have indicated that the survival of these patients is better with neoadjuvant chemotherapy plus surgical resection than with resection alone. Phase II trials using preoperative concurrent chemoradiotherapy have been carried out with encouraging results. The majority of patients with stage IIIA NSCLC require multimodality therapy if they are to achieve a 5-year survival.Combined modality treatment in locally advanced NSCLC continues to evolve and is a subject of ongoing research. One focus for present research is to integrate new active agents into the neoadjuvant setting. Another challenge is to find better treatment approaches in earlier stages of disease. Some data suggest that induction chemotherapy in stage I-II is feasible, does not appear to compromise surgery and yields high response rates. A further aim is to use molecular biological markers of malignancy to identify patients at highest risk of metastatic relapse.