Current Drug Therapy - Volume 3, Issue 1, 2008

Some physiopathological processes involved in the genesis of diseases could suggest the necessity of designing bioligands or prototypes that aggregate, in only one molecule, dual pharmacodynamical properties, becoming able to be recognized by two elected bioreceptors. This approach can have distinct aspects and, when a novel ligand or a prototype acts in two elected targets belonging to the same biochemical pathway, e.g. arachidonic acid cascade, it receives the denomination of dual or mix agent. On the other hand, if these two targets belong to distinct biochemical routes and both are related to the same disease, we can characterize the agents able to modulate it as symbiotic ligands or prototypes. In the present work, we provide some examples and applications of the molecular hybridization concept for the structural design of new symbiotic ligands and prototypes, especially those applied in the treatment of chronic-degenerative disorders.

Postoperative nausea and vomiting (PONV) are two of the commonest and most distressing complications of general anesthesia and surgery, with a remarkably high incidence after gynecological laparoscopic surgery. Numerous antiemetics have been studied for the prevention of PONV after gynecological laparoscopic surgery. Traditional antiemetics, including butyrophenones (e.g., droperidol) and benzamide (e.g., metoclopramide), are used for preventing PONV. The available non-traditional antiemetics for the prophylaxis against PONV are propofol, dexamethasone, and ephedrine. Serotonin receptor antagonists (ondansetron, granisetron, and dolasetron), compared with traditional antiemetics, are highly effective for PONV prophylaxis. None of the available antiemetics is entirely effective, perhaps because most of them act through the blockade on one type of receptor. There is a possibility that combined antiemetics with different sites of activity would be more effective than one drug alone for preventing PONV Combination antiemetic therapy with ondansetron and droperidol or dexamethasone is highly effective in the prevention of PONV. P6 acupoint injection is non-pharmacological technique and is as effective as droperidol for preventing PONV. Management of PONV after gynecological laparoscopic surgery depends on the prophylaxis. If the prophylactic therapy fails, treatment would be required. Ondansetron is effective in the treatment of established PONV. Knowledge regarding antiemetics is necessary to completely prevent and treat PONV in women undergoing gynecological laparoscopic surgery.

Gram-negative bacteria contain lipopolysaccharides (LPS), which are generally considered to be an endotoxin that has negative impacts on humans. There have been very few therapeutic drugs developed that contain LPS. Recently, it has been reported that hygienic improvements have decreased exposure to LPS, and this is correlated with an increase in allergenic diseases. Lack of exposure to LPS may adversely affect the immune balance in the body. LPS is the substance that has the greatest known effect in activating macrophages which play a central role in the innate immune system. We have hypothesized the existence of a network formed by tissue macrophages and have termed this putative communications network a macrophage network. We studied certain edible Gram-negative bacteria that have a long history of use in traditional food production, in order to discover ways to improve and/or maintain health. In 1991 we discovered that the LPS of Pantoea agglomerans (named IP-PA1 by us) was a macrophage-activating substance that could be obtained from water extracts of wheat flour. LPS is also part of the make-up of cells of other well known Gram-negative bacteria used in food processing such as Acetobacter (vinegar, yogurt) and Xanthomonas (xanthan gum). This demonstrates that humans have a long history of consuming Gram-negative bacteria and LPS. In this manuscript, we discuss the potential for utilizing IP-PA1 and other LPS from edible Gram-negative bacteria. Forms of LPS can be used in various fields, such as in health food, to prevent and improve metabolic syndromes and allergies. They can also be used in feedstuffs for stockbreeding and in aquatic culture as defenses against infection where they can replace antibiotics or chemical substances.

Opioids remain an important cornerstone and the most effective mainstay analgesics for acute and terminal cancer pain treatments. Effective analgesia is obtained in the majority of cancer pain patients with the application of fairly straightforward rational treatment algorithms using opioids as the main therapy. A major barrier to be overcome, however, is that chronic pain is often not viewed as a physical illness worthy of treatment. Many studies demonstrating that specific changes occur in the peripheral and central nervous systems of patients with chronic pain provide the rationale for changing the approaches to chronic pain management and instituting more aggressive and comprehensive treatment. This review describes the role of opioids in the treatment of cancer pain, including a brief overview of cancer pain syndromes, essential aspects of opioid therapy, opioid pharmacology, opioid rotation, properties of the individual opioids, and management of common side effects of opioids. As understanding of the pharmacology of this class of drugs becomes more sophisticated, clinicians may anticipate dosage-limiting adverse effects and variations in individual response.

The purpose of this review is 1) to introduce our studies of newly-discovered mammalian DNA polymerase inhibitors; 2) to elucidate their precise molecular action based on three-dimensional structural models and comparisons with the spatial positioning on the smallest DNA polymerase, β, of specific amino acids binding to them; and 3) to document their promising clinical anti-tumor activity. Multiple DNA polymerases have been identified in eukaryotes, and recent investigations have revealed at least sixteen types. An effective approach to study the in vivo roles of each of these is to use selective DNA polymerase inhibitors to distinguish between them. Using a broad natural product screening approach, we have identified many different types of novel DNA polymerase inhibitor which we have exploited to analyze the structure and function of the DNA polymerases. The aim was not only to understand the function of each inhibitor in vitro, but also to develop a drug design strategy for cancer chemotherapy agents. We have found a class of such DNA polymerase inhibitors, the sulfoquinovosylacylglycerols (SQAG), which could represent clinically-promising anti-tumor agents. We discussed about the mechanism of the anti-tumor action, and suggested new concept about cancer chemotherapy.

With increasing antibiotic resistance reported worldwide, there is a great interest in the development of new antibacterial agents for the treatment of severe skin and skin structure infections (SSSIs). SSSIs mainly involve Grampositive pathogens. Although many of older antibiotics remain effective, new drug development remains crucial owing to the increase in drug resistance among the major Gram-positive pathogens. Since 1999 new antibacterial agents have entered the market or are being evaluated in clinical trials for the treatment of SSSIs. These agents have novel mechanism of action and sufficient improvements in potency to overcome resistance. Linezolid, quinupristin-dalfopristin, daptomycin and tigecycline have been approved by the FDA for the treatment of SSSIs. Other antimicrobials (dalbavancin, oritavancin, telavancin) are currently in clinical development for this indication. This review focuses on the chemistry, microbiology, pharmacology, clinical efficacy and safety of several novel antibacterial agents for the treatment of SSSIs.

Purpose: Development of a controlled delivery of metoprolol tartrate using the synergistic activity of locust bean gum (LBG) and Xanthan gum (X). Method: Metoprolol tartrate granules were prepared using different ratios of drug: gum (X, LBG and mixture of XLBG). To increase the flowability and compressibility of the granules, and to prevent its adhesion to punch and die, magnesium stearate and talc were added to the granules in 1:2 ratio respectively before punching. The tablets were analysed for their hardness, friability, % assay and in vitro release study was carried out. Results: The release of drug from a gelatinous swollen mass, which controls the diffusion of drug molecules through the polymeric material into aqueous medium. The XLBG matrices show precise controlled release than the X and LBG matrices because of burst effect and fast release in case of X and LBG alone respectively. FTIR and DSC thermogram studies confirmed that there was no chemical interaction between drug and polymers in XLBG formulation. First pass effect of metoprolol tartrate can be avoided by this formulation. However, according to the similarity factor (f2) XLBG3 was most similar to Meto-ER as the reference standard. Conclusion: The XLBG matrices leads to more precise result than X and LBG matrices due the utilization of synergistic interaction between two biopolymers and lower average size of this allowing a uniformity with the tablet hydration in dissolution media.