Current Pharmaceutical Design - Volume 9, Issue 12, 2003

In the last decades of the 20th century, infectious diseases have re-emerged as a significant public health problem in the developed world. However, the available anti-infective armamentarium has proven to be alarmingly insufficient to combat many of the microbes that cause these diseases, such as drug resistant microbes, microbes for which therapy is not available or ineffective because of underlying host immune impairment, and microbes that only cause disease in the setting of impaired immunity but are not pathogens in normal individuals. Hence, there is an urgent need for new approaches to the treatment of infectious diseases that can increase the efficacy of anti-infective therapy and bolster the immune response to microbial agents in immunocompromised hosts, circumvent rising rates of antimicrobial drug resistance and be rapidly developed to fight emerging epidemics. Immune therapy, which encompasses pathogen-specific and non-pathogen specific modalities designed to augment or restore host immunity against disease causing microbes, are poised to play an important part in modern anti-infective therapy. Our growing understanding of host-microbe interaction and mechanisms of protective immunity have allowed for an increasingly rational approach to the design of immune based therapeutic modalities. As part of this effort, it is important to remember that the origin of modern anti-infective therapy was serum therapy, a pathogen-specific immune therapeutic modality. In this paper, we review the historical underpinnings and present and future applications of immune therapy for infectious diseases in light of current challenges to the field.

Establishing local, national, and global surveillance networks for monitoring the dissemination of antimicrobial resistance and detecting the emergence of new resistance mechanisms has been recommended by the American Society for Microbiology Task Force on Antibiotic Resistance and other national organizations. While the need to develop and deploy surveillance strategies cannot be argued, the design and implementation of effective regional, national, and global surveillance networks is a daunting task with geographic, participatory, logistic, and funding challenges. Using information technology to capture, combine, collate, and analyze daily clinical microbiology laboratory data would seem to be a far more robust and logical approach to surveillance than traditional centralized studies that generally focus on only a few bacterial species or on isolates from a single body site. Information technology allows long-term, continuous tracking of antimicrobial resistance trends among large numbers of isolates over a broad range of species, and across entire regions or countries. The rationale for wanting to use networks of clinical laboratories for surveillance is obvious: susceptibility data are generated every day by thousands of laboratories located around the world, and most of these laboratories perform antimicrobial susceptibility testing on the bacterial species that pose the greatest public health problems. By virtue of information technology, large volumes of data can readily be managed and stored to allow timely and thorough analysis on institutional, regional, national, and global levels.

The relationship between urinary infections and stone formation has been recognized since antiquity and it has been over a century since bacterial degradation of urea was postulated to cause struvite stones. Specific therapy for urease-producing bacteria, such as urease-inhibitors and antibiotics, has allowed for treatment for this subset of urinary stones. Future directions for research include development of novel urease-inhibitors and chemicals to enhance the protective glycosaminoglycan layer.An improved understanding of the pathogenesis of calcium-based stones has led to the discovery of potential roles for nanobacteria and Oxalobacter formingenes. Methods of altering intestinal regulation of oxalate by reintroduction of lactic acid bacteria may significantly impact the treatment of calcium oxalate stones.The use of catheters, both urethral and ureteral, is common in the urinary tract and is associated with significant morbidity, primarily from associated infections. Catheters to prevent bacterial colonization and formation of biofilms have been created using various coatings, including ciprofloxacin, hydrogel, and silver. Use of these types of catheters may minimize infections and encrustation inherent with their placement in the urinary tract.

Antibiotics developed over the past quarter century have greatly improved toxic to therapeutic ratios compared to older agents. This is due to both a wider spectrum of in vitro antibacterial activity and less frequent side effects. In combination with once daily dosing and nearly complete bioavailability of some newer agents, the better risk to benefit ratios have led to empiric antibiotic use in many situations even when bacterial infections are not likely. Many newer antibiotics are not often considered toxic, although their side effects have been documented in medical literature, and several antibiotics that were considered very safe have been removed from the market or their use severely restricted within a relatively short time after their introduction. An understanding of the frequency and mechanism of unintended effects helps physicians minimize them, treat them quickly and effectively when they occur, and even avoid them. Drug interactions and potential adverse effects of β-lactam antibiotics, penicillins, cephalosporins, and carbapenems, are presented.

The implantation of prosthetic devices is an ever-increasing practice in urologic surgery. The most common devices are penile prostheses, artificial urinary sphincters, synthetic pubovaginal slings, and bone anchors used for pelvic floor reconstruction and incontinence surgery. While their efficacy has been supported over time, infection and rejection are severe complications. Explantation of the entire prosthetic device has been the standard treatment of such complications, often necessitating long-term antibiotics and prolonged recovery before future reimplantation. The dense inflammatory response associated with prosthetic surgery may obliterate tissue planes and further complicate reoperative efforts. These factors support the need for effective antibiotic prophylaxis, with the goal of preventing bacterial seeding of the prosthesis during implantation. Antibiotic regimens should be effective against biofilm-forming bacteria, especially S. epidermidis and P. aeruginosa, and vancomycin should be a mainstay. Prevention of intraoperative infection by treating existing skin and urinary tract reservoirs and employing strict sterile technique cannot be overemphasized. While data is scant, it appears that routine prophylaxis prior to dental procedures, in patients with urologic prostheses, is unwarranted; however, if the patient is immunocompromised or has severe comorbidities, prophylaxis should be employed.

The structurally related neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) are released within the lymphoid organs following antigenic stimulation, and modulate the function of inflammatory cells through specific receptors. In activated macrophages, VIP and PACAP inhibit the expression at both mRNA and protein level of pro-inflammatory cytokines and chemokines, through effects on de novo expression or nuclear translocation of a number of transcription factors, i.e. NFkB, CREB, c-Jun, JunB, and IRF-1. In addition, VIP and PACAP promote Th2-type, and inhibit Th1-type responses in vivo and in vitro, through several mechanisms, including preferential survival of Th2 effectors and subsequent generation of Th2 memory cells. The function of VIP / PACAP as “macrophage deactivating factors” appears to be responsible for their protective effect in vivo in models of septic shock. Both deactivation of macrophages and inhibition of Th1-type responses appear to be responsible for the beneficial effect of VIP/PACAP in models of Th1-type autoimmune diseases such as rheumatoid arthritis.

Vasoactive intestinal peptide (VIP), secretin and pituitary adenylate cyclase-activating peptide1-38 (PACAP1-38) are widely distributed amphipathic mammalian neuropeptides that exert diverse biological effects in target tissues located distant from their site of release. However, the half-life of exogenously-administered VIP, secretin and PACAP1-38 in the bloodstream is relatively short (minutes) due to rapid degradation and inactivation. This seemingly paradoxical behavior suggests the presence of an innate system(s) that protects the peptides from degradation in vivo.To this end, VIP, secretin and PACAP1-38 express distinct biophysical properties that once released may protect them from degradation in biological fluids. They self-aggregate at low (nanomolar) concentrations and interact avidly with biomimetic phospholipid monolayers and bilayers at physiological concentrations. The latter evokes conformational transition of the VIP, secretin and PACAP1-38 molecules from predominantly random coil in aqueous solution to a-helix, the preferred peptide conformation for receptor interaction, in phospholipids. These features increase peptide stability and amplify bioactivity in vivo.Collectively, these data suggest the presence of an endogenous targeted delivery platform for VIP, secretin and PACAP1- 38. This innate system may constitute a novel molecular recognition paradigm that could also apply to other amphipathic neuropeptides. Importantly, the distinct behavior of VIP, secretin and PACAP1-38 in the presence of phospholipids could be exploited to develop novel, long-acting therapeutic formulations of these peptides.

Bombesin (BBS) is proved to have a wide variety of the pharmacologic effects, including effects on the release of gastrointestinal hormones and control of gastrointestinal motility. More recently, the role of BBS in tumor growth, cellular proliferation and inflammation has attracted attention. There is evidence that increased BBS receptor expression may be considered as a specific marker for small-cell lung cancer, colorectal adenocarcinoma, gastric and pancreatic cancer, prostate, ovarian and breast cancer, neuroblastoma, renal cell carcinoma, malignant melanoma and thyroid carcinoma. BBS expression was found to be correlated with the histological grade of the tumor. Similarly, BBS treatment significantly improves the healing of chronic gastric ulcers and ameliorates the severity of burn- or colitis-induced gut injury. Although there is much complexity still to be elucidated to understand fully the physiologic and pathologic roles of BBS-like peptides several clinical or experimental trials have addressed that circulating or tissue levels of BBS-like peptides or their receptor expression may be used as diagnostic or prognostic markers of neoplastic disease, and incorporation of BBS receptor antagonists in the treatment of human cancer could provide substantial benefit to the cancer patients. Moreover, trophic, anti-ulcerogenic and anti-inflammatory actions of exogenous BBS make this peptide a potential supplement in minimizing or reversing tissue damage against several injurious challenges. In conclusion, based on the evidence summarized herein, related to the mitogenic and anti-inflammatory effects of BBS-like peptides, further investigations are needed to derive the benefit of BBS-like peptides in pharmacologic strategies.

In recent years, the simple paradigm of adipose tissue as merely a fat store is rapidly evolving into a complex paradigm of this tissue as multipotential secretory organ, partitioned into a few large depots, including visceral and subcutaneous location, and many small depots, associated with a variety of organs in the human body. The major secretory compartment of adipose tissue consists of adipocytes, fibroblasts, and mast cells. These cells, using endocrine, paracrine and autocrine pathways, secrete multiple bioactive molecules, conceptualized as adipokines or adipocytokines. This review examines current information in adipobiology of various diseases besides obesity and related diseases such as type 2 diabetes, metabolic syndrome, and cardiovascular disease. Finally, we emphasize the possibilities for adipokine-targeted pharmacology in adiponectin (Acrp30, apM1, AdipoQ, GBP28), angiotensin II, estrogens, nerve growth factor, tumor necrosis factor-a, and also adipose mast cells.