Current Pharmaceutical Biotechnology - Volume 4, Issue 4, 2003

Immunotherapy with the anti-CD20 monoclonal antibody rituximab has been shown in clinical trials to be effective in the treatment of both indolent and aggressive non-Hodgkin's lymphomas (NHL). Recent studies have demonstrated improved clinical benefit with extended dose and maintenance therapies in patients with indolent lymphomas and chronic lymphocytic leukemia. Rituximab's label was recently expanded to include treatment of bulky disease, retreatment of patients previously treated with rituximab, and an eight-week extended treatment schedule. Rituximab has also been effectively combined with chemotherapy, resulting in higher response rates and longer response durations in randomized trials in patients with aggressive lymphoma. Studies continue to evaluate and expand the role of rituximab in the treatment of NHL, including its use in combined immunotherapy approaches and autologous stem cell transplant as well as in the treatment of autoimmune disorders. Radioimmunotherapy with the rituximab and ibritumomab tiuxetan (Zevalin) regimen was recently approved for the treatment of relapsed or refractory low-grade, follicular or CD20+ transformed NHL, including rituximab refractory follicular NHL. The regimen is delivered on an outpatient basis over the course of a week. Studies are currently exploring sequential dose therapy, radioimmunotherapy with rituximab maintenance, and ibritumomab tiuxetan radioimmunotherapy as part of autologous stem cell transplant. Current understanding of the mechanisms of action of rituximab and the use of rituximab and ibritumomab tiuxetan in patients with indolent and aggressive NHL will be discussed.

Intravenous immunoglobulins (IVIg) have been used as a substitutive treatment for primary and secondary humoral immune deficiencies for several decades. In the meantime, increased experience has been acquired with IVIg in the management of other inflammatory and autoimmune disorders, such as Kawasaki's disease, idiopathic thrombocytopenic purpura, dermatomyositis or Guillain-Barre syndrome, in which several clinical trials have demonstrated its efficacy. In other pathologies, IVIg seem to be effective, although further studies are required. Nevertheless, the exact mechanism by which IVIg exert their beneficial actions is not completely understood. According to in vitro as well as in vivo data, several mechanisms of action have been proposed: Fc receptor blockade, idiotype-antiidiotype interactions, neutralisation of bacterial toxins and superantigens, competitive inhibition of complement activation, down-regulation of B- and T-cell function, enhancement of pathogenic autoantibodies clearance, modulation of soluble products, apoptosis blockade via Fas receptor and administration of soluble products which could interfere with the immune response. Both IVIg structure, as well as its obtention from pooled human plasma donors, seem to play an important role in IVIg immunomodulatory properties. Thus, the objective of the present article is to review the current evidence upon the mechanisms of action of IVIg.

Isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) are the precursors for all isoprenoid compounds. Two pathways are found in Nature for their biosynthesis. The mevalonate (MVA) pathway is found in eukaryotes, algae, archae and some gram-positive bacteria. Gram-negative bacteria, plants and some gram-positive bacteria utilize the methyl erythritol phosphate (MEP) pathway. The distribution and the orthogonal nature of the pathways make the MEP pathway an attractive new target for antibiotics and herbicides. The MEP pathway is essential for bacterial viability. Inhibitors to the MEP pathway represent a “dual-use technology” because potential targets include potential biological warfare agents in addition to common human pathogens. The CDC has three categories designated for Biological Diseases / Agents. Three of the six entities designated as the highest priority (Category A) are organisms that utilize, or appear to utilize, the MEP pathway. Among the 12 second highest priority agents (Category B) listed, 8 are organisms that appear to utilize the MEP pathway. Common human pathogens that can be targeted include the organisms responsible for peptic ulcers, tuberculosis, malaria, food safety threats, and sexually transmitted diseases. There is so far only one inhibitor reported that specifically blocks the MEP pathway and is being investigated clinically. This compound, fosmidomycin, has been shown to be somewhat effective in treating Plasmodium falciparum, the parasite responsible for malaria. We foresee that new MEP pathway inhibitors will open up an entirely new class of antibiotics. An MEP pathway intermediate has also been shown to be the most potent γδ T cell activator.

Chemotherapy agents induce apoptotic cell death and loss of cell proliferation in the intestinal crypt epithelium, resulting in intestinal mucosal damage called “mucositis”. Small intestinal mucositis is characterized structurally by crypt loss and villus atrophy, and functionally by absorptive and barrier impairments. The increased use of chemotherapy in cancer treatment and the clinical importance of the intestinal mucositis as a common side effect have stimulated more active research into understanding the pathophysiology of intestinal mucositis and developing agents for preventing or treating this condition. Rodent studies have shown that, following the chemotherapy-induced initial apoptosis and loss of crypt cell proliferation, many different growth factors or their receptors are upregulated locally at the crypts, preceding or coinciding with the epithelial hyperproliferative repair response. Aiming to reduce crypt cell apoptotic sensitivity to cytotoxic chemotherapy and / or to enhance crypt epithelial proliferative repair, several exogenous growth factor treatments have been tested, either preclinically and / or clinically, and are showing promise for their efficacy or safety in preventing or treating chemotherapy-induced mucositis. These tested growth factors include keratinocyte growth factor, interleukin- 11, transforming growth factor beta, milk-derived growth factor extract, macrophage / granulocyte colony stimulating factors, and glucagon-like peptide 2. Further research on the basic and discovery levels and subsequent translational studies are needed to understand more about chemotherapy-induced intestinal mucositis and to identify candidates of growth factors or other agents that will potentially prevent or treat chemotherapy-induced mucositis more effectively, specifically, safely, and practically in chemotherapy patients.

Opioids have long been thought to act exclusively within the central nervous system. An increasing number of studies recently reported the existence of opioid receptors outside the central nervous system and therefore suggested that opioids are also able to produce analgesic effects in the periphery. Such effects are particularly prominent under painful inflammatory conditions, both in animals and in humans. During inflammatory processes, opioid receptors are transported from dorsal root ganglia towards the peripheral sensory nerve endings. At the same time, immune cells containing endogenous opioid peptides accumulate within the inflamed tissue. Environmental stimuli (e.g. stress) as well as releasing agents (e.g. corticotropin releasing factor, cytokines) can liberate these opioid peptides to interact with the neuronal opioid receptors and elicit local analgesia. The inflammation-induced activation of opioid production and the release of endogenous opioids from immune cells may lead to novel approaches for the development of peripherally acting analgesics. Clinical investigation now focuses on the development of new peripheral opioid agonists as well as on ways to stimulate the endogenous analgesic system in order to induce effective peripheral analgesia with reduced central side effects typically associated with opioids.