Recent Patents on Anti-Infective Drug Discovery - Volume 2, Issue 3, 2007

Antibodies have a long, successful and yet bumpy history of effectiveness against viruses and bacteria. Polyclonal antibodies have a century-old history of being effective against some viruses and bacteria; recently, monoclonal antibodies (mAbs) have also shown success. The humanized mAb Synagis (palivizumab), which is still the only mAb against a viral disease approved by the U.S. Food and Drug Administration (FDA), has been widely used as a prophylactic measure against respiratory syncytial virus (RSV) infections in neonates and immune-compromised individuals. Patents and patent applications in anti-infective monoclonal antibodies reflect to certain degree the advancement of the relevant technologies, the room for improvement, and the potential for commercialization. This article reviews representative monoclonal antibody patents and patent applications that reflect the current state of monoclonal antibody development and its future prospects.

Sepsis is a complex, multifactorial syndrome that can develop into conditions of different severity, described as septic shock or severe sepsis. In spite of the great progress in understanding the mechanisms involved in the pathogenesis and management of sepsis, only a few therapeutic strategies were able to show a decrease in the mortality from septic shock. Although sepsis consists on a systemic inflammatory response, the anti-inflammatory therapies have failed to improve the outcome of critically ill patients. Here the role of gastrin-releasing peptide in immune processes is reviewed and the data that have prompted the recent patent for GRP receptor antagonists RC-3095 as a therapeutic agent on inflammatory conditions are described.

After 10 years absence (between 1990-1999) of new antifungal agents and intensive research being introduced into clinical practice, 3 new azoles (Voriconazole - Pfizer, Posaconazole - Schering-Plough, Ravuconazole - Bristol-Myers Squibb) and 3 new echinocandins (Caspofungin - MSD, Anidulafungin - Astellas-Pfizer, Micafungin - Fujisawa) were patented. The question raises if we really need 6 new antifungal agents in such a short time? Perhaps, they are not here because we need them all, but because of at least fifteen years effort of many groups of investigators who successfully discovered, proved and introduced these agents to the drug market. Voriconazole (2000), Posaconazole (2005), Ravuconazole (2007) from the group of azoles; and Caspofungin (2002), Anidulafungin (2004) and Micafungin (2006) from the group of echinocandins, with unique mode(s) of action (cell wall synthesis inhibition) different from polyens, azoles, antimetabolites and new monoclonal antifungal antibody (Mycograb), were approved and introduced to the clinical practice. This paper contains some useful information regarding the recent patents on antifungal drug discovery, their current position in the strategy of treatment of invasive fungal infections is briefly reviewed.

Streptococcus pneumoniae affects millions of people worldwide. It is responsible for a wide spectrum of serious illnesses such as pneumonia, meningitis and bacteraemia. The highest rate of pneumococcal disease (and the highest mortality) occurs in young children, as well as in the elderly and the immunocompromised patients. Identification of S. pneumoniae in diagnostic procedures may significantly improve thanks to the descripion of new PCR-derived techniques. Vaccination based on the polysaccharidic capsule, together with benzylpenicillin-derived drugs, constitute the current choices to tackle pneumococcal diseases. However, the wide serotype diversity of S. pneumoniae and the emergence of antibiotic-resistant strains is fostering the development of new methods to fight this microorganism. In this sense, patents documenting the use of novel antibiotics of the fluoroquinolone or tetracycline families have recently been described. Moreover, surface-associated proteins are receiving an increasingly special attention, as they are synthesized by most pneumococcal strains and play an important role in virulence. New patented protein-based vaccines take into consideration these polypeptides. In this article we present the main relevant characteristics of this pathogen and review the most recent methods that have been patented for the prevention, diagnostic and treatment of the pneumococcal diseases.

The approach to the treatment of Helicobacter pylori infection has changed during the last years. In fact, during the last decade, the success rate of usual eradication regimens, based on a proton pump inhibitor plus clarithromycin associated with amoxicillin or metronidazole, declined from over 90% to about 80%, a critical threshold under which the eradication rate is considered unsatisfactory, according to current guidelines. This finding is mainly due to the raising prevalence of clarithromycin resistance, which is in turn linked to the widespread use of this antibiotic for respiratory tract infections. Therefore, obtaining a personal history negative for a previous use of macrolides is now mandatory, before administering clarithromycin-based antibiotic therapy. Should history data be uncertain, local resistance rates (if available) may be considered, with levels higher than 20% precluding the use of clarithromycin. In this case, alternative antibiotic combinations, previously used in the rare instances of failure of clarithromycin-based therapy, should be used. We examined also the possible additional beneficial effect of some novel non antibiotic agents such as lactoferrin, probiotics and natural substances. Other advances in the treatment of the infection are represented by the discovery that some extragastric disorders such as unexplained iron deficiency anemia and idiopathic thrombocytopenic purpura, may be causally linked to Helicobacter pylori, and that eradication therapy may lead to their regression in many cases. Finally, some “gray areas” (nonulcer dyspepsia, concomitant use of nonsteroidal anti-inflammatory drugs) which are the subject of debate as far the indication to treatment is concerned, have been discussed.

This paper reviews the inhibition of various enzymes by neuroleptics, anti-mycotics, antibiotics and other drugs on three species of human pathogenic amoebas, mainly Entamoeba histolytica, Acanthamoeba polyphaga and Naegleria fowleri, and their antiproliferative effects. A recent patent registered by Philip relates to the combination of an antibacterial formulation and antifungal agent for producing a therapeutically effective quantity of an antimicrobial that is suitable for suppressing or treating fungal growth. The rationale behind this patent focused on essential and valid targets with a description of the main pathogenic characteristics of these amoebas. The study of new targets, such as trypanothione and trypanothione reductase, and the drug effects of selected agents were arranged into six main groups: A) Inhibition of disulfide reducing enzymes by neuroleptics, antimycotics and antibiotics; B) Comparative evaluation of the efficacies of several drugs with antiproliferative activities; C) Inhibition of the enzymes for the synthesis of trypanothione, such as ornithine decarboxylase, spermidine synthase and trypanothione synthetase; D) Inhibition of the glycolytic enzyme PPi-dependent phosphofructokinase (PFK) from Entamoeba and Naegleria by pyrophosphate analogues, different from the host enzyme; E) Inhibition of enzymes secreted by these parasites to invade the human host, for example cysteine proteinases; and F) Inhibition of encystment pathways and cyst-wall assembly proteins.

Oral tolerance is a method to alter the immune response towards orally administered antigens. The use of oral tolerance as a method of therapy for various immune mediated processes, including infectious, inflammatory and neoplastic entities, has been the subject of much research in recent years. The therapeutic potential of modifying the immune response by oral ingestion of diseaseassociated antigens is gaining recognition, and is being assessed in diverse settings. Studies have shown that anti-viral immunity can be modulated by oral feeding of viral proteins in animal models, and recent data suggest that this can also be achieved in humans. Oral administration of HBV-envelope proteins to patients with chronic HBV infection has been shown to be beneficial, not only for alleviation of immune-mediated liver injury but also for enhancement of effective anti-viral immunity. Several patents described the use of oral administration of viral particles as a mean of altering the anti viral immune response. Natural killer T (NKT) lymphocytes, a subset of regulatory T lymphocytes, can induce pro-inflammatory or anti-inflammatory immune responses. This subset of cells appears to be crucial for induction of tolerance by several interventions, including oral tolerance. This review summarizes the data on induction of tolerance towards viruses, and on the role of NKT regulatory cells in this setting. Several patents described the use of this method a treatment mode for viral infections and the use of NKT cells in this settings.

Malaria is the number one disease in the world responsible for 1-3 million deaths each year. The world wide number of malaria patients is estimated at 400 to 900 million. Approximately one third of the world's population lives in malaria-endemic areas, including Central and South America, Asia, and Africa. Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae are malaria parasites responsible for infecting humans. Mosquitoes that carry malaria parasites have become resistant to insecticides, and the deadliest parasites have become resistant to previously effective antimalarial drugs such as chloroquine, quinine and other clinically used agents. Because of the widespread incidence of malaria in certain parts of the world and because of the increasing parasite resistance to standard anti-malarial agents, there is an urgent need for introducing new effective drugs. This review presents the recent patents that reveal development of novel antimalarial drugs.

Burkholderia mallei and Burkholderia pseudomallei are the causative micro-organisms of Glanders and Melioidosis, respectively. Although now rare in Western countries, both micro-organisms have recently gained much interest because of their unique potential as bioterrorism agents. This paper reviews the epidemiology, pathogenesis, diagnosis and treatment of Melioidosis and Glanders. Recent patents relating to these micro-organisms, especially potential vaccines, are presented. Continued research and development is urgently needed, especially in regard to rapid and accurate diagnosis of melioidosis and glanders, efficacious therapy and primary and secondary prevention.

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