Recent Patents on Anti-Infective Drug Discovery - Volume 3, Issue 2, 2008

The hepatitis C virus (HCV) non-structural 5A (NS5A) protein is essential for viral RNA replication and may play a role in subverting host intracellular signaling pathways. Although no intrinsic enzymatic activity has been ascribed to NS5A, this proline-rich hydrophilic phosphoprotein is likely to exert its functions by interacting with viral and cellular factors. Recent studies using the HCV replicon cell culture system as a model for HCV RNA replication as well as for high-throughput screening of pharmacological inhibitors have revealed blockade of NS5A as a promising therapeutic strategy for the treatment of HCV. This review will summarize our progress in understanding the role of NS5A in HCV RNA replication and will introduce the most recent patents on inhibitors of NS5A.

To date, vaccination is an active area of investigation for its application to a great variety of human diseases including infections and cancer. In particular, naked-DNA vaccination has arisen as effective strategy in the preventive medicine field with promising future prospects. The ability of plasmid DNA to activate the humoural and the cellular arms of the immune system against the encoded antigen have resulted in intensive study of new strategies aimed at increasing the DNA vaccine immunogenicity. Nevertheless, plasmid-based vaccines emerged as a safer and advantageous alternative with respect to viral vector vaccines. Recent advances in both the immunological and biotechnological research field made it possible to enhance significantly the DNA vaccine potency. Most of these approaches are based on both the discovery of novel delivery systems and the implementation of plasmid constructs, achieved through genetic engineering. In this review, we will describe some of the most relevant patents issued in the last ten years, supporting the progress made in naked-DNA vaccination against infectious diseases.

Tuberculosis (TB) remains one of the leading infectious killers in the world. New anti-TB drugs and more effective drug combinations are urgently needed, particularly given the increasing incidence of drug-resistant TB and HIV-TB co-infection. This review describes the available mouse models of TB and describes their utility in the evaluation of new TB drug candidates and in the evaluation of the efficacy of new TB drug combinations. Some of the most recent patents on promising TB drug-candidates are also mentioned here.

Acinetobacter baumannii (AB) is a gram-negative organism that has emerged recently as a major cause of nosocomial infections, because of the extent of its antimicrobial resistance and its persistence in the hospital environment, where intensive care units are the place of greatest risk for acquiring AB. There is no treatment of choice for AB and it's treatment is based on clinical experience and in vitro susceptibility testing. Also, nowadays Acinetobacter resistance to carbapenems is common and isolates resistant to colistin and polymyxin B have been reported. Tigecycline, the 9-tert-butyl-glycylamido derivative of minocycline, exhibits a broad-spectrum of activity against numerous pathogens, including AB and several reports place it among the antimicrobials with lower MIC for AB. Tigecycline overcomes the two major mechanisms of resistance to tetracyclines (ribosomal protection and efflux), but tigecycline resistance emerging during therapy has been reported. Tigecycline efficacy has been demonstrated in clinical studies in skin and skin structure infections and in complicated intra-abdominal infections but, although it seems a good alternative for the treatment of AB infections, there is few evidence about its use in these cases and more clinical experience and adequate trials are needed. The present review shows the recent patents related to treatment by tigecycline in different AB infections.

Despite alarming data showing the ever increasing number of bacteria becoming resistant to different classes of antibiotics through various mechanisms, the carbapenems remain a unique class of antibiotics that possess the broadest spectrum against Gram-positive, Gram-negative, aerobic and anaerobic organisms. However, bacteria, such as methicillinresistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, carry mechanisms that can inactivate the carbapenems. This article gives a review of the carbapenems that are currently in clinical use as well as discusses the new carbapenems that are in clinical trials. These new carbapenems show promising potential to overcome the resistance against the presently existing carbapenems. The present article shows the recent patents using carbapenems as an effective antibiotic.

HIV infection is a serious but treatable disease, yet current treatment is limited by development of resistance and high rates of adverse drug reactions. Antiretroviral therapy is especially suitable for pharmacogenomic investigation as both drug exposure and treatment response can be reliably measured. Increasing knowledge about genes implicated in pharmacokinetics, mode of action, efficacy, and toxicity of drugs has already provided relevant results for clinical practice, for example: • The strong association of the abacavir hypersensitivity reaction with HLA-B*5701 permits testing patients for the allele, and if present avoiding the drug and therefore preventing the reaction. • Persons with the allele CYP2B6*6 present higher efavirenz “area under the curve” and have increased risk of neuropsychological toxicity. Additional gene variants are being discovered that influence the action of antiretroviral drugs. And, moreover, it is expected that larger-scale comprehensive genome approaches will profoundly improve the landscape of knowledge of HIV therapy in the future. The present article shows some recent patents related to the treatment of viral infections.

Recent advances in molecular biology have enhanced the understanding of the pathology of melanocytic lesions. Several targetable pathways, responsible for survival and apoptosis resistance in melanoma cells, have been described and current research has focused on mechanism inactivating these pathways. However, the therapeutic resistance of malignant melanoma remains the main limit that cast the poor prognosis of cutaneous melanoma. Current advances in high-resolution genome-wide technologies, as well as gene-specific mutational analysis, in conjunction with genetic and phenotypic analyses, improved animal models, may ultimately help to better define the seminal molecular events contributing to disease pathogenesis and ultimately identify more effective therapeutic targets. The focus of this review is to summarize the emerging patents in the treatment and diagnosis of melanoma related to the latest genetic models and bio-molecular discoveries.

Cefepime is a semi-synthetic fourth generation cephalosporin with broader Gram-positive and excellent Gramnegative bacterial coverage. Its extended anti-microbial activity and infrequent tendency to develop resistance makes it popular for treatment of infections due to multi-drug resistant organisms. It has good efficacy against β-lactamase and ESBL (extended spectrum β-lacatamase)-secreting pathogens, and it has shown great promise in management of children with severe and nosocomial infections. It possesses superior bactericidal action compared to other cephalosporins and is a cheaper and safe alternative to the carbapenems. It is well-tolerated but needs dose adjustments in newborns, and in children with renal insufficiency. Cefepime is a valuable antibiotic but it should be used judiciously as unnecessary, improper and prolonged use may lead to emergence of cefepime-insensitive bacteria and risk of drop in the efficacy of cefepime. Various recent patents of cefepime have been launched which deal with improvements in its preparation, and with its combinations with β-lactamase inhibitors and newer antibiotics such as linezolid. These developments may further augment the usefulness of cefepime in pediatric infections.

This study was performed to investigate the anthelmentic (nematodes) effect of garlic in Swiss albino mice naturally infected with Aspiculuris tetraptera. Natural infection was determined by the use of cellophane tape method on the perianal region and by the technique of centrifugal flotation of stool samples. The infected mice were divided into three groups; namely, Group 1: garlic treatment groups (n: 18), Group 2: positive control (treated with ivermectin, n: 19) and Group 3: untreated control group (n: 19). The mice in Group 1 were given orally freshly crushed garlic homogenates every day for 7 days. The animals in Group 2 were treated with ivermectin intramuscular at a dose of 0.2 mg/kg body weight. The mice in Group 3 received only serum physiologic orally. After 8 days of administrations, all mice were killed humanely using inhalation anaesthesia and then the parasites in the intestine were counted. It was observed that garlic and ivermectin were 91.24 % and 78.03 % effective against A. tetraptera in naturally infected mice, respectively. Results obtained from this study were compared statistically and differences were found to be significant (p<0.001). It was found that garlic was efficient along the duration of the treatment in mice. Garlic may be useful as an alternative treatment against nematode parasites in animals and human. This article includes a new research using Allium sativum anthelmentic effect on mouse and has been patented.

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