The therapeutic potential of lactoferrin

Lactoferrin (Lf), a natural defence iron-binding protein, is present in exocrine secretions that are commonly exposed to normal flora: milk, tears, nasal exudate, saliva, bronchial mucus, gastrointestinal fluids, cervicovaginal mucus and seminal fluid. Additionally, Lf is produced in polymorphonuclear leukocytes and is deposited by these circulating cells in septic sites. A principal function of Lf is that of scavenging non-protein-bound iron in body fluids and inflamed areas so as to suppress free radical-mediated damage and decrease accessibility of the metal to invading bacterial, fungal and neoplastic cells. Adequate sources of bovine and recombinant human Lf are now available for development of commercial applications. Among the latter are use of Lf in food preservation, fish farming, infant milk formula and oral hygiene. Other readily accessible body compartments for Lf administration include skin, throat and small intestine. Further research is needed for possible medicinal use in colon and systemic tissues. Although Lf is a natural product and should be highly biocompatible, possible hazards have been documented.     

The therapeutic potential of lactoferrin

Lactoferrin (Lf), a natural defence iron-binding protein, is present in exocrine secretions that are commonly exposed to normal flora: milk, tears, nasal exudate, saliva, bronchial mucus, gastrointestinal fluids, cervicovaginal mucus and seminal fluid. Additionally, Lf is produced in polymorphonuclear leukocytes and is deposited by these circulating cells in septic sites. A principal function of Lf is that of scavenging non-protein-bound iron in body fluids and inflamed areas so as to suppress free radical-mediated damage and decrease accessibility of the metal to invading bacterial, fungal and neoplastic cells. Adequate sources of bovine and recombinant human Lf are now available for development of commercial applications. Among the latter are use of Lf in food preservation, fish farming, infant milk formula and oral hygiene. Other readily accessible body compartments for Lf administration include skin, throat and small intestine. Further research is needed for possible medicinal use in colon and systemic tissues. Although Lf is a natural product and should be highly biocompatible, possible hazards have been documented.     

The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential

Identification of the enigmatic nociceptin/orphanin FQ peptide (N/OFQ) in 1995 represented the first successful use of reverse pharmacology and led to deorphanization of the N/OFQ receptor (NOP). Subsequently, the N/OFQ-NOP system has been implicated in a wide range of biological functions, including pain, drug abuse, cardiovascular control and immunity. Although this could be considered a hurdle for the development of pharmaceuticals selective for a specific disease indication, NOP represents a viable drug target. This article describes potential clinical indications and highlights the current status of the very limited number of clinical trials.     

PKC412--a protein kinase inhibitor with a broad therapeutic potential

The staurosporine derivative PKC412 was originally identified as an inhibitor of protein kinase C (PKC) and subsequently shown to inhibit other kinases including the kinase insert domain receptor (KDR) (vascular endothelial growth factor receptor, VEGF-R2), the receptor of platelet-derived growth factor, and the receptor for the stem cell factor, c-kit. PKC412 showed a broad antiproliferative activity against various tumor and normal cell lines in vitro, and was able to reverse the Pgp-mediated multidrug resistance of tumor cells in vitro. Exposure of cells to PKC412 resulted in a dose-dependent increase in the G2/M phase of the cell cycle concomitant with increased polyploidy, apoptosis and enhanced sensitivity to ionizing radiation. PKC412 displayed a potent antitumor activity as single agent and was able to potentiate the antitumor activity of some of the clinically used cytotoxins (Taxol and doxorubicin) in vivo. The combined treatment of PKC412 with loco-regional ionizing irradiation showed significant antitumor activity against tumors which are resistant to both ionizing radiation and chemotherapeutic agents (dysfunctional p53). The finding that PKC412 is an inhibitor of the VEGF-mediated cellular signaling via inhibition of KDR and PKC in vitro is consistent with the in vivo inhibition of VEGF-dependent angiogenesis in a growth factor implant model. Orally administered PKC412 also strongly inhibited retinal neovascularization as well as laser-induced choroidal neovascularization in murine models. In summary, PKC412 may suppress tumor growth by inhibiting tumor angiogenesis in addition to directly-inhibiting tumor cell proliferation via its effects on PKC and/or other protein kinases. PKC412 is currently in Phase I clinical trials for treatment of advanced cancer as well as for the treatment of ischemic retinopathy.     

Metvan: a novel oxovanadium(IV) complex with broad spectrum anticancer activity

Among the 25 bis(cyclopentadienyl)vanadium(IV) and 14 oxovanadium(IV) compounds synthesised and evaluated for anticancer activity, bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) (metvan) was identified as the most promising multitargeted anticancer vanadium complex with apoptosis-inducing activity. At nanomolar and low micromolar concentrations, metvan induces apoptosis in human leukaemia cells, multiple myeloma cells and solid tumour cells derived from breast cancer, glioblastoma, ovarian, prostate and testicular cancer patients. It is highly effective against cisplatin-resistant ovarian cancer and testicular cancer cell lines. Metvan is much more effective than the standard chemotherapeutic agents dexamethasone and vincristine in inducing apoptosis in primary leukaemia cells from patients with acute lymphoblastic leukaemia, acute myeloid leukaemia or chronic acute myeloid leukaemia. Metvan-induced apoptosis is associated with a loss of mitochondrial transmembrane potential, the generation of reactive oxygen species and depletion of glutathione. Treatment of leukaemia cells from acute lymphoblastic leukaemia, acute myeloid leukaemia and chronic acute myeloid leukaemia patients with metvan inhibits the constitutive expression as well as the gelatinolytic activities of matrix metalloproteinase-9 and -2. Treatment of human malignant glioblastoma and breast cancer cells with metvan at concentrations > 1 microM is associated with a nearly complete loss of the adhesive, migratory and invasive properties of the treated cancer cell populations. Metvan shows favourable pharmacokinetics in mice and does not cause acute or subacute toxicity at the dose levels tested (12.5 - 50 mg/kg). Therapeutic plasma concentrations > or = 5 microM, which are highly cytotoxic against human cancer cells, can be rapidly achieved and maintained in mice for at least 24 h after intraperitoneal bolus injection of a single 10 mg/kg non-toxic dose of metvan. Metvan exhibits significant antitumour activity, delays tumour progression and prolongs survival time in severe combined immunodeficient mouse xenograft models of human malignant glioblastoma and breast cancer. The broad spectrum anticancer activity of metvan together with favourable pharmacodynamic features and lack of toxicity warrants further development of this oxovanadium compound as a new anticancer agent. Metvan could represent the first vanadium complex as an alternative to platinum-based chemotherapy.     

A novel somatostatin mimic with broad somatotropin release inhibitory factor receptor binding and superior therapeutic potential

A rational drug design approach, capitalizing on structure-activity relationships and involving transposition of functional groups from somatotropin release inhibitory factor (SRIF) into a reduced size cyclohexapeptide template, has led to the discovery of SOM230 (25), a novel, stable cyclohexapeptide somatostatin mimic that exhibits unique high-affinity binding to human somatostatin receptors (subtypes sst1-sst5). SOM230 has potent, long-lasting inhibitory effects on growth hormone and insulin-like growth factor-1 release and is a promising development candidate currently under evaluation in phase I clinical trials.     

Kidney protective potential of lactoferrin: pharmacological insights and therapeutic advances

Kidney disease is becoming a global public health issue. Acute kidney injury (AKI) and chronic kidney disease (CKD) have serious adverse health outcomes. However, there is no effective therapy to treat these diseases. Lactoferrin (LF), a multi-functional glycoprotein, is protective against various pathophysiological conditions in various disease models. LF shows protective effects against AKI and CKD. LF reduces markers related to inflammation, oxidative stress, apoptosis, and kidney fibrosis, and induces autophagy and mitochondrial biogenesis in the kidney. Although there are no clinical trials of LF to treat kidney disease, several clinical trials and studies on LF-based drug development are ongoing. In this review, we discussed the possible kidney protective mechanisms of LF, as well as the pharmacological and therapeutic advances. The evidence suggests that LF may become a potent pharmacological agent to treat kidney diseases.     

Pregabalin may represent a novel class of anxiolytic agents with a broad spectrum of activity

The present study examines the effect of pregabalin (previously S-Isobutylgaba and CI-1008) in two distinct rat models of anxiety. Pregabalin binds with high affinity and selectivity to the alpha(2)delta subunit of voltage dependent calcium channels (VDCC). Its corresponding R-enantiomer (R-isobutylgaba) is approximately 10 fold weaker. Pregabalin dose-dependently induced anxiolytic-like effects in both the rat conflict test and elevated X-maze with respective minimum effective doses (MED) of 3 and 10 mg kg(-1). In contrast, R-isobutylgaba only showed activity at the highest dose of 100 mg kg(-1) in the conflict test. These data indicate that pregabalin may possess clinical utility as a novel anxiolytic agent and demonstrates the importance of the alpha(2)delta subunit of VDCC in the mediation of anxiety related behaviours.     

Ceftobiprole: a new broad spectrum cephalosporin

Ceftobiprole, formerly designated BAL9141/Ro 63-9141, is a pyrrolidinone-3-ylidene-methyl cephalosporin with demonstrated in vitro activity against MRSA, Enterococcus faecalis, Enterobacteriaceae and Pseudomonas aeruginosa. Ceftobiprole has a low potential for inducing chromosomal AmpC β-lactamases but it is hydrolyzed by most extended spectrum β-lactamases and metallo-β-lactamases. Glomerular filtration is predominantly responsible for removal of the free drug from the systemic circulation. The efficacy of ceftobiprole in the treatment of complicated skin and ski-structure infections has been recently demonstrated in two Phase III randomized clinical trials involving 1600 patients. Two other Phase III clinical trials to assess ceftobiprole's efficacy in community-acquired pneumonia and nosocomial pneumonia have also concluded. While the drug met the noninferiority criteria for community-acquired pneumonia and nosocomial pneumonia involving non-ventilator associated pneumonia, ceftobiprole was less effective than the comparator in ventilator associated pneumonia subjects. Ceftobiprole was well tolerated with a safety profile consistent with the cephalosporin class of antibiotic. The most frequent drug-related adverse event was dysgeusia. Ceftobiprole is intended for use in the hospital for the treatment of infections that frequently involve β-lactam-resistant Gram-negative and Gram-positive organisms.     

HHT: a rare disease with a broad spectrum of clinical aspects

HHT is an autosomal dominant disease characterised by diffuse muco-cutaneous and visceral telangiectases in potentially all organs. Mutations in two different genes identify HHT type 1 and HHT type 2: endoglin located on chromosome 9q33-q34 and ALK-1 or ACVRL1 on chromosome 12q13, respectively. The existence of a third locus has also been hypothesised. HHT-1 is considered a more severe form of the disease with an earlier onset of epistaxis and telangiectases and a higher prevalence of pulmonary arteriovenous malformations than that found in HHT-2 subjects. Usually, a typical HHT patient has epistaxis, muco-cutaneous telangiectases and GI bleeding in later life, even though this clinical scenario represents only one of the possible HHT patterns. In fact, vascular malformations often remain silent until the onset of a severe complication, which frequently is the first clinical manifestation of HHT. The lung and brain are of particular concern because each may contain clinically silent lesions that can result in sudden morbidity and mortality. At present, awaiting the availability of genetic testing, only an expert in the clinical patterns and diagnostic imaging of HHT can permit a definite diagnosis in individuals at high risk for the disease.     

Sphingolipid metabolism and leukemia: a potential for novel therapeutic approaches

Since the discovery and initial characterizations of sphingolipids (SLs) in 1884, extensive research has established that these molecules not only are structural components of eukaryotic membranes but they are also critical bioactive lipids involved in fundamental cellular processes such as proliferation, differentiation, apoptosis, inflammation, migration, and autophagy. Altered SL metabolism has been observed in many pathological conditions including hematological malignancies. Thus, targeting the SL pathway to induce lipid changes to counteract specific pathologies is currently being pursued as a promising, novel therapeutic intervention. In this review, we discuss the general characteristics of the SL pathway, illustrating those features relevant to the understanding of the role of SLs in leukemia, and we address novel SL-targeting therapeutic approaches.     

Trifluoperazine: a broad spectrum bactericide especially active on staphylococci and vibrios.

Trifluoperazine showed some significant antimicrobial activity when tested against 293 strains from two Gram-positive and eight Gram-negative genera. Minimum inhibitory concentrations of the drug were measured using an agar dilution technique. Forty six of 55 strains of Staphylococcus aureus were inhibited by 10-50 microg/ml of trifluoperazine. This drug also inhibited strains of Shigella spp., Vibrio cholerae and V. parahaemolyticus at a concentration of 10-100 microg/ml. Other bacteria including Pseudomonas spp. were moderately sensitive to trifluoperazine. In the in vivo studies this compound offered significant protection to Swiss albino mice at a concentration of 30 microg/mouse (P<0.001) when challenged with 50 median lethal dose of Salmonella typhimurium NCTC 74.     

MicroRNAs： a novel class of potential therapeutic targets for cardiovascular diseases

Currently, cardiovascular diseases remain one of the leading causes of morbidity and mortality in the world, indicating the need for innovative therapies and diagnosis for heart disease. MicroRNAs (miRNAs) have recently emerged as one of the central players in regulating gene expression. Numerous studies have documented the implications of miRNAs in nearly every pathological process of the cardiovascular system, including cardiac arrhythmia, cardiac hypertrophy, heart failure, cardiac fibrosis, cardiac ischemia and vascular atherosclerosis. More surprisingly, forced expression or suppression of a single miRNA is enough to cause or alleviate the pathological alteration, underscoring the therapeutic potential of miRNAs in cardiovascular diseases. In this review we summarize the key miRNAs that can solely modulate the cardiovascular pathological process and discuss the mechanisms by which they exert their function and the perspective of these miRNAs as novel therapeutic targets and/or diagnostic markers. In addition, current approaches for manipulating the action of miRNAs will be introduced.     

The therapeutic potential of novel anticoagulants

For several decades, conventional anticoagulant therapy has been based on indirect inhibition of coagulation factors with heparin and warfarin (coumadin). Although used widely and effectively, heparin and warfarin display liabilities which have prompted the development of new anticoagulants over the last two decades. The first to be developed was a series of low molecular weight heparins (LMWHs). Their favourable pharmacokinetic profiles and risk/benefit ratios led to widespread use in Europe and more recently, approval for their use in the USA. Paralleling the development of LMWHs, but lagging behind in terms of clinical development, has been the pursuit of a different strategy focused on direct rather than indirect inhibition of enzymes in the coagulation cascade. In contrast to heparin, LMWHs, or other glycosaminoglycans, direct inhibitors, exert their effects independent of either antithrombin III (ATIII) or heparin co-factor II (HCII) and more effectively inhibit clot-bound thrombin or FXa. Highly potent, selective (versus other serine proteases), direct thrombin and FXa inhibitors have been identified and isolated from natural sources, such as leeches, ticks and hookworms. The recombinant forms and analogues of these natural proteins have been produced using molecular biology techniques, i.e., rHirudin, Hirulogs, recombinant tick anticoagulant peptide (rTAP), recombinant antistasin (rATS) and recombinant nematode anticoagulant factor (rNAP-5). The design of novel structures or the modification of existing chemicals has led to the synthesis of many non-peptide, low molecular weight inhibitors of thrombin and FXa. Some of them are orally active and may be suitable for long-term clinical use. In addition, considerable progress has been made in developing specific TF/VIIa complex inhibitors. The anticoagulation properties of the new agents have been and are being characterised in experimental studies. Some of them have been advanced to large scale clinical trials and their effectiveness (and sometimes relative ineffectiveness compared with conventional therapy) in arterial and venous thromboembolic disorders has been demonstrated. These novel anticoagulents are curently being tested or will for their validity and potential as new antithrombotic agents acting via direct enzyme inhibition. In doing so, it is hoped that the clinician will in future be able to turn to proven specific anticoagulant interventions, targeted at each respective thrombotic state.     

The therapeutic potential of novel anticoagulants

Conventional anticoagulant therapy has been based on indirect inhibition of coagulation factors with heparin and warfarin. These agents display liabilities prompting the development of new anticoagulants over the last two decades. The first to be developed was a series of low molecular weight heparins(LMWHs). Their favourable pharmacokinetic profiles and risk/benefit ratios led to widespread use in Europe and, more recently, approval for their use in the USA. Paralleling the development of LMWHs has been the pursuit of a different strategy focused on direct rather than indirect inhibition of enzymes in the coagulation cascade. In contrast to heparin, LMWHs, or other glycosaminoglycans, direct inhibitors exert their effects independent of either antithrombin III (ATIII) or heparin cofactor II (HCII) and more effectively inhibit clot-bound thrombin or FXa. Highly potent, selective (versus other serine proteases)direct thrombin and FXa inhibitors have been identified and isolated from natural sources, such as leeches, ticks and hookworms. The recombinant forms and analogues of the senatural proteins have been produced using molecular biology techniques, i.e., rHirudin, Hirulogs, recombinant tick anticoagulant peptide (rTAP), recombinant antistasin (rATS) and recombinant nematode anticoagulant peptide-5 (rNAP-5). The design of novel structures or the modification of existing chemicals has led to the synthesis of many non-peptide, low molecular weight inhibitors of thrombin and FXa. Some of them are orally active and may be suitable for long-term clinical use. In addition, considerable progress has been made in developing specific TF/VIIa complex inhibitors. The anticoagulation properties of the new agents are being characterised in experimental studies. Some of them have been advanced to large scale clinical trials and their effectiveness, and sometimes relative ineffectiveness,in arterial and venous thromboembolic disorders has been demonstrated. They are being tested for their potential as new antithrombotic agents that act via direct enzyme inhibition. Thus,the clinician should in future be able to target different thrombotic conditions with proven, specific anticoagulant interventions.     

Voriconazole: review of a broad spectrum triazole antifungal agent

Voriconazole is a second-generation triazole antifungal agent, structurally derived from fluconazole with an extended spectrum of activity against a wide variety of yeasts and moulds. Developed for the treatment of life-threatening fungal infections, it appears to be an effective therapy option for invasive aspergillosis, fluconazole-resistant candidiasis and refractory or less-common invasive fungal infections. It is available for both oral and intravenous administration and is characterised by an acceptable safety and tolerability spectrum.     

Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger

Melatonin was found to be a potent free radical scavenger in 1993. Since then over 800 publications have directly or indirectly confirmed this observation. Melatonin scavenges a variety of reactive oxygen and nitrogen species including hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide and peroxynitrite anion. Based on the analyses of structure-activity relationships, the indole moiety of the melatonin molecule is the reactive center of interaction with oxidants due to its high resonance stability and very low activation energy barrier towards the free radical reactions. However, the methoxy and amide side chains also contribute significantly to melatonin's antioxidant capacity. The N-C=O structure in the C3 amide side chain is the functional group. The carbonyl group in the structure of N-C=O is key for melatonin to scavenge the second reactive species and the nitrogen in the N-C=O structure is necessary for melatonin to form the new five membered ring after melatonin's interaction with a reactive species. The methoxy group in C5 appears to keep melatonin from exhibiting prooxidative activity. If the methoxy group is replaced by a hydroxyl group, under some in vitro conditions, the antioxidant capacity of this molecule may be enhanced. However, the cost of this change are decreased lipophility and increased prooxidative potential. Therefore, in in vivo studies the antioxidant efficacy of melatonin appears to be superior to its hydroxylated counterpart. The mechanisms of melatonin's interaction with reactive species probably involves donation of an electron to form the melatoninyl cation radical or through an radical addition at the site C3. Other possibilities include hydrogen donation from the nitrogen atom or substitution at position C2, C4 and C7 and nitrosation. Melatonin also has the ability to repair damaged biomolecules as shown by the fact that it converts the guanosine radical to guanosine by electron transfer. Unlike the classical antioxidants, melatonin is devoid of prooxidative activity and all known intermediates generated by the interaction of melatonin with reactive species are also free radical scavengers. This phenomenon is defined as the free radical scavenging cascade reaction of the melatonin family. Due to this cascade, one melatonin molecule has the potential to scavenge up to 4 or more reactive species. This makes melatonin very effective as an antioxidant. Under in vivo conditions, melatonin is often several times more potent than vitamin C and E in protecting tissues from oxidative injury when compared at an equivalent dosage (micromol/kg). Future research in the field of melatonin as a free radical scavenger might be focused on: 1), signal transduction and antioxidant enzyme gene expression induced by melatonin and its metabolites, 2), melatonin levels in tissues and in cells, 3), melatonin structure modifications, 4), melatonin and its metabolites in plants and, 5), clinical trials using melatonin to treat free radical related diseases such as Alzheimer's, Parkinson's, stroke and heart disease.     

Difficidin and oxydifficidin: novel broad spectrum antibacterial antibiotics produced by Bacillus subtilis. II. Isolation and physico-chemical characterization

The isolation of difficidin (1) and oxydifficidin (2) from fermentation broth of Bacillus subtilis ATCC 39320 and the physico-chemical characterization of these labile antibiotics are described. The structures of the compounds represent a new class of antibiotics, characterized as highly unsaturated 22-membered macrolide phosphates. Difficidin and oxydifficidin undergo reversible thermal isomerization to 3 and 4 respectively. Biological evaluation of the isomers is presented.     

HR 810, a new parenteral cephalosporin with a broad antibacterial spectrum

3-[(2,3-Cyclopenteno-1-pyridinium)-methyl]-7-[2-syn-methoximino-2-(2-aminothiazol-4-yl)-acetamido]-ceph-3-em-4-carboxylate (HR 810) is a new cephalosporin derivative with an extremely broad antimicrobial spectrum. It is active against all bacterial species of clinical relevance, including strains which are frequently resistant towards cephalosporins of the third generation.