Current Drug Therapy (v.6, #4)

Tetracyclines are the second most common antibiotic family in the human and veterinary medicine usage,worldwide. These groups of drugs originally developed as antibiotics with antibacterial activity are able to exert biologicaleffects different from their antimicrobial action. The actions occur by multiple mechanisms and include inflammatorycytokine regulation, antioxidation, inhibition of leucocyte chemostasis and activation. Several studies have reported antiinflammatoryand anti-apoptopic effects of tetracyclines with neuroprotection.This review summarizes the available data supporting the non-antimicrobial actions of tetracyclines linked to reactiveoxygen species. We extend our discussion to the potential applications of the drugs for combining with otherpharmacological molecules for neurodegenerative diseases such as Parkinson’s disease, Huntington’s disease,Alzheimer’s disease, multiple sclerosis and other linked to reactive oxygen species.Participation of tetracyclines in inhibition of matrix metalloproteinase, scavenging of reactive oxygen species and theiranti-inflammatory and anti-apoptopic effects as examples of beneficial effects are presented.Particular attention is focused on the reactive oxygen species and reactive nitrogen species linked with pathogenesis ofsome human diseases as overproduction of these species results in oxidative stress leading to damage of cell structures.

Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: A Review by Rajashree Hirlekar, Harshal Garse, Vilasrao Kadam (240-250).
Solid lipid nanoparticles (SLN) were developed at the beginning of the 1990s as an alternative carrier systemto emulsions, liposomes and polymeric nanoparticles. SLN are defined as aqueous colloidal carrier systems in the sizerange of 50-1000nm made up of solid lipid matrix. SLN combine advantages of the traditional systems but avoid some oftheir major disadvantages. They exhibit major advantages such as modulated release, improved bioavailability, protectionof chemically labile molecules, cost effective excipients, improved drug incorporation and wide application spectrum.As a novel type of lipid nanoparticles with solid matrix, the nanostructured lipid carriers (NLC) are presentedwhich overcomes the problems associated with SLN such as expulsion of drug from the matrix over the period of time.This paper presents an overview about the selection of the ingredients, different ways of production, drug incorporationand release, characterization of quality and structure, sterilization, storage, stability and applications of SLN & NLCdispersions.

Advanced Vectors for Gene Delivery by Rajashree Hirlekar, Pramod Jagtap, Vilasrao Kadam (251-262).
Gene therapy is an important tool in the treatment of many diseases involving malfunctioning of deoxyribonucleic acid (DNA). Development of various techniques for efficiently transferring and expression of recombinant DNAor ribonucleic acid (RNA) at target site is a significant challenge. Viral vectors which have been used classically have anumber of restrictions due to their induced toxicity and immunogenicity, the limited size of DNA that can be carried, thelack of specificity and the high cost of production. To overcome these problems nonviral vectors like nanoparticles,dendrimers, molecular conjugates, liposomes, microbubbles etc. are being explored. This review encompasses the detailsof these nonviral vectors.

Pharmaceutical and Biomedical Applications of Interpenetrating Polymer Network by Neelam Jain, Pramod Kumar Sharma, Arunabha Banik, Amit Gupta, Vineet Bhardwaj (263-270).
Interpenetrating polymer network (IPN) based drug delivery system is basically designed to deliver drugs at apredetermined rate for a desired period of time with minimum fluctuation. Due to its physical and biologicalcharacteristics such as enhanced solubility of hydrophobic drugs, excellent swelling capacity, imparting drug stability inthe formulations, biodegradability, biocompatibility, weak antigenecity and targeting of drug in a specific tissue make itsuitable for drug delivery as well as biomedical applications. IPN based drug delivery is primarily used for controlledrelease of drugs. These systems are also used for tissue engineering such as cartilage scaffolds, bone substitutes etc. Thepurpose of this review article is to cover recent advances on IPN based on its utilization as drug delivery matrix system forpharmaceutical applications as well as in tissue engineering for biomedical applications. Consequently, IPN is regarded asone of the most valuable novel biomaterials.

Use and Results of Antidepressant Treatment: Patients’ Perception by Maria-Jose Martin-Vazquez, Mauro Garcia-Toro, Francisco Campoamor, Antonio Pareja, Iratxe Aguirre, Joan Salva, Miquel Roca (271-277).
AIMS AND METHOD: Response to antidepressants depends on patients’ use. Our objective is to take a look overantidepressants use in a real sample. In determining relevant factors, data were gathered from 550 patients, currentlytaking antidepressants. The questionnaire included two items, patients’ perceived difficulty of following treatment andlevel of acknowledged non-compliance, which may be considered as a way of approximating the patients’ real use oftreatment. RESULTS: compliance was poor among the less educated, living in rural areas and receiving concomitanttreatment. Use perceived as good in 61.5%, better in affective disorder (69.8%). Patients without response present higherincidence of non-compliance (49.1%). It should be mandatory to explore and reinforce a good use of antidepressants inclinical settings, particularly if the indication is not an affective disorder and in case of multiple treatments, rural setting,and lower educational level. If response is inadequate, compliance must be revised specially.

Hepatoma-Derived Growth Factor in Carcinogenesis and Cancer Progression by Hideji Nakamura, Hirayuki Enomoto (278-285).
Hepatoma-derived growth factor (HDGF) has been purified and cloned from a human hepatocellular carcinoma(HCC) cell line. HDGF and five HDGF-related proteins form a new protein family with a significant homology in theiramino terminus containing a PWWP domain. HDGF is a unique growth factor with nuclear localization signals, anddominantly located in the nucleus. HDGF translocates to the nucleus and displays a mitogenic activity. Exogenous HDGFalso stimulates the cellular proliferation via a signal pathway through MAP kinase activation from cell membrane binding.HDGF is strongly expressed in cancer cells. HDGF over-expression in NIH3T3 cells induced tumorigenesis and that inHCC cells enhanced the growth of tumors in vivo. HDGF stimulated the migration, tubule formation and proliferation ofhuman endothelial cells as well as the proliferation of smooth muscle cells, thus indicating that HDGF is an angiogenicfactor. HDGF induced tumorigenesis in vivo through both its direct angiogenic activity and induction of VEGF. Thedown-regulation of endogenous HDGF in cancer cells suppressed their proliferation, invasive activity and anchorageindependentgrowth in soft agar in vitro. HDGF is involved in an anti-apoptotic pathway. The higher expression of HDGFshows a more malignant potential for cancer progression. Clinically, HDGF may be a useful prognostic factor fordetermining the disease-free and/or overall survivals in patients who have undergone a resection of several types of cancerby immunohistochemical studies. This review will describe the current knowledge of HDGF in carcinogenesis and cancerprogression, and evaluate its possible clinical utility in cancer regulation.

Sepsis, a progressive immunological, metabolic and cardiovascular disorder, is a major cause of morbidity andmortality in Intensive care units (ICU) worldwide. Models simulating sepsis, such as endotoxemia, peritonitis, cecalligation and puncture, provide substantial molecular and cellular evidence for structural and functional damage to cardiacmyocytes during sepsis. Clinical evidence suggests abnormal left ventricular impairment and cardiac contractiledysfunction during sepsis. Norepinephrine (NE), a clinically approved positive inotrope traditionally used in ICUs forhemodynamic support, can also cause increased lactate levels and cardiomyocyte toxicity during early stages of sepsis.Our recent results demonstrated that sepsis-induced myocyte dysfunction (SIMD) is associated with decreased time ofdeformation and loss of contractile activity in the myocytes. The data further support the involvement of the apoptoticpathway, particularly mitochondrial-mediated intrinsic apoptosis cascade in sepsis-induced myocardial dysfunction. Therecent data from our laboratory demonstrated that SIMD is a potentially life threatening event which can be exacerbatedby the use of positive inotropes such as NE, which are ideally used in the management of sepsis.

Efficacy of Duloxetine in Patients with Chronic Pain Conditions by Vladimir Skljarevski, Shuyu Zhang, Smriti Iyengar, Deborah D’Souza, Karla Alaka, Amy Chappell, Joachim Wernicke (296-303).
The primary objective of this study is to review the efficacy of duloxetine in treating chronic pain using theInitiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations for clinicalsignificance across chronic pain states. These include pain intensity, patient ratings of overall improvement, physicalfunctioning, and mental functioning. This review comprised the side-by-side analyses of 12 double-blind, placebocontrolledtrials of duloxetine in patients with chronic pain (diabetic peripheral neuropathic pain, fibromyalgia, chronicpain due to osteoarthritis, and chronic low back pain). Patients received duloxetine (60 to 120 mg/day) or placebo.Average pain reduction was assessed over 3 months as the primary efficacy outcome. Other measures used were physicalfunction and Patient Global Impression of Improvement. In 10 of the 12 studies, statistically significant greater painreduction was observed for duloxetine- compared with placebo-treated patients. The response rates based on average painreduction, improvement of physical function, and global impression were comparable across all 4 chronic pain states.Compared with patients on placebo, significantly more patients treated with duloxetine reported a moderately importantpain reduction (..30% reduction) in 9 of the 12 studies, a minimally important improvement in physical function in 8 ofthe 12 studies, and a moderately important to substantial improvement in Patient Global Impression of Improvementrating in 11 of the 12 studies. The analyses reported here show that duloxetine is efficacious in treating chronic pain asdemonstrated by significant improvement in pain intensity, physical functioning, and patient ratings of overallimprovement.

Erratum by Bentham Science Publishers (304-304).
Due to an oversight on the part of the authors, Robinson MJ, Ahl J, Meyers AL, McCarberg BH, Iyengar S, errorswere published in the manuscript entitled -Management of Painful Symptoms with Duloxetine: A Review of the Efficacy inPre-Clinical and Clinical Studies-, Curr Drug Ther 2011; 6: pp. 121-136.On page 123, an incorrect study length was reported for the DPNP studies. The correct study length is 12 weeks instead of12-13 weeks.On page 131, an incorrect dose was listed in Table 9 in the column heading under Studies V & VI. The correct dose is 60 mgQD instead of 60 mg BID.Finally, references 54 and 55 were reversed. The correct Reference 54 is Raskin J, Pritchett YL, Wang F, et al. A double-blind,randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain.Pain Med 2005; 6(5): 346-56. The correct Reference 55 is Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomizedcontrolled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 2006; 67(8): 1411-20.