Targeting hypercoagulation to alleviate Alzheimer's disease progression in metabolic syndrome.

INTRODUCTION: Metabolic Syndrome (MetS) constitutes an important risk factor for Alzheimer's disease (AD); however, the mechanism linking these two disorders has not been completely elucidated. Hence, hypercoagulation may account for the missing hallmark connecting MetS and AD. The present review proposes how hemostatic imbalance triggered in MetS advances in the context of AD. MetS causes interruption of insulin signaling and inflammation, inciting insulin resistance in the brain. Subsequently, neuroinflammation and brain endothelial dysfunction are prompted that further intensify the exorbitant infiltration of circulating lipids and platelet aggregation, thereby causing hypercoagulable state, impairing fibrinolysis and eventually inducing prothrombic state in the brain leading to neurodegeneration. OBJECTIVE: This study aims to understand the role of hypercoagulation in triggering the progression of neurodegeneration in MetS. It also offers a few interventions to prevent the progression of AD in MetS targeting hypercoagulation. METHODS: Literature studies based on MetS related neurodegeneration, the impact of coagulation on aggravating obesity and AD via the mechanisms of BBB disruption, neuroinflammation, and hypofibrinolysis. CONCLUSION: The present paper proposes the hypothesis that hypercoagulation might amplify MetS associated insulin resistance, neuroinflammation, BBB disruption, and amyloid beta accumulation which eventually leads to AD.

Therapeutic Potential, Challenges and Future Perspective of Cancer Stem Cells in Translational Oncology: A Critical Review.

Stem cell research is a rapidly developing field that offers effective treatment for a variety of malignant and non-malignant diseases. Stem cell is a regenerative medicine associated with the replacement, repair, and restoration of injured tissue. Stem cell research is a promising field having maximum therapeutic potential. Cancer stem cells (CSCs) are the cells within the tumor that posses capacity of selfrenewal and have a root cause for the failure of traditional therapies leading to re-occurrence of cancer. CSCs have been identified in blood, breast, brain, and colon cancer. Traditional therapies target only fast growing tumor mass, but not slow-dividing cancer stem cells. It has been shown that embryonic pathways such as Wnt, Hedgehog and Notch, control self-renewal capacity and involved in cancer stem cell maintenance. Targeting of these pathways may be effective in eradicating cancer stem cells and preventing chemotherapy and radiotherapy resistance. Targeting CSCs has become one of the most effective approaches to improve the cancer survival by eradicating the main root cause of cancer. The present review will address, in brief, the importance of cancer stem cells in targeting cancer as better and effective treatment along with a concluding outlook on the scope and challenges in the implication of cancer stem cells in translational oncology.

High performance liquid chromatography determination of dexamethasone in plasma to evaluate its systemic absorption following intra-space pterygomandibular injection of twin-mix (mixture of 2 % lignocaine with 1:200,000 epinephrine and 4 mg dexamethasone): randomized control trial.

PURPOSE: To determine systemic absorption of dexamethasone by detection of plasma concentration using high performance liquid chromatography following its administration along with local anesthetic agent as a mixture via pterygomandibular space. METHODS: A prospective randomized double-blind clinical study was undertaken to analyze the plasma concentration of dexamethasone after intra-space pterygomandibular injection along with local anesthesia. The study was performed as per split mouth model where the mandibular quadrant allocation was done on a random basis considering each of the 30 patients is included in the two study interventions (SS and CS). For the study site (SS) procedures, dexamethasone was administered as a mixture (2 % lignocaine with 1:200,000 epinephrine and 4 mg dexamethasone) intra-space. In the control site (CS) procedures, a regular standard inferior alveolar nerve block was administered, and dexamethasone was given as intramuscular injection. The plasma dexamethasone determination was done in venous blood 30- and 60-min post injection using high performance liquid chromatography (HPLC). The clinical parameters like pain; swelling; and mouth opening on the first, third, and seventh post-operative day were analyzed and compared. RESULTS: No significant difference was found in the clinical parameters assessed; comparative evaluation showed less swelling in the SS interventions. The plasma concentration of dexamethasone for the CS interventions was 226 ± 47 ng/ml at 30-min and 316 ± 81.6 ng/ml at 60-min post injection, and for SS, it was 221 ± 81.6 ng/ml at 30-min and 340 ± 105 ng/ml at 60-min post injection. On inter-site (CS and SS) comparison, no statistically significant difference was ascertained in dexamethasone plasma concentration at 30-min post injection (P = 0.77) and at 60-min post injection. (P = 0.32). CONCLUSION: Intra-space (pterygomandibular space) administration of dexamethasone can achieve statistically similar plasma concentration of the drug as when the same dose is administered intramuscularly with demonstration of similar clinical effects.

Hydroxyproline: A Potential Biochemical Marker and Its Role in the Pathogenesis of Different Diseases.

Hydroxyproline is a non-essential amino acid found in collagen and few other extracellular animal proteins. It's two isomeric forms trans-4-hydroxy-L-proline and trans-3-hydroxy-L-proline play a crucial role in collagen synthesis and thermodynamic stability of the triple-helical conformation of collagen and associated tissues. Various abnormalities in hydroxyproline metabolism have been shown to play key roles in the pathophysiology and pathogenesis of different diseases. The elevated level of hydroxyproline is observed in several disorders, e.g., graft versus host disease, keloids, and vitiligo while its decreased level is a marker of poor wound-healing. This review explores the potential of using hydroxyproline as a biochemical marker to understand the pathogenesis, molecular pathophysiology and treatment of these diseases. The review concludes with an outlook on the scope and challenges in the clinical implementation of hydroxyproline as a biomarker.

Validation of data on the use of twin mix in minor oral surgery: comparative evaluation of efficacy of twin mix versus 2 % lignocaine with 1:200000 epinephrine based on power analysis and an UV spectrometry study for chemical stability of the mixture.

INTRODUCTION: There is convincing evidence supporting the addition of dexamethasone to lignocaine and its administration as an intra-space injection to achieve benefit of a single dose steroid after third molar surgery. This study was undertaken to validate the existing data on the use of twin mix in minor oral surgery based on power analysis, statistical sample size estimation and an ultraviolet (UV) spectrometry study for chemical stability of the mixture. MATERIAL AND METHODS: A prospective, randomized, double-blind trial was designed to validate the pilot study on the efficacy of twin mix and 2 % lignocaine with 1:200,000 epinephrine in the surgical removal of impacted mandibular third molars. Clinical parameters of anaesthetic latency, anaesthetic duration, efficacy of twin mix as an anaesthetic and post-operative patient discomfort were assessed. The stability of active ingredients in the solution was assessed using a double beam UV-visible spectrophotometery. RESULTS: The results of the study showed better post-operative outcome with administration of dexamethasone and lignocaine as an intra-space injection in decreasing the post-operative patient discomfort. The anaesthetic efficacy of the twin-mix admixture was found statistically similar to the control solution of 2 % lignocaine with 1:200,000 epinephrine. The λmax recorded for dexamethasone and local anaesthetic individually was obtained with the twin-mix solution, which indicated no change in the active pharmacological compounds. DISCUSSION: Clinical anaesthetic efficacy of twin mix is comparable to 2 % lignocaine with 1:200,000 epinephrine when administered in the pterygomandibular space with the additional advantage of a single prick co-administration of dexamethasone with local anaesthetic, lesser sting of the local anaesthetic injection, shorter anaesthetic latency, prolonged duration of the soft tissue anaesthesia and decrease in post-operative discomfort after the oral surgical procedure.

Mannosylated liposomes bearing Amphotericin B for effective management of visceral Leishmaniasis.

The cationic and mannosylated liposomes were prepared using the cast film method and compared for their antileishmaniasis activity. The surface of the Amphotericin B (Amp B)-bearing cationic multilamellar liposomes was covalently coupled with p-aminophenyl-α-D-mannoside using glutaraldehyde as a coupling agent, which was confirmed by agglutination of the vesicles with concanavalin A. The prepared liposomes were characterized for shape, size, percent drug entrapment, vesicle count, zeta potential, and in vitro drug release. Vesicle sizes of cationic and mannosylated liposomes were found to be 2.32 ± 0.23 and 2.69 ± 0.13 µm, respectively. Zeta potential of cationic liposomes was higher (30.38 ± 0.3 mV), as compared to mannosylated liposomes (17.7 ± 0.8 mV). Percentage drug release from cationic and mannose-coupled liposomes was found to be 45.7% ± 3.1 and 41.9% ± 2.8, respectively, after 24 hours. The in vivo antileishmanial activity was performed on Leishmania donovani-infected golden hamster, and results revealed that Amp B solution was reduced by 42.5 ± 1.8% in the parasite load, whereas the placebo cationic liposomes and drug-containing cationic liposomes showed a reduced parasite load (i.e., 28.1 ± 1.5 and 61.2 ± 3.2%, respectively). The mannose-coupled liposomes showed a maximum reduction in parasite load (i.e., 78.8 ± 3.9%). The biodistribution study clearly showed the higher uptake of mannosylated liposomes in the liver and spleen and hence the active targeting to the reticular endothelial system, which, in turn, would provide a direct attack of the drug to the site where the pathogen resides, rendering the other organs free and safe from the toxic manifestations of the drug.

Development and characterization of dutasteride bearing liposomal systems for topical use.

Dutasteride loaded liposomal system were developed for topical application in order to avoid the side effects associated with the oral administration of the drug. Drug-loaded multilamellar liposomes were prepared using thin-film hydration method followed by sonication and optimized with respect to entrapment efficiency, drug payload, size and lamellarity. The vesicular systems consisting of egg phosphatidylcholine (100 mg), cholesterol (50 mg), and dutasteride (5 mg) showed highest drug entrapment efficiency (94.6%) and drug payload (31.5 µg/mg of total lipids). Mean vesicle size of these liposomes was noted to be 1.82 ± 0.15 µm. Significantly higher skin permeation of dutasteride through excised abdominal mouse skin was achieved via the developed liposomal formulations as compared to hydro-alcoholic solution and conventional gels. The formulation exhibited about seven fold higher deposition of drug in skin. Stability studies indicated that the liposomal formulations were quite stable in the refrigerated conditions for 10 weeks with negligible drug leakage or vesicle size alteration. Results of the current studies exhibited improved and localized drug action in the skin and thus could be formulated as a better option to cure androgenetic alopecia.

Design and development of solid lipid nanoparticles for topical delivery of an anti-fungal agent.

Topical application of the drugs at the pathological sites offers potential advantages of delivering the drug directly to the site of action. The main aim of this work was to formulate and evaluate Miconazole nitrate (MN) loaded solid lipid nanoparticles (SLN) for topical application. MN-loaded SLN were prepared by modified solvent injection method and characterized for shape, surface morphology, particle size, and drug entrapment. These solid lipid nanoparticles were spherical in shape with smooth surface and possessed mean average size of 206.39 +/- 9.37 nm. In vitro drug release of MN-loaded SLN-bearing hydrogel was compared with MN suspension and MN hydrogel; MN-loaded SLN-bearing hydrogel depicted a sustained drug release over a 24-h period. Tape stripping experiments demonstrated 10-fold greater retention with MN-loaded SLN-bearing hydrogel as compared to MN suspension and MN hydrogel. The in vivo studies were performed by infecting the rats with candida species. It was observed that MN-loaded SLN-bearing hydrogel was more efficient in the treatment of candidiasis. Results indicate that MN-loaded SLN-bearing hydrogel provides a sustaining MN topical effect as well as quicker relief from fungal infection.

Lactose-Conjugated PLGA Nanoparticles for Enhanced Delivery of Rifampicin to the Lung for Effective Treatment of Pulmonary Tuberculosis.

Lactose conjugated poly(lactic co-glycolic acid) nanoparticles (L-PLGA-NPs) were investigated for lung delivery of rifampicin for effective treatment of pulmonary tuberculosis. Lactose-PLGA conjugate was synthesized using lactose and PLGA and characterized by infrared spectroscopy. L-PLGA-NPs were prepared by the solvent displacement method. NPs were characterized for shape, particle size, zeta potential, and percent drug entrapment. The size of NPs was found to be in the range 121-184 nm and maximum drug payload was found to be 38.4-42.2%. Average size and drug payload was found to be greater in the case of L-PLGA-NPs as compared to unconjugated NPs. The results of the in vitro release profile, which was determined using the dialysis technique, demonstrated that noncoupled NPs release a comparatively higher percent of drug than lactose coupled NPs. Fluorescence studies revealed the enhanced uptake of L-PLGA-NPs in the lung tissue when compared with unmodified PLGA NPs. Intravenous administration of free drug solution resulted in a high concentration of drug in serum while it was much less in the case of PLGA NPs. Coupling of the NPs with lactose significantly enhanced the lung uptake of drug, which is reflected in the recovery of a higher percentage of dose from the lungs as compared to that recovered in the case of uncoupled drug-loaded NPs and plain drug solution.

Solid lipid nanoparticles bearing oxybenzone: in-vitro and in-vivo evaluation.

In the present project, Solid Lipid Nanoparticles (SLNs) bearing oxybenzone were prepared by ethanol injection method to improve its effectiveness as sunscreen. SLNs were characterized for particle size,polydispersity index, zeta potential and surface morphology. The optimized SLNs bearing oxybenzone were incorporated into water-removable cream base and compared with SLNs unloaded water-removable cream base for in vitro and in vivo parameters. Cream base formulation containing SLNs (Csd) with 5% oxybenzone showed slow drug release and better sun protecting factor (more than 25) compared to cream base containing 5% oxybenzone. Confocal Laser Scanning Microscopy was used to visualize the distribution of developed formulations in skin. CLSM indicated prolonged retention of SLNs in the stratum corneum as compared to plain cream base. These studies revealed that the cream base bearing SLNs exhibited good skin retention as well as enhanced sun protection effect compared to cream base.

Steroid-coupled liposomes for targeted delivery to tumor.

The steroidal receptors play a key role in protein synthesis and maintain the homeostasis in normal and diseased state, including tumorigenesis at the target tissues when overactivated. Thus steroidal receptors may act as potential targets for selective delivery of different therapeutic agents as they are overexpressed by a number of endocrinal tumors. The selective delivery of these agents may be a better treatment strategy for endocrinal cancer as it may also result in cytosolic and nuclear delivery of cytotoxic agents. In this review, the targeting potential of steroidal receptors for the drug or bioactive(s) delivery is discussed. The ligands that have been proven to be effective for specific steroidal receptors can be used as vectors for carrying the drug or drug-delivery system to the desired site of drug action in an optimum concentration. This strategy will not only minimize the undesired side effects associated with nonspecific delivery of drug, but will also maximize the drug utilization. Ligand-conjugated liposomes as a carrier of bioactives prevent passive diffusion of the encapsulated drug to normal cells, increase the time of circulation and reduce the undesirable side effects of a drug.

Influence of rheology of dispersion media in the preparation of polymeric microspheres through emulsification method.

Chitosan microspheres as drug delivery system have attained importance and attracted the attention of researchers in last few years. This study was aimed toward the elucidation of the effect of viscosity of external oil phase on the properties of microspheres prepared by emulsification method. Chitosan microspheres were prepared utilizing oil phase of different viscosity viz. castor oil, heavy liquid paraffin, light liquid paraffin and mixture of light paraffin, and petroleum ether (1:1 v/v ratio). Microspheres prepared in highly viscous castor oil exhibited an average size of 11.52+/-0.57 microm with a percentage drug entrapment of 43.12+/-2.14. On the other hand, very small microspheres of 3.15+/-0.04 microm and 68.87+/-1.03% drug entrapment were obtained when mixture of liquid paraffin and petroleum ether was utilized as oil phase. Effect of viscosity on percent mucoadhesion, percent drug entrapment, zeta potential, percent process yield, etc. of microspheres has been observed. In vitro drug release in phosphate buffer pH 7.4 was determined for different batch of microspheres. The results revealed a difference in the drug release pattern of the different microspheres prepared as a function of viscosity of different oil phase. Use of low viscose oil resulted in the formulation of spherical and small size microspheres. This work was a part of our ongoing thrust and project to develop microparticulate drug delivery system.

Steroid receptors as molecular targets for cancer diagnosis and therapy.

The targeted delivery of chemotherapeutics is essential to minimizing the side effects by sparing the normal tissues by exposure to cytotoxic agents. The various receptors are overexpressed on the surface of the tumor tissues as compared to the normal tissues because their requirement for various essential components is high for the growth and development of tumor tissues. These overexpressed receptors on the tumor surface have been investigated for selective delivery of imaging, cytotoxic, or other therapeutic agents. Hormonal receptors viz. peptide and steroid receptors (SRs), which are present over the tumor surface, are also used for tumor targeting of various molecules for therapeutic use or imaging purpose. The key role of SRs is in the transactivation step of protein synthesis and to maintain the homeostasis in normal and diseased states. These receptors are overactivated in different diseases, including tumorigenesis. Hence, these SRs may act as a potential target for selective delivery of different therapeutic or cytotoxic agents. The selective delivery of these agents may be a better treatment strategy for endocrine cancer because it results in cytosolic and nuclear delivery of cytotoxic agents as well. The objective of the present review is to explore the importance of sex SRs as a vital target in endocrine cancer therapy. Potential strategies investigated for the delivery of imaging agents, chemotherapeutics, and toxins via steroidal ligands have been discussed. The importance of gene therapy in different diseases, including endocrine cancer, is well defined; thus, some effective gene delivery approaches investigated in endocrine cancer via steroidal ligands have also been discussed.

Bioconjugates: harnessing potential for effective therapeutics.

The accomplishment of selective delivery can be brought through efficient drug targeting in which the attack of drug moiety is visualized only by the diseased organ and not by the organs of the whole body. This, in turn, consequently minimizes the unwanted effects or side effects caused by the drug action on the other organs. Bioconjugation is a fascinating technique that explores new vistas of drug delivery, and at the same time opens new possibilities for safe and effective therapy. This review is dedicated to and describes the science of bioconjugation and its potential in the drug delivery field, including different bioconjugates and their use in various therapeutic strategies. These have been classified as polymer based, macromolecule based, carrier based, and novel bioconjugates. This review describes the utility of bioconjugates in major diseases like cancer and others, and discusses experiments and research on the same. Bioconjugates have immense potential and extend a promising future in the drug delivery field. The review can act as a quick reference for those actively engaged in drug delivery and drug research to help overcome the hurdles of therapeutics.

Metronidazole loaded pectin microspheres for colon targeting.

A multiparticulate system having pH-sensitive property and specific enzyme biodegradability for colon-targeted delivery of metronidazole was developed. Pectin microspheres were prepared using emulsion-dehydration technique. These microspheres were coated with Eudragit(R) S-100 using oil-in-oil solvent evaporation method. The SEM was used to characterize the surface of these microspheres and a distinct coating over microspheres could be seen. The in vitro drug release studies exhibited no drug release at gastric pH, however continuous release of drug was observed from the formulation at colonic pH. Further, the release of drug from formulation was found to be higher in the presence of rat caecal contents, indicating the effect of colonic enzymes on the pectin microspheres. The in vivo studies were also performed by assessing the drug concentration in various parts of the GIT at different time intervals which exhibited the potentiality of formulation for colon targeting. Hence, it can be concluded that Eudragit coated pectin microspheres can be used for the colon specific delivery of drug.

Glutamate-conjugated liposomes of dopamine hydrochloride for effective management of parkinsonism's.

The blood-brain barrier restricts the brain uptake of many important hydrophilic drugs and limits their efficacy in the treatment of brain diseases because of the presence of tight junctions, high metabolic capacity, low pinocytic vesicular traffic, and efficient efflux mechanisms. In the present project, amino acid-coupled liposomes bearing dopamine HCl were prepared to deliver the drug to the brain utilizing receptor-mediated transcytosis. Uncoupled liposomes were prepared by cast film method using phosphatidylcholine and cholesterol, whereas coupled liposomes were prepared using phosphatidylcholine, cholesterol, and glutamate stearylamine conjugate in the film. These liposomes were characterized for entrapment efficiency, vesicle size, shape, in vitro drug release, and in vivo studies. The in vitro drug release was analysed by using dialysis membrane. The vesicle size was found to increase upon coupling of liposomes, whereas percent entrapment efficiency was reduced from 38.89 +/- 1.94% to 34.15 +/- 1.70% after coupling of liposomes. The in vitro percent cumulative drug release studies exhibited 51.6% drug release for uncoupled liposome and 37.9% for coupled liposome at the end of 24 h. These selected formulations were subjected for in vivo performance, which was assessed by periodic measurement of drug (chlorpromazine)-induced catatonia in albino rats (Wistar strain) and fluorescence microscopy studies of the rat brain. The results were compared with plain dopamine HCl solution. Studies revealed that dopamine HCl can be effectively delivered to brain via glutamate-coupled liposomes, and results clearly indicated the superiority of the coupled liposomal formulation over the uncoupled formulation.

Mannosylated gelatin nanoparticles bearing an anti-HIV drug didanosine for site-specific delivery.

The present investigation was aimed at developing and exploring the use of mannosylated gelatin nanoparticles for the selective delivery of an anti-HIV drug, didanosine, to the target organs. The mannosylated gelatin nanoparticles (MN-G-NPs) were prepared using a two-step desolvation technique and coupled with mannose using the amino group of gelatin present on the surface of nanoparticles. The mannosylation was confirmed using infrared and nuclear magnetic resonance spectroscopy. MN-G-NPs were characterized for shape, particle size, zeta potential, and percentage drug entrapment. The size of nanoparticles was found to be in range of 248-325 nm, and maximum drug payload was found to be 40.2% to 48.5%. Average size was found to be more, but drug payload was less in the case of MN-G-NPs as compared with unconjugated nanoparticles (G-NPs). The results of the in vitro release profile demonstrated that G-NPs release a comparatively higher percentage of drug than MN-G-NPs. Cellular uptake by MN-G-NPs was 2.7 times more as compared with G-NPs. Fluorescence studies revealed the enhanced uptake of MN-G-NPs in the macrophage tissues when compared with unmodified G-NPs. Intravenous administration of free-drug solution resulted in a high concentration of drug in serum, whereas it was much less in the case of G-NPs. Coupling of the nanoparticles with mannose significantly enhanced the lung, liver, and lymph nodes uptake of drug, which is reflected in the recovery of a higher percentage of the dose from these organs following administration of MN-G-NPs in comparison to noncoupled G-NPs or free drug.

Biofilms--a microbial life perspective: a critical review.

Microorganisms attach to surfaces, start multiplying, and develop biofilms. Biofilm-associated cells can be differentiated from their suspended counterparts by the generation of an extracellular polymeric substance (EPS) matrix, reduced growth rates, and up- and downregulation of their specific genes. The attachment of microorganisms is a complex process regulated by diverse characteristics--growth medium, substratum, and cell surfaces. An established biofilm structure comprises microbial cells and EPS, has a defined architecture, and provides an optimal environment for the exchange of genetic material between cells. Cells may also communicate via quorum sensing, which may in turn affect biofilm processes such as detachment. Biofilms have great importance for public health because of their role in certain infectious diseases and their importance in a variety of device-related infections. Because many antibiotics are unable to eradicate dense biofilms, much work is required to devise ways to prevent their occurrence and clear them from the host. A greater understanding of biofilm processes should lead to novel, effective strategies for biofilm control and improvement in patient care and management.