Effects of Combination Treatments with Astaxanthin-Loaded Microparticles and Pentoxifylline on Intracellular ROS and Radiosensitivity of J774A.1 Macrophages.

Radiation-induced fibrosis (RIF) is a serious, yet incurable, complication of external beam radiation therapy for the treatment of cancer. Macrophages are key cellular actors in RIF because of their ability to produce reactive oxidants, such as reactive oxygen species (ROS) and inflammatory cytokines that, in turn, are the drivers of pro-fibrotic pathways. In a previous work, we showed that phagocytosis could be exploited to deliver the potent natural antioxidant astaxanthin specifically to macrophages. For this purpose, astaxanthin encapsulated into µm-sized protein particles could specifically target macrophages that can uptake the particles by phagocytosis. In these cells, astaxanthin microparticles significantly reduced intracellular ROS levels and the secretion of bioactive TGFß and increased cell survival after radiation treatments. Here we show that pentoxifylline, a drug currently used for the treatment of muscle pain resulting from peripheral artery disease, amplifies the effects of astaxanthin microparticles on J774A.1 macrophages. Combination treatments with pentoxifylline and encapsulated astaxanthin might reduce the risk of RIF in cancer patients.

Modulatory Effects of Caffeine and Pentoxifylline on Aromatic Antibiotics: A Role for Hetero-Complex Formation.

Antimicrobial resistance is a major healthcare threat globally. Xanthines, including caffeine and pentoxifylline, are attractive candidates for drug repurposing, given their well-established safety and pharmacological profiles. This study aimed to analyze potential interactions between xanthines and aromatic antibiotics (i.e., tetracycline and ciprofloxacin), and their impact on antibiotic antibacterial activity. UV-vis spectroscopy, statistical-thermodynamical modeling, and isothermal titration calorimetry were used to quantitatively evaluate xanthine-antibiotic interactions. The antibacterial profiles of xanthines, and xanthine-antibiotic mixtures, towards important human pathogens Staphylococcus aureus, Enterococcus faecium, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Enterobacter cloacae were examined. Caffeine and pentoxifylline directly interact with ciprofloxacin and tetracycline, with neighborhood association constant values of 15.8-45.6 M-1 and enthalpy change values up to -4 kJ·M-1. Caffeine, used in mixtures with tested antibiotics, enhanced their antibacterial activity in most pathogens tested. However, antagonistic effects of caffeine were also observed, but only with ciprofloxacin toward Gram-positive pathogens. Xanthines interact with aromatic antibiotics at the molecular and in vitro antibacterial activity level. Given considerable exposure to caffeine and pentoxifylline, these interactions might be relevant for the effectiveness of antibacterial pharmacotherapy, and may help to identify optimal treatment regimens in the era of multidrug resistance.

Structure-based redesigning of pentoxifylline analogs against selective phosphodiesterases to modulate sperm functional competence for assisted reproductive technologies.

Phosphodiesterase (PDE) inhibitors, such as pentoxifylline (PTX), are used as pharmacological agents to enhance sperm motility in assisted reproductive technology (ART), mainly to aid the selection of viable sperm in asthenozoospermic ejaculates and testicular spermatozoa, prior to intracytoplasmic sperm injection (ICSI). However, PTX is reported to induce premature acrosome reaction (AR) and, exert toxic effects on oocyte function and early embryo development. Additionally, in vitro binding studies as well as computational binding free energy (ΔGbind) suggest that PTX exhibits weak binding to sperm PDEs, indicating room for improvement. Aiming to reduce the adverse effects and to enhance the sperm motility, we designed and studied PTX analogues. Using structure-guided in silico approach and by considering the physico-chemical properties of the binding pocket of the PDEs, designed analogues of PTX. In silico assessments indicated that PTX analogues bind more tightly to PDEs and form stable complexes. Particularly, ex vivo evaluation of sperm treated with one of the PTX analogues (PTXm-1), showed comparable beneficial effect at much lower concentration-slower AR, higher DNA integrity and extended longevity of  spermatozoa and  superior embryo quality. PTXm-1 is proposed to be a better pharmacological agent for ART than PTX for sperm function enhancement.

Colloidal nanostructured lipid carriers of pentoxifylline produced by microwave irradiation ameliorates imiquimod-induced psoriasis in mice.

Psoriasis is a chronic inflammatory disease occurring due to a large cascade of molecular and biological processes. Pentoxifylline (PTX) has a profound anti-inflammatory activity and is clinically indicated in the management of psoriasis. PTX is highly hydrophilic and thus is permeation-limited to exert its action on the psoriatic lesions. Colloidal nanostructured lipid carriers (NLCs) is a boon for dermal drug delivery, but incorporation of hydrophilic medicaments is not only difficult to be achieved but is accompanied by suboptimal loading, erratic drug release and time-consuming. The present study was designed to develop NLCs incorporating PTX using the recently explored thin lipid film based microwave assisted rapid technique. Prior to the formulation, the crystal structure of PTX was analyzed by molecular modeling. NLCs formed within 4 min having a size of <200 nm, PDI of <0.250 and a surface charge <-28 mV. PTX was loaded and encapsulated to an extent of 10% and 90% in the NLCs. The drug flux was 4.848 µg/cm2/h at the end of 24 h with a detection of 14% in the receptor fluid indicating a higher retention of PTX within the skin (>84%). In addition, the PTX loaded NLCs were tested against imiquimod-induced psoriasis in mouse model. Histological examinations clearly showed a higher levels of remodeling of the skin layers compared to disease control. These results justify NLCs to be a promising topical delivery system for PTX during psoriasis and can be rapidly produced without the requirement of complex equipment and conditions.

Dynamics of water and xanthan chains in hydrogels studied by NMR relaxometry and their influence on drug release.

The dynamic properties of water and polymer molecules in xanthan hydrogels at different polymer mass fractions were investigated through the combination of conventional and fast-field cycling NMR relaxation to obtain the information about dynamics in different time scales. The results showed that water dynamics were faster in diluted than in concentrated hydrogels. However, the type of polymer-chain dynamics did not change for xanthan fractions from 0.1 to 0.5, although they slowed at higher xanthan fractions as the system approached transition to the glass state. The addition of the nonionic small drug molecules pentoxifylline did not change the dynamics in the hydrogels, but they were affected by the medium pH. The water and polymer-chain dynamics were faster in the hydrogels for the neutral than the acid medium. These differences resulted in slower swelling and thinner and more rigid hydrogel layer of the matrix tablet in the acid medium that was less susceptible to erosion. Consequently, pentoxifylline release from xanthan tablets in acid medium is dominated by drug diffusion. At neutral pH, the molecular mobility is greater, which resulted in rapid and extensive swelling of the hydrogel, leading to erosion-dominated drug release.

Self-assembling lisofylline-fatty acid conjugate for effective treatment of diabetes mellitus.

Lisofylline is an anti-inflammatory agent with proven anti-diabetic activity. Its high solubility and rapid metabolism results in poor bioavailability and short half-life, limiting its clinical utility. We have synthesized Lisofylline-Linoleic acid (LSF-LA) conjugate which self-assembled into micelles (156.9 nm; PDI 0.187; CMC 1 µg/mL; aggregation number 54) without any surfactant and showed enhanced cellular uptake. It protected MIN6 insulinoma cells from cytokine induced cell death and enhanced insulin production under inflammatory conditions. It also suppressed the proliferation of activated peripheral blood mononuclear cells and reduced the production of inflammatory cytokines, IFN-γ and TNF-α. LSF-LA micelles exhibited reduced protein binding, significantly higher half-life (5.7-fold) and higher apparent volume of distribution (5.3-fold) than free LSF. In T1D animals, reduced blood glucose levels were observed at a reduced dose (~15 mg/kg, once daily of LSF-LA micelles vs. 25 mg/kg, twice daily of free LSF) that was further confirmed by immunohistochemical analysis.

Physical compatibility of pentoxifylline and intravenous medications.

OBJECTIVE: To investigate the physical and chemical compatibility of pentoxifylline (PTX) with a wide range of parenteral medications used in the neonatal intensive care setting. DESIGN: PTX and drug solutions were combined in glass phials and inspected visually for physical incompatibility. The chemical compatibility was evaluated on the basis of PTX concentrations. RESULTS: Precipitation, colour change or turbidity was not visible in any of the test mixtures, indicating no observed physical incompatibility or apparent risk of blockage in narrow-bore intravenous tubing. The PTX concentration was approximately 2.5% and 4.5% lower when combined with dopamine and amoxicillin, respectively. The PTX concentration ratios for all other combinations were in the range of 99%-102%. CONCLUSION: In simulated Y-site conditions, physical compatibility testing of PTX and 30 parenteral medications revealed no evidence of precipitation. Based on PTX concentration tests, it could be prudent to avoid mixing PTX with dopamine or amoxicillin.

Pentoxifylline exerts anti-inflammatory effects on cerebral ischemia reperfusion­induced injury in a rat model via the p38 mitogen-activated protein kinase signaling pathway.

Pentoxifylline exhibits complex functions with extensive pharmacological effects and is used therapeutically due to its therapeutic effects and rapid metabolism in the body, with no cumulative effects and few side effects. The present study investigated the effects of pentoxifylline on cerebral ischemia reperfusion­induced injury (IRI) through suppression of inflammation in rats. Hematoxylin and eosin staining was performed to evaluate the number of neurocytes, and ELISAs were applied to measure tumor necrosis factor­α, interleukin­6, malondialdehyde and superoxide dismutase activities. Treatment with pentoxifylline significantly recovered the cerebral ischemia reperfusion­induced neurological deficit score and cerebral infarct volume in rats. In addition, pentoxifylline treatment significantly reversed the cerebral ischemia reperfusion­induced interleukin­6, tumor necrosis factor­α, malondialdehyde and superoxide dismutase levels in vivo. Furthermore, pentoxifylline significantly inhibited cyclooxygenase­2 and inducible nitric oxide synthase mRNA and protein expression in cerebral IRI mice. Treatment with pentoxifylline also significantly suppressed the expression of cleaved caspase­3 and p38 mitogen­activated protein kinase (MAPK) protein in cerebral IRI mice. These results indicate that the protective effects of pentoxifylline on cerebral IRI may occur via the p38 MAPK signaling pathway.

Pentoxifylline-Induced Apoptosis in Chronic Lymphocytic Leukemia: New Insights into Molecular Mechanism.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is an indolent B-lineage neoplasm, characterized by clonal expansion of CD5 positive B cells with constitutive activation of survival pathways including NF-kB. Pentoxifylline, a xanthine-derivative compound indicated for the treatment of microvascular disturbancies, has been suggested to have anti-proliferative and anti-metastatic activities in various types of cancer. In the present study we extend these data showing one of the potential molecular mechanisms through which Pentoxifylline may promote apoptosis in CLL clonal lymphocytes. METHODS: Peripheral blood mononuclear cells were isolated from 15 CLL patients 0 RAI stage and 15 healthy volunteers and treated for 24 and 48 hours with Pentoxifylline. Apoptosis induction was evaluated through Annexin V and TUNEL assays. Mitochondrial membrane potential depolarization analysis, active Caspase-3 assay, reactive oxygen species generation and Western Blot were assessed to further investigate the alterations induced by Pentoxifylline. RESULTS: We observed a statistically significant occurrence of apoptosis, DNA fragmentation and active Caspase-3 in lymphocytes from CLL patients compared to healthy volunteers after 48 hours of Pentoxifylline treatment. To clarify the molecular mechanism of the drug, we also evaluated the expression levels of NF-kB/p65 and its related proteins. In treated CLL cells, NF-kB/p65 was significantly decreased in comparison to normal cells, whereas we observed a less marked reduction of Bcl-2 expression. The treatment also induced a decrease of Mcl-1 in CLL cells with a greater down-regulation of the anti-apoptotic alternatively spliced isoform. CONCLUSION: These findings showed that Pentoxifylline induced apoptosis in leukemic cells through a molecular mechanism that involves the NF-kB signaling.

Simultaneous determination of pentoxifylline, metabolites M1 (lisofylline), M4 and M5, and caffeine in plasma and dried blood spots for pharmacokinetic studies in preterm infants and neonates.

Advances in bioanalytical methods are facilitating micro-volume and dried blood spot (DBS) analysis of drugs in biological matrices for pharmacokinetic studies in children and neonates. We sought to develop a UPLC-MS/MS assay for simultaneous measurement of caffeine, pentoxifylline (PTX) and three metabolites of PTX in both plasma and DBS. Caffeine, PTX, the metabolites M1 (lisofylline), M4 and M5, and the internal standards (caffeine-d9 and PTX-d6) were separated using a Waters Aquity T3 UPLC C18 column and gradient mobile phase (water-methanol-formic acid). Retention times for caffeine, M5, M4, PTX and M1 were 1.6, 1.7, 1.9, 2.0 and 2.1min, respectively, with a run time of 5min. The precision (≤10%) and accuracy (≤15%) across the concentration range 0.1-50mg/L for caffeine, PTX and the three metabolites in plasma and DBS were within accepted limits, as were the limits of quantification (100µg/L for caffeine and 10µg/L for PTX, M1, M4 and M5). Caffeine, PTX and the metabolites were stable in DBS for >34days at room and refrigerated temperatures. Plasma and DBS samples were obtained from 24 preterm infants recruited into a clinical pharmacokinetic study of PTX. Paired analysis indicated that DBS concentrations were 9% lower than concurrent plasma concentrations for caffeine, 7% lower for PTX (consistent with the blood:plasma ratio) and 13% lower for M1 (lisofylline). The validated UPLC-MS/MS method is suitable for micro-volume plasma and DBS analysis of caffeine, PTX and its metabolites for pharmacokinetic studies in paediatric patients.

Simultaneous estimation of lisofylline and pentoxifylline in rat plasma by high performance liquid chromatography-photodiode array detector and its application to pharmacokinetics in rat.

Lisofylline (LSF) is an anti-inflammatory and immunomodulatory agent with proven activity in serious infections associated with cancer chemotherapy, hyperoxia-induced acute lung injury, autoimmune disorders including type-1 diabetes (T1DM) and islet rejection after islet transplantation. It is also an active metabolite of another anti-inflammatory agent, Pentoxifylline (PTX). LSF bears immense therapeutic potential in multiple pharmacological activities and hence appropriate and accurate quantification of LSF is very important. Although a number of analytical methods for quantification of LSF and PTX have been reported for pharmacokinetics and metabolic studies, each of these have certain limitations in terms of large sample volume required, complex extraction procedure and/or use of highly sophisticated instruments like LC-MS/MS. The aim of current study is to develop a simple reversed-phase HPLC method in rat plasma for simultaneous determination of LSF and PTX with the major objective of ensuring minimum sample volume, ease of extraction, economy of analysis, selectivity and avoiding use of instruments like LC-MS/MS to ensure a widespread application of the method. A simple liquid-liquid extraction method using methylene chloride as extracting solvent was used for extracting LSF and PTX from rat plasma (200µL). Samples were then evaporated, reconstituted with mobile phase and injected into HPLC coupled with photo-diode detector (PDA). LSF, PTX and 3-isobutyl 1-methyl xanthine (IBMX, internal standard) were separated on Inertsil® ODS (C18) column (250×4.6mm, 5µm) with mobile phase consisting of A-methanol B-water (50:50v/v) run in isocratic mode at flow rate of 1mL/min for 15min and detection at 273nm. The method showed linearity in the concentration range of 50-5000ng/mL with LOD of 10ng/mL and LLOQ of 50ng/mL for both LSF and PTX. Weighted linear regression analysis was also performed on the calibration data. The mean absolute recoveries were found to be 80.47±3.44 and 80.89±3.73% for LSF and PTX respectively. The method was successfully applied for studying the pharmacokinetics of LSF and PTX after IV bolus administration at dose of 25mg/kg in Wistar rat. In conclusion, a simple, sensitive, accurate and precise reversed-phase HPLC-UV method was established for simultaneous determination of LSF and PTX in rat plasma.

Synergistic effect of PEGylation and pentoxifylline addition on immunoprotection of pancreatic islets.

In this study, a method is proposed to reduce immunological response of immune system against Langerhans islets by PEGylation of islets combined with adjuvant therapy. For this purpose, the best composition for a mixture of succinimidyl valeric acid activated mPEG (mPEG-SVA) with different molecular weights (MWs) and for a mixture of succinimidyl carbonate activated mPEG (mPEG-SC) with different MWs was determined separately. Then, the effect of pentoxifylline (PTX) as an adjuvant drug on immunological response against PEGylated islets at best mPEG composition was studied. The extent of mPEGs reaction, the amount of interlukin-2 (IL-2) and perforin secretion, and the viability of lymphocytes and islets in homo and co-cultures in the presence of PTX at different concentrations were considered for the in vitro evaluation of the proposed method. It was found, that a mixture of mPEG-SVA with MWs of 10 and 5 kDa at a composition of 75 and 25%, respectively, was the best formulation. Also, the addition of PTX drug to co-culture medium increased the protection of PEGylated islets against immune system and a concentration of 75 µg mL-1 of PTX was suitable for islet protection with no adverse effect on immune cells.

Active Site Crowding of Cytochrome P450 3A4 as a Strategy To Alter Its Selectivity.

Substrate-promiscuous enzymes are a promising starting point for the development of versatile biocatalysts. In this study, human cytochrome P450 3A4, known for its ability to metabolise hundreds of drugs, was engineered to alter its regio- and stereoselectivity. Rational mutagenesis was used to introduce steric hindrance in a specific manner in the large active site of P450 3A4 and to favour oxidation at a more sterically accessible position on the substrate. Hydroxylation of a synthetic precursor of (R)-lisofylline, a compound under investigation for its anti-inflammatory properties, was chosen as a first proof-of-principle application of our protein engineering strategy. In a second example, increasing active site crowding led to an incremental shift in the selectivity of oxidation from an internal double bond to a terminal phenyl group in a derivative of theobromine. The same correlation between crowding and selectivity was found in a final case focused on the hydroxylation of the steroid sex hormone progesterone.

Expression of the p66Shc protein adaptor is regulated by the activator of transcription STAT4 in normal and chronic lymphocytic leukemia B cells.

p66Shc attenuates mitogenic, prosurvival and chemotactic signaling and promotes apoptosis in lymphocytes. Consistently, p66Shc deficiency contributes to the survival and trafficking abnormalities of chronic lymphocytic leukemia (CLL) B cells. The mechanism of p66shc silencing in CLL B cells is methylation-independent, at variance with other cancer cell types. Here we identify STAT4 as a novel transcriptional regulator of p66Shc in B cells. Chromatin immunoprecipitation and reporter gene assays showed that STAT4 binds to and activates the p66shc promoter. Silencing or overexpression of STAT4 resulted in a co-modulation of p66Shc. IL-12-dependent STAT4 activation caused a coordinate increase in STAT4 and p66Shc expression, which correlated with enhanced B cell apoptosis. Treatment with the STAT4 inhibitor lisofylline reverted partly this effect, suggesting that STAT4 phosphorylation is not essential for but enhances p66shc transcription. Additionally, we demonstrate that CLL B lymphocytes have a STAT4 expression defect which partly accounts for their p66Shc deficiency, as supported by reconstitution experiments. Finally, we show that p66Shc participates in a positive feedback loop to promote STAT4 expression. These results provide new insights into the mechanism of p66Shc expression in B cells and its defect in CLL, identifying the STAT4/IL-12 pathway as a potential therapeutic target in this neoplasia.

Monitoring of Pentoxifylline Thermal Behavior by Novel Simultaneous Laboratory Small and Wide X-Ray Scattering (SWAXS) and Differential Scanning Calorimetry (DSC).

The thermal and structural evolutions associated to active pharmaceutical ingredient (API) purity are monitored using a laboratory instrument (S3-MicroCaliX) allowing simultaneous time-resolved X-ray scattering at both wide and small angles (SWAXS) as a function of temperature. This is performed simultaneously with differential scanning calorimetric (DSC) that is carried out in the same apparatus at scanning rate of 2 K/min on the same sample in the range from 20° to 200°C. We have studied simultaneous thermal and structural properties of pentoxifylline, as an active pharmaceutical ingredient (API), for its purity quality control. We have found a satisfying API purity, due to obtained melting temperature and enthalpy values, which are in a well agreement with literature. We have also found that the combination of these techniques allows the thermal monitoring of scanning rates of 2 K/min, continuously without the need for static thermal equilibration, particularly for X-ray spectra. Hence, DSC and SWAXS allowing better identification of the structural thermal events recorded by following of the phase transitions simultaneously. This interpretation is much better possible when X-ray scattering at small and wide angles is coupled with DSC from the same sample. Hence, as a laboratory tool, the method presents a reproducible thermal and crystallographic API purity quality control of non-complex samples, as crucial information for pharmaceutical technology.

Microemulsion for topical application of pentoxifylline: In vitro release and in vivo evaluation.

Microemulsion containing pentoxifylline was developed and characterized for use as a topical alternative to treat skin disorders. The transparent formulation was developed and optimized based on a pseudoternary phase diagram. Pentoxifylline-loaded microemulsion (PTX-ME) was composed of 44% Tween 80™/Brij 52™ mix as surfactants (S), 51% of caprylic/capric triglycerides as the oil phase (O) and 5% of water as aqueous phase (A). It was classified as an isotropic water-in-oil (W/O) system with droplets that had a heterogeneous spherical shape within the nanosized range (67.36±8.90nm) confirmed by polarized light microscopy, differential scanning calorimetry (DSC), transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis. In vitro studies using static diffusion Franz cells revealed that the release of PTX from ME followed the Higuchi kinetic model. Topical PTX-ME application developed superior anti-inflammatory activity when compared to the PTX solution, reducing the paw edema up to 88.83%. Our results suggested that this colloidal nanosystem is a promising agent for the delivery of pentoxifylline, increasing its ability to modulate the inflammatory aspects of skin disorders.

Optimization of elastic transfersomes formulations for transdermal delivery of pentoxifylline.

Pentoxifylline (PTX) is a xanthine derivative indicated in treatment of intermittent claudication and chronic occlusive arterial diseases. It has low oral bioavailability and short half-life; thus, it was considered as a good candidate drug for the transdermal transfersomes formulation. In the present study, an attempt has been made for development, in-vitro and in-vivo evaluation of transdermal transfersomes using sodium cholate (SC) and non-ionic surfactants as edge activators. The optimal formulation, F4(Gcholate), exhibited drug entrapment efficiency of 74.9±1.6%, vesicles elasticity of 145±0.6 (mgs(-1)cm(-2)), zeta potential of -34.9±2.2mV, average vesicle diameter of 0.69±0.049µm with PDI of 0.11±0.037 and permeation flux of 56.28±0.19µgcm(-2)h(-1). It attained a prolonged drug release where 79.1±2.1% of PTX released after 10h of the run. The drug release kinetic obeys Higuchi model (R(2)=0.997) with Fickian diffusion mechanism. Moreover, the formula enhanced drug permeation through the excised rat's skin predominantly via the carrier-mediated mechanism by 9.1 folds in comparison with the control. Results of the in vivo pharmacokinetics study in male volunteers showed that F4(Gcholate) transfersomes formulation increased PTX absorption and prolonged its half-life comparing to the commercial oral SR tablets. Hence, the elastic transfersomes formulation of PTX possesses admirable potential to avoid drug metabolism, improve PTX bioavailability and sustain its release.

Pentoxifylline affects idarubicin binding to DNA.

Anticancer drug idarubicin - derivative of doxorubicin - is commonly used in treatment of numerous cancer types. However, in contrast to doxorubicin, its biophysical properties are not well established yet. Additionally, potential direct interactions of idarubicin with other biologically active aromatic compounds, such as pentoxifylline - representative of methylxanthines - were not studied at all. Potential formation of such hetero-aggregates may result in sequestration of the anticancer drug and, in consequence, reduction of its biological activity. This work provide description of the idarubicin biophysical properties as well as assess influence of pentoxifylline on idarubicin interactions with DNA. To achieve these goals we employed spectrophotometric methods coupled with analysis with the appropriate mathematical models as well as flow cytometry and Ames test. Obtained results show influence of pentoxifylline on idarubicin binding to DNA and are well in agreement with the data previously published for other aromatic ligands. Additionally it may be hypothesized that direct interactions between idarubicin and pentoxifylline may influence the anticancer drug biological activity.

Development of PEGylated solid lipid nanoparticles of pentoxifylline for their beneficial pharmacological potential in pathological cardiac hypertrophy.

OBJECTIVE: The present study was designed to develop PEGylated solid lipid nanoparticles (SLNs) of pentoxifylline (with increased t½) for the management of cardiac hypertrophy. MATERIALS AND METHODS: PEGylated SLNs were prepared by melt emulsification method and characterised by zeta potential, polydispersity index, entrapment efficiency, in vitro release and pharmacokinetic profile. Hypertrophy was assessed as increase in tumour necrosis factor-alpha, mean arterial blood pressure, LV protein content and left ventricular end diastolic pressure. RESULT: PEGylated SLNs (F19) with increased t½ were developed and characterised. F19 attenuates hypertrophy assessed in terms of parameters employed. CONCLUSION: Thus, PEGylated SLNs (F19) of pentoxifylline have enhanced t½ and consequently more significantly preclude cardiac hypertrophy as compared to pentoxifylline.

Hypothesis: Pentoxifylline explores new horizons in treatment of preeclampsia.

Preeclampsia, the leading cause of maternal morbidity and perinatal mortality, initiates as inappropriate immune response to trophoblastic invasion impairs placentation and placental circulation. A poorly perfused placenta generates superoxide anions as well as anti-angiogenic factors and this series of events result in impairment of endothelial function, followed by maternal morbidities such as hypertension, kidney injury and proteinuria. Renal loss of anti-coagulant proteins and subsequent hyper-coagulable state along with endothelial dysfunction accelerates progression of the disease toward eclampsia. Since Pentoxifylline, a methyl-xanthine derivative known for enhancement of vascular endothelial function, down-regulation of many inflammatory cytokines increased during preeclampsia, improvement of placental circulation, reduction of ischemia-reperfusion injury, enhancement of vasodilatation and endothelial function, ameliorating proteinuria, inhibition of platelet aggregation and decreasing risk of preterm labor, which are all amongst morbidities of preeclampsia, here it is hypothesized that Pentoxifylline prevents development of preeclampsia and/or decelerate progression of the disease.