Polysaccharide-fecal microbiota-based colon-targeted self-nanoemulsifying drug delivery system of curcumin for treating polycystic ovarian syndrome.

The gut microbiome is involved in the pathogenesis of many diseases including polycystic ovarian syndrome (PCOS). Modulating the gut microbiome can lead to eubiosis and treatment of various metabolic conditions. However, there is no proper study assessing the delivery of microbial technology for the treatment of such conditions. The present study involves the development of guar gum-pectin-based solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing curcumin (CCM) and fecal microbiota extract (FME) for the treatment of PCOS. The optimized S-SNEDDS containing FME and CCM was prepared by dissolving CCM (25 mg) in an isotropic mixture consisting of Labrafil M 1944 CS, Transcutol P, and Tween-80 and solidified using lactose monohydrate, aerosil-200, guar gum, and pectin (colon-targeted CCM solid self-nanoemulsifying drug delivery system [CCM-CT-S-SNEDDS]). Pharmacokinetic and pharmacodynamic evaluation was carried out on letrozole-induced female Wistar rats. The results of pharmacokinetic studies indicated about 13.11 and 23.48-fold increase in AUC of CCM-loaded colon-targeted S-SNEDDS without FME (CCM-CT-S-SNEDDS (WFME)) and CCM-loaded colon-targeted S-SNEDDS with FME [(CCM-CT-S-SNEDDS (FME)) as compared to unprocessed CCM. The pharmacodynamic study indicated excellent recovery/reversal in the rats treated with CCM-CT-S-SNEDDS low and high dose containing FME (group 13 and group 14) in a dose-dependent manner. The developed formulation showcasing its improved bioavailability, targeted action, and therapeutic activity in ameliorating PCOS can be utilized as an adjuvant therapy for developing a dosage form, scale-up, and technology transfer.

Novel Therapeutic Hybrid Systems Using Hydrogels and Nanotechnology: A Focus on Nanoemulgels for the Treatment of Skin Diseases.

Topical and transdermal drug delivery are advantageous administration routes, especially when treating diseases and conditions with a skin etiology. Nevertheless, conventional dosage forms often lead to low therapeutic efficacy, safety issues, and patient noncompliance. To tackle these issues, novel topical and transdermal platforms involving nanotechnology have been developed. This review focuses on the latest advances regarding the development of nanoemulgels for skin application, encapsulating a wide variety of molecules, including already marketed drugs (miconazole, ketoconazole, fusidic acid, imiquimod, meloxicam), repurposed marketed drugs (atorvastatin, omeprazole, leflunomide), natural-derived compounds (eucalyptol, naringenin, thymoquinone, curcumin, chrysin, brucine, capsaicin), and other synthetic molecules (ebselen, tocotrienols, retinyl palmitate), for wound healing, skin and skin appendage infections, skin inflammatory diseases, skin cancer, neuropathy, or anti-aging purposes. Developed formulations revealed adequate droplet size, PDI, viscosity, spreadability, pH, stability, drug release, and drug permeation and/or retention capacity, having more advantageous characteristics than current marketed formulations. In vitro and/or in vivo studies established the safety and efficacy of the developed formulations, confirming their therapeutic potential, and making them promising platforms for the replacement of current therapies, or as possible adjuvant treatments, which might someday effectively reach the market to help fight highly incident skin or systemic diseases and conditions.

Question-based review for pharmaceutical development: An enhanced quality approach.

Over the last years, the pharmaceutical industry has faced real challenges regarding quality assurance. In this context, the establishment of more holistic approaches to the pharmaceutical development has been encouraged. The emergence of the Quality by Design (QbD) paradigm as systematic, scientific and risk-based methodology introduced a new concept of pharmaceutical quality. In essence, QbD can be interpreted as a strategy to maximize time and cost savings. An in-depth understanding of the formulation and manufacturing process is demanded to optimize the safety, efficacy and quality of a drug product at all stages of development. This innovative approach streamlines the pharmaceutical Research and Development (R&D) process, provides greater manufacturing flexibility and reduces regulatory burden. To assist in QbD implementation, International Conference on Harmonisation (ICH), U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) organized and launched QbD principles in their guidance for industry, identifying key concepts and tools to design and develop a high-quality drug product. Despite the undeniable advantages of the QbD approach, and the widespread information on QbD regulatory expectations, its full implementation in the pharmaceutical field is still limited. The present review aims to establish a crosswise overview on the current application status of QbD within the framework of the ICH guidelines (ICH Q8(R2) - Q14 and ICH Q2(R2)). Moreover, it outlines the way information gathered from the QbD methodology is being harmonized in Marketing Authorization Applications (MAAs) for European market approval. This work also highlights the challenges that hinder the deployment of the QbD strategy as a standard practice.

The Debate between the Human Microbiota and Immune System in Treating Aerodigestive and Digestive Tract Cancers: A Review.

The human microbiota comprises a group of microorganisms co-existing in the human body. Unbalanced microbiota homeostasis may impact metabolic and immune system regulation, shrinking the edge between health and disease. Recently, the microbiota has been considered a prominent extrinsic/intrinsic element of cancer development and a promising milestone in the modulation of conventional cancer treatments. Particularly, the oral cavity represents a yin-and-yang target site for microorganisms that can promote human health or contribute to oral cancer development, such as Fusobacterium nucleatum. Moreover, Helicobacter pylori has also been implicated in esophageal and stomach cancers, and decreased butyrate-producing bacteria, such as Lachnospiraceae spp. and Ruminococcaceae, have demonstrated a protective role in the development of colorectal cancer. Interestingly, prebiotics, e.g., polyphenols, probiotics (Faecalibacterium, Bifidobacterium, Lactobacillus, and Burkholderia), postbiotics (inosine, butyrate, and propionate), and innovative nanomedicines can modulate antitumor immunity, circumventing resistance to conventional treatments and could complement existing therapies. Therefore, this manuscript delivers a holistic perspective on the interaction between human microbiota and cancer development and treatment, particularly in aerodigestive and digestive cancers, focusing on applying prebiotics, probiotics, and nanomedicines to overcome some challenges in treating cancer.

Liposome-based diagnostic and therapeutic applications for pancreatic cancer.

Pancreatic cancer is one of the harshest and most challenging cancers to treat, often labeled as incurable. Chemotherapy continues to be the most popular treatment yet yields a very poor prognosis. The main barriers such as inefficient drug penetration and drug resistance, have led to the development of drug carrier systems. The benefits, ease of fabrication and modification of liposomes render them as ideal future drug delivery systems. This review delves into the versatility of liposomes to achieve various mechanisms of treatment for pancreatic cancer. Not only are there benefits of loading chemotherapy drugs and targeting agents onto liposomes, as well as mRNA combined therapy, but liposomes have also been exploited for immunotherapy and can be programmed to respond to photothermal therapy. Multifunctional liposomal formulations have demonstrated significant pre-clinical success. Functionalising drug-encapsulated liposomes has resulted in triggered drug release, specific targeting, and remodeling of the tumor environment. Suppressing tumor progression has been achieved, due to their ability to more efficiently and precisely deliver chemotherapy. Currently, no multifunctional surface-modified liposomes are clinically approved for pancreatic cancer thus we aim to shed light on the trials and tribulations and progress so far, with the hope for liposomal therapy in the future and improved patient outcomes. STATEMENT OF SIGNIFICANCE: Considering that conventional treatments for pancreatic cancer are highly associated with sub-optimal performance and systemic toxicity, the development of novel therapeutic strategies holds outmost relevance for pancreatic cancer management. Liposomes are being increasingly considered as promising nanocarriers for providing not only an early diagnosis but also effective, highly specific, and safer treatment, improving overall patient outcome. This manuscript is the first in the last 10 years that revises the advances in the application of liposome-based formulations in bioimaging, chemotherapy, phototherapy, immunotherapy, combination therapies, and emergent therapies for pancreatic cancer management. Prospective insights are provided regarding several advantages resulting from the use of liposome technology in precision strategies, fostering new ideas for next-generation diagnosis and targeted therapies of pancreatic cancer.

Acanthus mollis Formulations for Transdermal Delivery: From Hydrogels to Emulsions.

Topical formulations of Acanthus mollis L. leaf and the optimization of the release of their active compounds and their topical bioavailability were investigated for the first time. In vitro, the release of active compounds from three formulations-an oil-in-water cream and two hydrogels (Carbopol 940 and Pluronic F-127)-was determined using Franz diffusion cells. Detection and quantification of the compounds was performed via high-performance liquid chromatography with a photodiode array (HPLC-PDA). DIBOA, a bioactive compound of this medicinal plant, exhibited release kinetics of the Weibull model for the Carbopol and Pluronic F-127 formulation, identifying it as a potential active agent to optimize the topical distribution of the formulations. The implications extend to applications in inflammation treatment and tyrosinase inhibition, suggesting that it can make a significant contribution to addressing skin conditions, including melanoma and various inflammatory diseases.

Naringenin: A potential flavonoid phytochemical for cancer therapy.

Naringenin is an important phytochemical which belongs to the flavanone group of polyphenols, and is found mainly in citrus fruits like grapefruits and others such as tomatoes and cherries plus medicinal plants derived food. Available evidence demonstrates that naringenin, as herbal medicine, has important pharmacological properties, including anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, and anti-cancer activities. Collected data from in vitro and in vivo studies show the inactivation of carcinogens after treatment with pure naringenin, naringenin-loaded nanoparticles, and also naringenin in combination with anti-cancer agents in various malignancies, such as colon cancer, lung neoplasms, breast cancer, leukemia and lymphoma, pancreatic cancer, prostate tumors, oral squamous cell carcinoma, liver cancer, brain tumors, skin cancer, cervical and ovarian cancer, bladder neoplasms, gastric cancer, and osteosarcoma. Naringenin inhibits cancer progression through multiple mechanisms, like apoptosis induction, cell cycle arrest, angiogenesis hindrance, and modification of various signaling pathways including Wnt/ß-catenin, PI3K/Akt, NF-ĸB, and TGF-ß pathways. In this review, we demonstrate that naringenin is a natural product with potential for the treatment of different types of cancer, whether it is used alone, in combination with other agents, or in the form of the naringenin-loaded nanocarrier, after proper technological encapsulation.

Trichilia catigua and Turnera diffusa phyto-phospholipid nanostructures: Physicochemical characterization and bioactivity in cellular models of induced neuroinflammation and neurotoxicity.

Flavonoid-based therapies supported by nanotechnology are considered valuable strategies to prevent or delay age-related and chronic neurodegenerative disorders. Egg yolk phospholipids were combined with flavonoid-rich extracts obtained from Trichilia catigua A.Juss. (rich in flavan-3-ols and phenylpropanoid derivatives) or Turnera diffusa Willd. ex Schult (dominated by luteolin derivatives) to prepare nanophytosomes. The nanophytosomes showed that size and surface charge of the lipid-based vesicles are dependent of their phenolic composition. In vitro assays with SH-SY5Y cells showed that both formulations protect cells from glutamate-induced toxicity, but not from 6-hydroxydopamine/ascorbic acid. T. diffusa nanophytosomes promote a decrease of nitric oxide produced by BV-2 cells stimulated with interferon-γ. Nanophytosomes dialysed against a mannitol solution, and then lyophilised, allow to obtain freeze-dried products that after re-hydration preserve the essential physicochemical features of the original formulations, and exhibit improved colloidal stability. These results indicate that these flavonoid/phospholipid-based nanophytosomes have suitable features to be considered as tool in the development of therapeutic and food applications.

Preclinical developments of natural-occurring halloysite clay nanotubes in cancer therapeutics.

The natural world holds useful resources that can be exploited to design effective therapeutic approaches. Ready-to-use tubular nanoclays, such as halloysite clay nanotubes (HNTs), are widely available, cost-effective, and sustainable submicron crystalline materials that have been showing great potential towards chronic multifactorial and malignant diseases, standing out as a promising anticancer nanotherapeutic strategy. Currently, several preclinical studies have reported the application of HNTs in cancer research, diagnosis, monitoring, and therapeutics. This groundbreaking review highlights the preclinical knowledge hitherto collected concerning the application of HNTs towards cancer therapy. Despite their reproducibility issues, HNTs were used as nanoarchitectonic platforms for the delivery of conventional chemotherapeutic, natural-occurring, biopharmaceutical, and phototherapeutic anticancer agents in a wide range of in vitro and in vivo solid cancer models. Overall, in different types of cancer mice models, the intratumoral and intravenous administration of HNTs-based nanoplatforms induced tumor growth inhibition without causing significant toxic effects. Such evidence raises a relevant question: does the therapeutic benefit of the parenteral administration of HNTs in cancer outweigh their potential toxicological risk? To answer this question further long-term absorption-distribution-metabolism-excretion studies in healthy and cancer animal models need to be performed. In cancer therapeutics, HNTs are envisaged as promising platforms for cancer multi-agent therapy, enabling the combination of different therapeutic modalities. Furthermore, HNTs might constitute suitable nanotheranostic platforms. Nevertheless, to confirm the potential and safety of the application of HNTs as nanodelivery systems for cancer therapy, it is necessary to perform in-depth in vivo pharmacokinetics and pharmacodynamic studies to further the translation to clinical trials.

Plant-mediated green synthesis of metal-based nanoparticles for dermopharmaceutical and cosmetic applications.

The skin is the primordial barrier that protects the human body against environmental factors. Due to the arise of dermatological pathologies, the development of efficient delivery systems for topical applications has received increased interest. The highest challenge consists of increasing the penetration of the active ingredients through the skin barrier, alongside to the need of obtaining enough skin retention to achieve therapeutic concentrations. Metals, specially noble metals, have been used for years to treat and prevent health issues, among them dermatological disorders. Nanoparticles have been extensively used for topical applications given their advantages, namely by enhancing solubility of apolar drugs, the possibility of controlled release, the higher stability and the capability to target specific areas and delivery of high concentrations of active ingredients. In order to take advantage of the before mentioned unique properties of nanoparticles and the biological activities of metals, various metal-based nanoparticles (MNPs) have been synthesized in the past few years, such as silver (AgNPs), gold (AuNPs), zinc (ZnNPs), zinc oxide (ZnONPs), copper (CuNPs) and copper oxide (CuONPs) nanoparticles. These MNPs are flexible structures that allow the control of physical characteristics, with enhanced surface properties, which provides a high applicability in dermopharmacy and cosmetics. The conventional methods for synthesizing nanoparticles (physical and chemical approaches) are associated with major drawbacks, being the most concerning the high cost (in resources, energy, time and space) and human/environmental toxicity. Hence, the need to develop an alternative synthesis pathway was imposed, giving rise to the green synthesis methodology. In general, green synthesis consist of using biological sources (plants, bacteria or fungi) to synthesize ecological benign, non-hazard and biocompatible nanoparticles. With the development of green synthesis, starting materials have been used more frequently, among them plants. Plant-mediated green synthesis of nanoparticles is based on the use of plant extracts to synthesize nanoparticles, and their outstanding advantages have paved the way for exciting developments on nanoparticle synthesis to the detriment of complex and toxicity-associated chemical and physical synthesis. MNPs produced by plant-mediated synthesis also demonstrate notorious biological activities, i.e., anticancer, antioxidant, anti-inflammatory, antimicrobial, wound healing and antiaging activities. However, safety assessment of phyto MNPs (phyto-MNPs) holds significant importance due to the lack of toxicological studies and the conception issues that some of the available studies show. In general, current studies suggest the biocompatibility and safety of phyto-MNPs, together with significantly improved and relevant biological activities towards dermopharmaceutical and cosmetic applications. Against this backdrop, there is still a long way to run until the application of phyto-MNPs in the medical, pharmaceutical and cosmetic fields, but studies so far show a very high potential towards their clinical translation for dermopharmaceutical and cosmetics applications. This review focuses on phyto-MNPs synthesized resorting to various plant extracts, including their production, characterization and the biological activities that support their topical application for dermopharmaceutical and cosmetic purposes.

Trichilia catigua and Turnera diffusa extracts: In vitro inhibition of tyrosinase, antiglycation activity and effects on enzymes and pathways engaged in the neuroinflammatory process.

ETHNOPHARMACOLOGICAL RELEVANCE: Flavonoids interact with multiple targets in Central Nervous System resulting in a broad neuroprotection mediated by complementary processes and synergic interactions. Therefore, flavonoid-based therapies may input positive outcomes in the prevention and early management of neurodegenerative diseases. In Brazilian folk medicine Trichilia catigua is used for its neuroactive properties, such as neurostimulant, antioxidant and anti-neuroinflammatory, while Turnera diffusa is traditionally used as a tonic in neurasthenia. Both species are known to be rich in flavonoids. AIM OF THE STUDY: To study aqueous extracts of T. catigua and T. diffusa in terms of their antioxidant and antiglycation effects, inhibition of tyrosinase activity, and interaction with enzymes and pathways engaged in neuroinflammation. Moreover, whenever possible, to establish a relationship between the studied activities and the traditional usage of the species. MATERIALS AND METHODS: The phenolic profiles of the aqueous extracts were validated by HPLC-DAD. The effect of the extracts over mushroom tyrosinase and 5-lipoxygenase activities, as well as their capacity to impair bovine serum albumin glycation, were assessed by in vitro assays. The anti-neuroinflammatory potential of the same extracts was evaluated by their capacity to mitigate the pro-inflammatory stimulus induced in BV-2 microglia cells by interferon-gamma. RESULTS: T. catigua extract, a rich mixture of phenolic acids, catechins and flavonolignans, excels by its ability to decrease lipid peroxidation (EC50 = 227.18 ±â€¯9.04 µg/mL), and to work as anti-glycation agent, and inhibitor of both tyrosinase and 5-lipoxigenase (IC50 = 358.84 ±â€¯19.05 and 56.25 ±â€¯14.53 µg/mL, respectively). However, only T. diffusa extract, mainly composed by luteolin derivatives, is able to lower NO production by BV-2 microglia cells stimulated with interferon-gamma, despite its lower activities in the other assays. CONCLUSIONS: Overall, this work highlights the value of medicinal plant extracts as sources of bioactive flavonoid-rich extracts with neuroactive effects. Furthermore, these results support their application as alternative strategies to develop functional foods and therapeutics to fight chronic neurodegenerative disorders.

Cyclodextrin-based delivery systems for in vivo-tested anticancer therapies.

Cyclodextrins (CDs) are naturally occurring macromolecules widely used as excipients on pharmaceutical formulations, evidencing a large spectrum of applications in the pharmaceutical industry. Their unique ability to act as molecular containers by entrapping a wide range of guest molecules in their internal cavity makes them a remarkable excipient to improve drug apparent solubility, stability, and bioavailability, and a valuable tool for the assembly of new drug delivery systems. These features are especially useful when it comes to chemotherapy, as most of the anticancer drugs present both low permeability and reduced water solubility. Therefore, guest-host inclusion complexes offer several potential advantages not only regarding the improvement of pharmaceutical formulations characteristics but also considering the reduction of drug toxic side effects. The combination of CDs with additional technologies and materials constitutes a potential strategy towards the development of advanced and multifunctional CD-based delivery systems. Paclitaxel, curcumin, camptothecin, doxorubicin, and cisplatin are among the most studied molecules with anticancer activities and have been successfully incorporated in such nanosystems. Exciting results using CDs and CD-based delivery systems have been obtained so far, paving the way towards the attainment of intelligent delivery systems to possibly address cancer therapeutics' unmet needs. In this review, a comprehensive exposition concerning in vivo-tested CD and CD-based delivery systems for anticancer therapy is undertaken. Additionally, the authors address the multivalent functionalities of CD-based delivery systems, namely the incorporation of active target ligands, stimuli-responsiveness components, surface functionalization, or further associations with other delivery systems, aiming at improved in vivo anticancer therapies. Graphical abstract.

Evolution of Hair Treatment and Care: Prospects of Nanotube-Based Formulations.

A new approach for hair treatment through coating with nanotubes loaded with drugs or dyes for coloring is suggested. This coating is produced by nanotube self-assembly, resulting in stable 2-3 µm thick layers. For medical treatment such formulations allow for sustained long-lasting drug delivery directly on the hair surface, also enhanced in the cuticle openings. For coloring, this process allows avoiding a direct hair contact with dye encased inside the clay nanotubes and provides a possibility to load water insoluble dyes from an organic solvent, store the formulation for a long time in dried form, and then apply to hair as an aqueous nanotube suspension. The described technique works with human and other mammal hairs and halloysite nanoclay coating is resilient against multiple shampoo washing. The most promising, halloysite tubule clay, is a biocompatible natural material which may be loaded with basic red, blue, and yellow dyes for optimized hair color, and also with drugs (e.g., antilice care-permethrin) to enhance the treatment efficiency with sustained release. This functionalized nanotube coating may have applications in human medical and beauty formulations, as well as veterinary applications.

Bioequivalence of topical generic products. Part 1: Where are we now?

Regulatory accepted methods for bioequivalence assessment of topical generic products generally involve long and expensive clinical endpoint studies. The only alternative relies on pharmacodynamic trials, solely applicable to corticosteroids. Considerable efforts have been channeled towards the development and validation of other analytical surrogates. The majority of these alternative methods rely on in vitro methodologies that allow a more sensitive and reproducible bioequivalence assessment, avoiding at the same time the financial burden that deeply characterizes clinical trials. The development and validation of these methods represent interesting areas of opportunities for generic drugs, since by enabling faster submission and approval processes, an enlargement of topical drug products with generic version is more easily attainable. This review aims to present a critical discussion of the most promising alternative methods, with particular emphasis on in vitro permeation studies and near infrared spectroscopy studies. Since the last technique is not broadly forecast as a bioequivalence assessment tool, its suitability is assessed by a careful analysis of patents that claim the use of NIR radiation in the skin. In fact, the extensive coverage of the devices that use this technology highlights its applicability towards a better understanding of the mechanism underlying topical drug delivery.

In vitro multimodal-effect of Trichilia catigua A. Juss. (Meliaceae) bark aqueous extract in CNS targets.

ETHNOPHARMACOLOGICAL RELEVANCE: The bark of Trichilia catigua A. Juss. (Meliaceae), popularly known as "big catuaba", is traditionally used in Brazilian folk medicine for its neuroactive potential as memory stimulant, and antinociceptive and antidepressant effects. AIM OF THE STUDY: To study the aqueous extract of T. catigua bark as dual inhibitor of monoamine oxidase A (MAO-A) and acetylcholinesterase (AChE). To explore its antioxidant potential through interaction with xanthine/xanthine oxidase (X/XO) pathway, and to attempt a relationship between its phenolic profile and effects displayed. MATERIALS AND METHODS: Phenolic profiling was achieved by HPLC-DAD-ESI/MSn and UPLC-ESI-QTOF-MS analyses. The capacity to inhibit hMAO-A was assessed in vitro, as was that for AChE, evaluated in rat brain homogenates. The direct inhibition of the X/XO pathway and the scavenging of superoxide anion radical were the selected in vitro models to explore the antioxidant potential. The cytotoxic effects were assayed in the human neuronal SH-SY5Y cells by MTT reduction, after direct exposure (24h). RESULTS: Twenty-six compounds were identified and quantified (551.02 ± 37.61mg/g of lyophilized extract). The phenylpropanoid substituted flavan-3-ols were the most representative compounds (~81% of quantified mass). The extract inhibited hMAO activity in a concentration-dependent manner (IC50 = 121.06 ± 2.13µg/mL). A mixed model of inhibition of AChE activity was observed, reflected by the pronounced increase of Km values and a more discreet effect over the Vmax parameters, calculated from Michaelis-Menten fitted equations. In addition, it was demonstrated that the extract directly inhibits the X/XO pathway (IC50 = 121.06 ± 2.13µg/mL) and also imbalances the oxidative stress acting as superoxide anion radical scavenger (EC50 = 104.42 ± 10.67µg/mL), an oxidative by-product of this reaction. All these neuroprotective and neurotrophic effects were displayed within the non-toxic range of concentrations (0.063-0.500µg/mL) in SH-SY5Y cells. CONCLUSIONS: Our results validate the traditional use of T. catigua bark for its neuroactive and neuroprotective potential. A novel approach upon its application towards the management of neurodegenerative and related symptomatology was likewise demonstrated.

Recent advances in characterization of nonviral vectors for delivery of nucleic acids: impact on their biological performance.

INTRODUCTION: Nucleic acid delivery is a complex process that requires transport across numerous extracellular and intracellular barriers, whose impact is often neglected during optimization studies. As such, the development of nonviral vectors for efficient delivery would benefit from an understanding of how these barriers relate to the physicochemical properties of lipoplexes and polyplexes. AREAS COVERED: This review focuses on the evaluation of parameters associated with barriers to delivery such as blood and immune cells compatibility which, as a collective, may serve as a useful prescreening tool for the advancement of nonviral vectors in vivo. An outline of the most relevant rationally developed polyplexes and lipoplexes for clinical application is also given. EXPERT OPINION: The evaluation of scientifically recognized parameters enabled the identification of systemic delivered nonviral vectors' behavior while in blood as one of the key determinants of vectors function and activity both in vitro and in vivo. This multiparametric approach complements the use of in vitro efficacy results alone for prescreening and improves in vitro-in vivo translation by minimizing false negatives. Further, it can aid in the identification of meaningful structure-function-activity relationships, improve the in vitro screening process of nonviral vectors before in vivo use and facilitate the future development of potent and safe nonviral vectors.

[Impact of predictive models and decision making in prostate cancer: An integral debate]. / Impacto de los modelos predictivos y la toma de decisiones en cáncer de próstata: un debate integral.

OBJECTIVES: To review the various methods to predict the risk of having prostate cancer, or that localized disease may be cured or progress after a given treatment. METHODS: We performed a review of the various mathematic models known for the probability analysis of the event, with a critical analysis of weaknesses and strengths of each method. In a Medline update we review the most relevant papers referred to diagnosis and management of localized prostate cancer in its diagnosis and management sides, as well as the probability of developing metastatic disease and to die. RESULTS: There are multiple methods and models to predict the various events in a patient candidate to diagnosis of prostate cancer, as well as to analyze the possibilities of success of a specific treatment, in many cases with an important exactness. We emphasize the heterogeneity in the methods, data and variables used for the analysis, basically about retrospective studies. Many of the most sophisticated methods, Neural Network or cart, do not present greater exactness than classic methods like logistic regression. CONCLUSIONS: Predictive models are an important element for decision making in usual clinical practice, favoring the decision of a diagnosis or certain treatment is not taken in a random manner and therefore it is taken following scientific criteria. Waiting for more precise methods, we have to know no method is perfect, and therefore it is an important tool, which should not by pass personal knowledge or the experience of a specific working group.

Hepatic and renal toxicities of indomethacin acid, salt form and complexed forms with hydroxypropyl-ß-cyclodextrin on Wistar rats after oral administration.

Indomethacin (IM), a non-steroidal anti-inflammatory drug, has the capacity to induce hepatic and renal injuries when administrated systemically. The aim of this study is to assess the IM absorption from complexed forms when orally administered to rats, by means of a comparative evaluation of its capacity to induce hepatic and renal injury in different forms, namely IM acid, IM sodium salt or IM complexed with hydroxypropyl-ß-cyclodextrin (HP-ß-CD), using freeze- and spray-drying methods. A total of 135 Wistar rats weighing 224.4 ± 62.5 g were put into 10 groups. They were allowed free access to water but were maintained on fast for 18 h before the first administration until the end of the experiment. Water and HP-ß-CD (control groups) and IM acid form, IM trihydrated-sodium-salt and IM-HP-ß-CD spray- and freeze-dried, at normal and toxic doses (test groups), were orally administered once/day for 3 days. Seventy-two hours after the first administration, the animals were sacrificed and a fragment of the liver and one kidney were collected and prepared for histopathological evaluation. Lesion indexes (rated 0/4 for liver and 0/3 for kidney) were developed and the type of injury scored according to the severity of damage. A statistical analysis of the severity and incidence of lesions was carried out. Animals administered with IM complexed forms showed similar hepatic and renal lesions, both in toxic and therapeutic doses, when compared with those observed in animals administered with IM acid or salt forms. This suggests that under the present experimental conditions, IM is equally absorbed from the gastrointestinal tract, independently of the administered IM form.

Starch-based coatings for colon-specific drug delivery. Part I: the influence of heat treatment on the physico-chemical properties of high amylose maize starches.

In this study, the changes in the physico-chemical properties of different high amylose maize starches, i.e., Hylon VII, Hylon V and IM-DS acetate starch, were studied prior and after heat treatment used in the preparation of film coatings (WO 2008/012573 A1). Characterisation of the unprocessed maize starches was carried out with regard to the outer particle morphology, particle size distribution, specific surface area, moisture content, apparent particle density, swelling, polarised light microscopy, Fourier Transform Infrared (FT-IR), X-ray powder diffraction and modulated Differential Scanning Calorimetry (mDSC). Pure amylopectin and low amylopectin samples (LAPS) were also used to aid the interpretation of the results. The effect of heat processing was evaluated in terms of degree of crystallinity, FT-IR and mDSC. Enzymatic digestibility of both processed and unprocessed maize starches was estimated qualitatively using various alpha-amylases resembling those present under in vivo conditions. A significant decrease in the degree of crystallinity of the dried samples after processing was observed, in particular for amylopectin. Only LAPS and Hylon VII samples showed differences in their thermal behaviour upon heat treatment, thus suggesting that a minimum amount of amylose is required for an effect to be detectable. High amylose starches maintained a well-ordered arrangement of their macromolecular chains, as was seen by X-ray and FT-IR studies. This effect could be explained by a formation of retrograded forms of the starches. The retrograded starches were found to be less digestible by various types of amylase, in particular those found in the upper intestines, indicating that the formation of a butanol complex as claimed elsewhere is not essential in the preparation of colon delivery devices.

Leiomiosarcoma de cava inferior. Hallazgo incidental / Leiomyosarcoma of the inferior vena cava. Incidental finding

Objetivo: El leiomiosarcoma de cava inferior es una entidad poco frecuente, clínicamente insidiosa o silente y detectable en muchas ocasiones únicamente mediante estudios de imagen. Se presenta un caso intervenido en nuestro servicio y se revisa la literatura al respecto. Método: Mujer de 58 años con una masa suprarrenal derecha de 6 cm evidenciando su origen en la pared de vena cava durante el acto quirúrgico. Se realiza exeresis completa de la tumoración, y posteriormente , radioterapia adyuvante sobre el lecho quirúrgico. Resultados: Tras más de 2 años de evolución, la paciente se encuentra libre de enfermedad. Conclusiones: Esta entidad presenta una escasa prevalencia, y en muchas ocasiones su hallazgo es incidental. La resección quirúrgica completa es la clave del tratamiento, aunque la probabilidad de recidiva local es elevada (AU)

Objective: Leiomyosarcoma of the inferior vena cava is a rare tumor, clinically silent which often remains undiagnosed for much longer. Imaging methods allow us to detect these entities. We report a single case and perform a bibliographic review. Methods: 58-year-old woman with a 6 cm adrenal mass, which during surgery was found to be a tumor from the wall of the vena cava. We performed complete removal of the mass. Radiotherapy of the surgical area was applied within three months following surgery. Results: Two years later, there is no evidence of disease recurrence. Conclusion: This is a rare entity, with low prevalence. Complete surgical excision is the gold standard for treatment. Local recurrence is a common finding during follow up (AU)