The role of molecular imaging in modern drug development

Drug development represents a highly complex, inefficient and costly process. Over the past decade, the widespread use of nuclear imaging, owing to its functional and molecular nature, has proven to be a determinant in improving the efficiency in selecting the candidate drugs that should either be abandoned or moved forward into clinical trials. This helps not only with the development of safer and effective drugs but also with the shortening of time-to-market. The modern concept and future trends concerning molecular imaging will assumedly be hybrid or multimodality imaging, including combinations between high sensitivity and functional (molecular) modalities with high spatial resolution and morphological techniques.

Characterization of an antioxidant surfactant-free topical formulation containing Castanea sativa leaf extract

Context: Inclusion of antioxidants in topical formulations can contribute to minimize oxidative stress in the skin, which has been associated with photoaging, several dermatosis and cancer. Objective: A Castanea sativa leaf extract with established antioxidant activity was incorporated into a semisolid surfactant-free formulation. The objective of this study was to perform a comprehensive characterization of this formulation. Materials and methods: Physical, microbiological and functional stability were evaluated during 6 months storage at 20 °C and 40 °C. Microstructure elucidation (cryo-SEM), in vitro release and in vivo moisturizing effect (Corneometer® CM 825) were also assessed. Results and discussion: Minor changes were observed in the textural and rheological properties of the formulation when stored at 20 °C for 6 months and the antioxidant activity of the plant extract remained constant throughout the storage period. Microbiological quality was confirmed at the end of the study. Under accelerated conditions, higher modifications of the evaluated parameters were observed. Cryo-SEM analysis revealed the presence of oil droplets dispersed into a gelified external phase. The release rate of the antioxidant compounds (610 ± 70 µgh−0.5) followed Higuchi model. A significant in vivo moisturizing effect was demonstrated, that lasted at least 4 h after product’s application. Conclusion: The physical, functional and microbiological stability of the antioxidant formulation was established. Specific storage conditions should be recommended considering the influence of temperature on the stability. A skin hydration effect and good skin tolerance were also found which suggests that this preparation can be useful in the prevention or treatment of oxidative stress-mediated dysfunctions.

Development of paper-based color test-strip for drug detection in aquatic environment: Application to oxytetracycline

The wide use of antibiotics in aquaculture has led to the emergence of resistant microbial species. It should be avoided/minimized by controlling the amount of drug employed in fish farming. For this purpose, the present work proposes test-strip papers aiming at the detection/semi-quantitative determination of organic drugs by visual comparison of color changes, in a similar analytical procedure to that of pH monitoring by universal pH paper. This is done by establishing suitable chemical changes upon cellulose, attributing the paper the ability to react with the organic drug and to produce a color change. Quantitative data is also enabled by taking a picture and applying a suitable mathematical treatment to the color coordinates given by the HSL system used by windows. As proof of concept, this approach was applied to oxytetracycline (OXY), one of the antibiotics frequently used in aquaculture. A bottom-up modification of paper was established, starting by the reaction of the glucose moieties on the paper with 3-triethoxysilylpropylamine (APTES). The so-formed amine layer allowed binding to a metal ion by coordination chemistry, while the metal ion reacted after with the drug to produce a colored compound. The most suitable metals to carry out such modification were selected by bulk studies, and the several stages of the paper modification were optimized to produce an intense color change against the concentration of the drug. The paper strips were applied to the analysis of spiked environmental water, allowing a quantitative determination for OXY concentrations as low as 30 ng/mL. In general, this work provided a simple, method to screen and discriminate tetracycline drugs, in aquaculture, being a promising tool for local, quick and cheap monitoring of drugs.

Development of paper-based color test-strip for drug detection in aquatic environment: Application to oxytetracycline

The wide use of antibiotics in aquaculture has led to the emergence of resistant microbial species. It should be avoided/minimized by controlling the amount of drug employed in fish farming. For this purpose, the present work proposes test-strip papers aiming at the detection/semi-quantitative determination of organic drugs by visual comparison of color changes, in a similar analytical procedure to that of pH monitoring by universal pH paper. This is done by establishing suitable chemical changes upon cellulose, attributing the paper the ability to react with the organic drug and to produce a color change. Quantitative data is also enabled by taking a picture and applying a suitable mathematical treatment to the color coordinates given by the HSL system used by windows. As proof of concept, this approach was applied to oxytetracycline (OXY), one of the antibiotics frequently used in aquaculture. A bottom-up modification of paper was established, starting by the reaction of the glucose moieties on the paper with 3-triethoxysilylpropylamine (APTES). The so-formed amine layer allowed binding to a metal ion by coordination chemistry, while the metal ion reacted after with the drug to produce a colored compound. The most suitable metals to carry out such modification were selected by bulk studies, and the several stages of the paper modification were optimized to produce an intense color change against the concentration of the drug. The paper strips were applied to the analysis of spiked environmental water, allowing a quantitative determination for OXY concentrations as low as 30 ng/mL. In general, this work provided a simple, method to screen and discriminate tetracycline drugs, in aquaculture, being a promising tool for local, quick and cheap monitoring of drugs.

Development of novel ionic liquids based on valproate anion

Valproic acid (2-propyl pentanoic acid) is a pharmaceutical drug used for treatment of epileptic seizures absence, tonic-clonic (grand mal), complex partial seizures, and mania in bipolar disorder [1]. Valproic acid is a slightly soluble in water and therefore as active pharmaceutical ingredient it is most commonly applied in form of sodium or magnesium valproate salt [1].However the list of adverse effects of these compounds is large and includes among others: tiredness, tremor, sedation and gastrointestinal disturbances [2]. Ionic liquids (ILs) are promising compounds as Active Pharmaceutical Ingredients (APIs)[3]. In this context, the combinations of the valproate anion with appropriate cation when ILs and salts are formed can significantly alter valproate physical, chemical and thermal properties.[4] This methodology can be used for drug modification (alteration of drug solubility in water, lipids, bioavailability, etc)[2] and therefore can eliminate some adverse effect of the drugs related to drug toxicity due for example to its solubility in water and lipids (interaction with intestines). Herein, we will discuss the development of ILs based on valproate anion (Figure 1) prepared according a recent optimized and sustainable acid-base neutralization method [4]. The organic cations such as cetylpyridinium, choline and imidazolium structures were selected based on their biocompatibility and recent applications in pharmacy [3]. All novel API-ILs based on valproate have been studied in terms of their physical, chemical (viscosity, density, solubility) and thermal (calorimetric studies) properties as well as their biological activity.

Development and biological evaluation of API-ILs based on anti-bacterial and anti-fungal drugs

In recent years Ionic Liquids (ILs) are being applied in life sciences. ILs are being produce with active pharmaceutical drugs (API) as they can reduce polymorphism and drug solubility problems [1] Also ILs are being applied as a drug delivery device in innovative therapies What is appealing in ILs is the ILs building up platform, the counter-ion can be carefully chosen in order to avoid undesirable side effects or to give innovative therapies in which two active ions are paired. This work shows ILs based on ampicillin (an anti-bacterial agent) and ILs based on Amphotericin B. Also we show studies that indicate that ILs based on Ampicillin could reverse resistance in some bacteria. The ILs produced in this work were synthetized by the neutralization method described in Ferraz et. al. [2] Ampicillin anion was combined with the following organic cations 1-ethyl-3-methylimidazolium, [EMIM]; 1-hydroxy-ethyl-3-methylimidazolium, [C2OHMIM]; choline, [cholin]; tetraethylammonium, [TEA]; cetylpyridinium, [C16pyr] and trihexyltetradecylphosphonium, [P6,6,6,14]. Amphotericin B was combined with [C16pyr], [cholin] and 1-metohyethyl-3-methylimidazolium, [C3OMIM]. The ILs-APIs based on ampicillin[2] were tested against sensitive Gram-negative bacteria Escherichia coli ATCC 25922 and Klebsiella pneumonia (clinical isolated), as well as on Gram positive Staphylococcus Aureus ATCC 25923, Staphylococcus epidermidis and Enterococcus faecalis. The arising resistance developed by bacteria to antibiotics is a serious public health threat and needs new and urgent measures. We study the bacterial activity of these compounds against a panel of resistant bacteria (clinical isolated strains): E. coli CTX M9, E. coli TEM CTX M9, E. coli TEM1, E. coli CTX M2, E. coli AmpC Mox2. In this work we demonstrate that is possible to produce ILs from anti-bacterial and anti-fungal compounds. We show here that the new ILs can reverse the bacteria resistance. With the careful choice of the organic cation, it is possible to create important biological and physic-chemical properties. This work also shows that the ion-pair is fundamental in ampicillin mechanism of action.

Exploring nature profits: development of novel and potent lipophilic antioxidants based on galloylecinnamic hybrids

Phenolic acids are ubiquitous antioxidants accounting for approximately one third of the phenolic compounds in our diet. Their importance was supported by epidemiological studies that suggest an inverse relationship between dietary intake of phenolic antioxidants and the occurrence of diseases, such as cancer and neurodegenerative disorders. However, until now, most of natural antioxidants have limited therapeutic success a fact that could be related with their limited distribution throughout the body and with the inherent difficulties to attain the target sites. The development of phenolic antioxidants based on a hybrid concept and structurally based on natural hydroxybenzoic (gallic acid) and hydroxycinnamic (caffeic acid) scaffolds seems to be a suitable solution to surpass the mentioned drawbacks. Galloylecinnamic hybrids were synthesized and their antioxidant activity as well as partition coefficients and redox potentials evaluated. The structureepropertyeactivity relationship (SPAR) study revealed the existence of a correlation between the redox potentials and antioxidant activity. The galloylecinnamic acid hybrid stands out as the best antioxidant supplementing the effect of a blend of gallic acid plus caffeic acid endorsing the hypothesis that the whole is greater than the sum of the parts. In addition, some hybrid compounds possess an appropriate lipophilicity allowing their application as chain-breaking antioxidant in biomembranes or other type of lipidic systems. Their predicted ADME properties are also in accordance with the general requirements for drug-like compounds. Accordingly, these phenolic hybrids can be seen as potential antioxidants for tackling the oxidative status linked to the neurodegenerative, inflammatory or cancer processes.

Exploring cinnamic acid scaffold: development of promising neuroprotective lipophilic antioxidants

New lipophilic hydroxycinnamic acid based derivatives were designed and synthesized and their antioxidant and neuroprotective activities evaluated. The chemical modification introduced in the cinnamic acid scaffold leads to compounds with amplified lipophilicity and in general with increased antioxidant activity when compared to natural models (caffeic and ferulic acids). The compounds did not display cytotoxicity and present a significant neuroprotective effect against 6-OH-DA induced damage to SH-SY5Y cells. Compound 6 stands out as an efficient radical scavenger and iron(II) chelator that ensures drug-like properties. Moreover, neuroprotection against oxidative damage was observed even at low concentration (1 μM). Therefore, compound 6 developed by a biology-oriented approach displays a combination of important features for a further optimization process that will generate a new effective antioxidant with therapeutic application for oxidative-stress-related events, namely neurodegenerative diseases.