Evaluation of anti-inflammatory and ulcerogenic potential of zinc-ibuprofen and zinc-naproxen complexes in rats

Because of numerous indications and high availability, non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed and used medicines in the world. However, long-term therapy with and improper use of NSAIDs may lead to gastrointestinal damage. Therefore, improving the therapeutic index of the existing drugs has become a priority over the past decades. Considerable attention in the field has been concentrated on metal complexes of non-steroidal anti-inflammatory drugs. The aim of this study is to evaluate the effect of complexation with zinc on the anti-inflammatory and ulcerogenic effects of ibuprofen and naproxen after single and triple intragastric administration to rats. The anti-inflammatory effect was assessed in carrageenan-induced inflammatory edema in the hind paw of male albino Wistar rats. The mucosal lesions were inspected and evaluated for gross pathology. Single administration of both the investigated complexes, namely zinc-ibuprofen and zinc-naproxen (20 mg/kg equivalent to ibuprofen and naproxen, respectively) and their parent drugs and physical mixtures with zinc hydroaspartate (ZHA doses: 16.05 and 14.37 mg/kg), caused a significant reduction of the edema after the same time from the carrageenan injection in comparison to the control groups. However, no statistically significant differences between the investigated drugs were observed after their single administration. The mean ulceration score for the mixture of ibuprofen and ZHA was statistically lower than the mean score achieved in rats after treatment with ibuprofen alone. On the other hand, triple intragastric administration of the ZHA-ibuprofen and ZHA- naproxen combination showed substantial enhancement of the anti-inflammatory activity against control groups, as well as against the parent NSAIDs. The most potent anti-inflammatory activity was demonstrated after 2 h from the carrageenan injection in animals receiving ZHA together with naproxen. The edema growth was reduced in these animals by 80.9% as compared to the control group. This result was significantly higher than the results achieved in animals receiving zinc-naproxen (50.2%) or naproxen alone (47.9%). Both NSAID complexes with zinc and mixtures with ZHA alleviated ulcerations caused by parent NSAIDs; however, the mixtures of both ibuprofen and naproxen with ZHA after triple administration were the least damaging. In view of the above results, zinc supplementation during NSAID therapy may have a beneficial effect on ulcer prevention and healing by reducing the effective dose of the parent drug and increasing its potency

Study of the anti-inflammatory, analgesic, ulcerogenic and anti-ulcerogenic activity of Nisopropenylimidazole zinc complex derivative

The aim of the study was to investigate the anti-inflammatory, analgesic, ulcerogenic and anti-ulcerogenic activities of N-isopropenylimidazole zinc complex derivativ

Galactosylated Prodrugs: A Strategy to Improve the Profile of Nonsteroidal Anti-Inflammatory Drugs

Carbohydrates are one of the most abundant and important classes of biomolecules. The variety in their structures makes them valuable carriers that can improve the pharmaceutical phase, pharmacokinetics and pharmacodynamics of well-known drugs. D-galactose is a simple, naturally occurring monosaccharide sugar that has been extensively studied for use as a carrier and has proven to be valuable in this role. With the aim of validating the galactose-prodrug approach, we have investigated the galactosylated prodrugs ibuprofen, ketoprofen, flurbiprofen and indomethacin, which we have named IbuGAL, OkyGAL, FluGAL and IndoGAL, respectively. Their physicochemical profiles in terms of lipophilicity, solubility and chemical stability have been evaluated at different physiological pH values, as have human serum stability and serum protein binding. Ex vivo intestinal permeation experiments were performed to provide preliminary insights into the oral bioavailability of the galactosylated prodrugs. Finally, their anti-inflammatory, analgesic and ulcerogenic activities were investigated in vivo in mice after oral treatment. The present results, taken together with those of previous studies, undoubtedly validate the galactosylated prodrug strategy as a problem-solving technique that can overcome the disadvantages of NSAIDs

Cyclodextrins as Anti-inflammatory Agents: Basis, Drugs and Perspectives

Inflammation is a biological response of the immune system to harmful stimuli. Importantly, inflammation is also a hallmark of several human diseases such as cancer or diabetes. Novel drugs to treat this response are constantly researched, but the formulation is usually forgotten. Cyclodextrins (CDs) are a well-known excipient for complexing and drug delivery. Anti-inflammatory drugs and bioactive compounds with similar activities have been favored from these CD processes. CDs also illustrate anti-inflammatory activity per se. This review tried to describe the capacities of CDs in this field, and is divided into two parts: Firstly, a short description of the inflammation disease (causes, symptoms, treatment) is explained; secondly, the effects of different CDs alone or forming inclusion complexes with drugs or bioactive compounds are discussed

Desenvolvimento de novos metalofármacos anticancerígenos

The success of chemotherapy has been achieved with low molecular weight drugs that have been shown to destroy cancer cells or to control their proliferation. However, there are several side effects associated with the use of many of these drugs, mainly due to the fact that they do not have selectivity, acting on both tumor and non-tumor cells. The use of coordinating compounds (metallo-pharmaceuticals) for anticancer therapy began with the use of platinum compounds, which, despite their well-known severe limitations, are still widely used. These disadvantages led to the need to explore new metallo-pharmaceuticals with different transition metals. Diversified metal ions can lead to complexes with different characteristics, such as geometries or reduction potentials. This flexibility makes them attractive for the development of new therapeutic agents. The use of pre-active drugs as ligands is a good example of how metal compounds can alter/enhance the activity of parent drugs. The present work shows the results of the synthesis and characterization of new metallo-pharmaceuticals of different transition metals, the study of their ability to interact with deoxyribonucleic acid (DNA) and bovine albumin (BSA), as well as their anticancer behaviour.This performance was evaluated by in vitro biological assays, in tumoral and normal breast cell lines, which allowed to measure their anti-tumor capacity and selectivity.O sucesso da quimioterapia tem sido conseguido à base de fármacos de baixo peso molecular que têm demonstrado capacidade para destruir as células cancerígenas ou para controlar a sua proliferação. No entanto, existem vários efeitos secundários associados ao uso de muitos destes fármacos, maioritariamente devido ao facto de não apresentarem seletividade, isto é, tanto atuarem nas células tumorais como nas não tumorais. O uso de compostos de coordenação (metalofármacos) para terapia anticancerígena começou com o uso de compostos de platina, os quais, apesar das suas bem conhecidas severas limitações, continuam ainda a ser muito utilizados. Estas desvantagens levaram à necessidade de explorar novos metalofármacos com diferentes metais de transição. Iões metálicos diversificados podem levar à obtenção de complexos com características diferentes, como por exemplo, no que diz respeito a geometrias ou potenciais de redução. Esta flexibilidade torna-os atraentes para o desenvolvimento de novos agentes terapêuticos. O uso de fármacos pré-ativos como ligandos é um bom exemplo de como os compostos metálicos podem alterar/melhorar a atividade dos fármacos parentais. O presente trabalho mostra os resultados da síntese e caracterização de novos metalofármacos de diferentes metais de transição, do estudo da sua capacidade de interação com o ácido desoxirribonucleico (ADN) e com a albumina de origem bovina (BSA), bem como do seu comportamento anticancerígeno. Este desempenho foi avaliado através de ensaios biológicos in vitro, em linhas celulares cancerígenas e normais da mama que permitiram aferir da sua capacidade anti-tumoral e seletividade.Mestrado em Biomedicina Molecula

Synthesis and Investigation of Anti-Inflammatory Activity of New Thiourea Derivatives of Naproxen

The aim of the study was a synthesis and investigation of the dose-dependent anti-inflammatory effect of new thiourea derivatives of naproxen with selected aromatic amines and esters of aromatic amino acids. The results of the in vivo study indicate that derivatives of m-anisidine (4) and N-methyl tryptophan methyl ester (7) showed the most potent anti-inflammatory activity four hours after injection of carrageenan, with the percentage of inhibition of 54.01% and 54.12%, respectively. In vitro assays of COX-2 inhibition demonstrated that none of the tested compounds achieved 50% inhibition at concentrations lower than 100 µM. On the other hand, the aromatic amine derivatives (1–5) accomplished significant inhibition of 5-LOX, and the lowest IC50 value was observed for compound 4 (0.30 μM). High anti-edematous activity of compound 4 in the rat paw edema model, together with potent inhibition of 5-LOX, highlight this compound as a promising anti-inflammatory agen

Synthesis, Characterization, and Investigation of Anti-Inflammatory and Cytotoxic Activities of Novel Thiourea Derivatives of Naproxen

The objective of this study was to synthesize seven novel thiourea derivatives of naproxen (8–14), examine the anti-inflammatory activity of the newly synthesized compounds, investigate the cytotoxic potential of both sets of synthesized compounds (1–7 and 8–14), and select the most promising anti-inflammatory and antitumor drug candidates. The results of the in vivo anti-inflammatory study clearly showed that compounds 8 and 9 were capable of decreasing paw edema, as evident from a high percentage of inhibition (44.83% and 49.29%, respectively). In addition, the results of in vitro enzyme inhibition assays demonstrated that neither of the newly synthesized compounds reached 50% inhibition of 5-LOX at concentrations lower than 100 μM. In terms of antitumor potential, derivatives 3 and 8 exhibited strong cytotoxic effects on the HeLa cell line, suggesting the involvement of the extrinsic pathway of apoptosis. According to the overall results obtained for both sets of synthesized molecules, derivatives 4 and 8 can be underlined as molecules with the strongest anti-inflammatory activity, while derivatives 3 and 8 are the most promising cytotoxic agents

Zinc Complexes with Nitrogen Donor Ligands as Anticancer Agents

The search for anticancer metal-based drugs alternative to platinum derivatives could not exclude zinc derivatives due to the importance of this metal for the correct functioning of the human body. Zinc, the second most abundant trace element in the human body, is one of the most important micro-elements essential for human physiology. Its ubiquity in thousands of proteins and enzymes is related to its chemical features, in particular its lack of redox activity and its ability to support different coordination geometries and to promote fast ligands exchange. Analogously to other trace elements, the impairment of its homeostasis can lead to various diseases and in some cases can be also related to cancer development. However, in addition to its physiological role, zinc can have beneficial therapeutic and preventive effects on infectious diseases and, compared to other metal-based drugs, Zn(II) complexes generally exert lower toxicity and offer few side effects. Zinc derivatives have been proposed as antitumor agents and, among the great number of zinc coordination complexes which have been described so far, this review focuses on the design, synthesis and biological studies of zinc complexes comprising N-donor ligands and that have been reported within the last five years