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.     

Recent advances in the study of (–)clausenamide: chemistry,biological activities and mechanism of action

Clausenamide (clau) is one of seven novel compounds isolated from Clausena lansium (Lour) skeels. Clau is unusual in that it contains 4 chiral centers yielding 8 pairs of enantiomers. After identification of the configuration of these enantiomers, the synthesis of 16 enantiomers, including optically active clau and (+) and (–)clau was carried out. During this study, many stereochemical and synthetic difficulties were solved and the Baldwin principle was updated. Production scale is now sufficient to meet the needs of clinical practice. In a pharmacological study numerous models and indicators showed that (–)clau is the active enantiomer, while (+)clau is inactive and elicits greater toxicity than (–)clau. The principal pharmacological effects of (–)clau are to increase cognition, demonstrated in ten models of memory impairment, as well as to inhibit β-amyloid (Aβ) toxicity, blocking neurofibrillary tangle formation by inhibiting the phosphorylation of tau protein. This anti-dementia effect is characterized by increased synaptic plasticity both in efficacy and in structure and provides new support for the theory that synaptic loss is the main cause of dementia. (–)Clau is considered to be a promising drug candidate for treatment of Alzheimer׳s disease and other neurodegenerative disorders.KEY WORDS: (–)Clausenamide, Enantiomers, Cognition, Alzheimer׳s disease pathology, Tau, High phosphorylation, Synaptic plasticity     

Evaluation of the polyethylene glycol–KF–water system in the context of purifying PEG–protein adducts

Covalent binding of PEG to proteins leads to conjugates widely investigated in several biotechnological processes. Their use as pharmaceuticals requires both careful purification and proper characterization. In this context, this paper examines the potentialities offered by hydrophobic interaction chromatography and compares aqueous potassium fluoride and ammonium sulfate as the eluents. Relative contribution of the various forces which dictate the chromatographic behaviour of PEG–protein adducts on Fractogel TSK–Butyl 650 is discussed.     

Alkaloids from the Roots of Aristolochia Triangularis(I)

从马兜铃科植物Ａｒｉｓｔｏｌｏｃｈｉａｔｒｉａｎｇｕｌａｒｉｓ的根部分离出十五个生物碱成分。其中两种成分ｔｒｉａｎｇｕｌａｒｉｎｅ－Ａ和ｔｒｉａｎｇｕｌａｒｉｎｅ－Ｂ系新生物碱，三种系阿卟啡类季铵碱。这些化合物的结构经各种波谱（ＩＲ，ＵＶ，ＭＳ，２ＤＮＭＲ）解析和化学转化技术得以确定。     

Synthesis,structure–activity relationship and antinociceptive activities of some 2-(2′-pyridyl) benzimidazole derivatives

In the present study, a new series of 2-(2′-pyridyl) benzimidazole derivatives 1–11 were resynthesized and evaluated for analgesic activity. The 2-(2′-pyridyl) benzimidazole was quaternized at its nitrogen atom in the ring with various substituted and unsubstituted phenacyl halides. As a result, eleven novel derivatives were synthesized. The structures of these new synthetic derivatives of 2-(2′-pyridyl) benzimidazole were confirmed by using different spectroscopic techniques i.e., UV/Visible, IR, ¹HNMR and Mass spectroscopy. Percentage of carbon, hydrogen and nitrogen was also determined by elemental analysis. All the synthetic compounds showed significant analgesic activity with dose-dependent manner.     

Evaluation of the Threshold of Toxicological Concern (TTC) – Challenges and approaches

Thresholds of Toxicological Concern (TTCs) have been used in the risk assessment of chemicals to which humans are exposed at very low levels. TTC values were developed using data from rodent cancer bioassays and from oral chronic and sub-chronic toxicity studies for non-cancer effects. The workshop assessed the adequacy and fitness for purpose of the TTC approach and the potential for future modifications of critical aspects. The current TTC value for cancer was considered adequate and fit for purpose because it is derived by linear extrapolation from the lowest TD₅₀ for each compound in the largest available rodent carcinogenicity database. The database on non-cancer endpoints was considered adequate and fit for purpose because the chemical domain, the distributions of NOAELs and the calculated TTC values are comparable across different databases. Application of the TTC approach gives conclusions compatible with the risk assessment approaches currently used by international advisory committees. The workshop recognised the desirability of developing better tools to assess the comparability of the chemical domain covered in different toxicological databases, and the need to develop an internationally acceptable framework and databases for updating the aspects critical to application of the TTC approach.     

Possible evidence for contribution of arbuscular mycorrhizal fungi (AMF) in phytoremediation of iron–cyanide (Fe–CN) complexes

Arbuscular mycorrhizal fungi (AMF) are integral functioning parts of plant root systems and are widely recognized for enhancing contaminants uptake and metabolism on severely disturbed sites. However, the patterns of their influence on the phytoremediation of iron–cyanide (Fe–CN) complexes are unknown. Fe–CN complexes are of great common interest, as iron is one of the most abundant element in soil and water. Effect of ryegrass (Lolium perenne L.) roots inoculation, using mycorrhizal fungi (Rhizophagus irregularis and a mixture of R. irregularis, Funneliformis mosseae, Rhizophagus aggregatus, and Claroideoglomus etunicatum), on iron–cyanide sorption was studied. Results indicated significantly higher colonization of R. irregularis than the mixture of AMF species on ryegrass roots. Series of batch experiments using potassium hexacyanoferrate (II) solutions, in varying concentrations revealed significantly higher reduction of total CN and free CN content in the mycorrhizal roots, indicating greater cyanide decrease in the treatment inoculated with R. irregularis. Our study is a first indication of the possible positive contribution of AM fungi on the phytoremediation of iron–cyanide complexes.     

Racemic total synthesis and evaluation of the biological activities of the isoquinoline–benzylisoquinoline alkaloid muraricine

The first racemic total synthesis of the isoquinoline–benzylisoquinoline alkaloid muraricine is reported herein. Pharmacological characterization identified muraricine as a moderate inhibitor of P-glycoprotein, a crucial factor of multidrug resistance in cancer. When combined with vincristine, muraricine partly reversed the chemoresistance of vincristine-resistant leukemia cells at a nontoxic concentration. Furthermore, no cytotoxic effects on noncancerous human cells in therapeutically relevant concentrations were observed.     

Optimization of the Central Core of Indolinone–Acetic Acid-Based CRTH2 (DP2) Receptor Antagonists

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Evaluation of the efficacy of dicyclomine hydrochloride (‘Merbentyl’) syrup in the treatment of infant colic

Summary

A double-blind crossover trial was carried out in 25 babies with infant colic to compare the symptomatic relief provided by dicyclomine hydrochloride (5mg4-times daily) or placebo. Patients received each treatment, in random order, for 1 week. A scoring system was used to measure the total symptom complex as well as the individual parameters of post-prandial crying, post-prandial vomiting, and sleep disturbance. Dicyclomine hydrochloride syrup was found to be superior to placebo in relieving the total symptom complex (p < 0.025) and in reducing sleep disturbance (p < 0.05). Side-effects with both therapies were minimal.     

Thermodynamic Study of Sulfanilamide Polymorphism: (I) Monotropy of the α-Variety

Purpose. Sulfanilamide was chosen as a model compound in order to gain insights on the stability hierarchy of drug polymorphs from structural and thermodynamic criteria. Despite numerous studies, disagreements remained on the reported enthalpies associated with the mutual interconvertions of the -, -, and -forms of sulfanilamide. Therefore, the unambiguous determination of these enthalpies was the purpose of this work. Methods. Samples, free of solvent inclusions and made of only one form, were prepared, and analyzed combining X-ray powder diffraction and Differential Scanning Calorimetry (DSC). Results. The enthalpy values associated with the - to - and - to -transitions were found to be + 10.2 and + 10.9 J g^–1, respectively. The calculated enthalpy of the - to -transition is consistent with the experimental one ( + 1 J g^–1). Conclusions. The monotropy of the -form was ascertained over the explored temperature range at ordinary pressure.     

Diorganotin (IV) derivative of 2-thiophene acetic acid: characterizations and biological activities of {[n-Bu2SnO2C–CH2–C4H3S]2O}2

New organotin (IV) derivatives of thiophene acetic acid have been prepared and characterized by IR, ¹H- and ¹³C-NMR spectroscopic techniques. A single crystal of {[n-Bu₂SnO₂C–CH₂–C₄H₃S]₂O}₂ has been synthesized and its cell parameters were measured. It crystallizes in the monoclinic system (P2₁) [a?=?15.1337(7), b?=?12.2587(5), c?=?18.8766(9), and β?=?105.811(5)°]. The compound showed selective inhibitory effect against β-glucuronidase enzyme (IC₅₀ 3.1?±?0.1?μM), which is more potent than our standard, d-saccharic acid 1,4-lactone (IC₅₀ 48.4?±?1.3?μM). Also, it exhibited immunomodulatory activity, and cytotoxicity against PC-3 cell line (IC₅₀?=?16.9?±?1.3?μM, and 1.2?±?0.1?μM, respectively), which are close to the standards ibuprofen (IC₅₀ 11.8?±?1.8?μM), and doxorubicin (IC₅₀ 0.9?±?0.1?μM), respectively. This compound did not show any significant inhibition for other biological test such as α-chymotrypsin, urease, phosphodiesterase enzymes, and antiglycation activity.     

Synthesis and antibacterial evaluation of Cu(II) and Zn(II) complexes of the β-lactum antibiotic, cefdinir

In this study, the coordination chemistry of the antibiotic, cefdinir, and its metal complexes with Cu (II) and Zn (II) was described and characterized on the basis of analytical and spectral studies. The synthesized complexes were evaluated in vitro for their antibacterial activity against Staphylococcus aureus, Bacillus subtilis, and Escherichia coli. The metal complexes possessed the better antibacterial activity against the selected species of bacteria than the free antibiotic (cefdinir). The results were supported by the increase in log P values of metal complexes in comparison to the free ligand cefdinir. The importance of these findings lies in the fact that these complexes could be applied in the treatment of common bacterial infections.     

Evaluation of single nucleotide polymorphisms in the miR-183–96–182 cluster in adulthood attention-deficit and hyperactivity disorder (ADHD) and substance use disorders (SUDs)

Attention deficit-hyperactivity disorder (ADHD) is a neuropsychiatric disorder characterized by inappropriate and impaired levels of hyperactivity, impulsivity and inattention. Around 75% of adults with ADHD show comorbidity with other psychiatric disorders such as disruptive behavior disorders or substance use disorders (SUDs). Recently, there has been growing interest in studying the role of microRNAs (miRNAs) in the susceptibility to complex disorders. Interestingly, converging evidence suggests that single nucleotide polymorphisms (SNPs) within miRNAs or miRNA target sites may modulate the miRNA-mediated regulation of gene expression through the alteration of the miRNA maturation, structure or expression pattern as well as the silencing mechanisms of target genes. Genetic studies and animal models support the involvement of the serotonin receptor (HTR1B) in ADHD. We evaluated the contribution of one SNP in the miR-96 target site at HTR1B and eight tagSNPs within the genomic region containing this miRNA in 695 adults with ADHD (266 and 396 subjects with and without comorbid SUD, respectively), 403 subjects with SUD without life-time diagnosis of ADHD and 485 sex-matched controls from Spain. Single and multiple marker analyses revealed association between two SNPs located at the 3′ region of miR-96 (rs2402959 and rs6965643) and ADHD without SUD. Our results provide preliminary evidence for the contribution of two sequence variants at the miR-183–96–182 cluster to ADHD without comorbid SUD, and emphasize the need to take comorbidities into account in genetic studies to minimize the effect of heterogeneity and to clarify these complex phenotypes.     

Alteration of Na~ -K~ -exchanging ATPase and Ca~(2 )-Mg~(2 )-ATPase activities at initial stage of isoprenaline-induced ischemia in mouse cerebrum

AIM: To study the possible protection by isoprenaline (Iso) on cerebral ischemia. METHODS: Cerebral ischemia was induced by sc Iso 15 mg·kg~(-1) at different time. Molondialdehyde(MDA)content, Na~ -K~ -