Search

Vitamin E, essential for human health, is widely used worldwide for therapeutic or dietary reasons. The differences in the metabolism and excretion of the multiple vitamin E forms are presented in this review. The important steps that influence the kinetics of each form and the distribution and processing of vitamin E forms by the liver are considered. The antioxidant as well as non-antioxidant properties of vitamin E forms are discussed. Finally, synthetic tocopherol and trolox derivatives, based on the design of multitarget directed compounds, are reviewed. It is demonstrated that selected derivatization of vitamin E or trolox structures can produce improved antioxidants, agents against cancer, cardiovascular and neurodegenerative disorders.

Byline: P. Rekka, P. Rathna, S. Jagadeesh, S. Seshadri Mucopolysaccharidoses (MPS) are a family of inherited metabolic diseases that results from the deficiency of lysosomal enzymes involved in the degradation [...]

Byline: V. Prabhu, P. Rekka, Ramesh, S. Swathi Epidermolysis bullosa (EB) is a wide spectrum of rare genetic disorders characterized by marked fragility of the skin and mucous membranes in [...]

Background: The biotransformation of xenobiotics is a homeostatic defensive response of the body against bioactive invaders. Xenobiotic metabolizing enzymes, important for the metabolism, elimination and detoxification of exogenous agents, are found in most tissues and organs and are distinguished into phase I and phase II enzymes, as well as phase III transporters. The cytochrome P450 superfamily of enzymes plays a major role in the biotransformation of most xenobiotics as well as in the metabolism of important endogenous substrates such as steroids and fatty acids. The activity and the potential toxicity of numerous drugs are strongly influenced by their biotransformation, mainly accomplished by the cytochrome P450 enzymes, one of the most versatile enzyme systems. Objective: In this review, considering the importance of drug metabolising enzymes in health and disease, some of our previous research results are presented, which, combined with newer findings, may assist in the elucidation of xenobiotic metabolism and in the development of more efficient drugs. Conclusion: Study of drug metabolism is of major importance for the development of drugs and provides insight into the control of human health. This review is an effort towards this direction and may find useful applications in related medical interventions or help in the development of more efficient drugs.

Background: Non-steroidal anti-inflammatory drugs are the oldest and most widely used medicines. However, their untoward effects, especially gastrointestinal toxicity, remain the main obstacle to their application. Because of their mechanism of action, cycloxygenase (COX) inhibition, in combination with the weekly acidic character of most of them, major protective mechanisms of the gastrointestinal system are suppressed and deregulated. Objective: In this review, several compounds designed to retain anti-inflammatory activity, but devoid of gastrointestinal side effects, are presented. Thus, gastro-protective drugs, selective COX-2 inhibitors, nitric monoxide- and hydrogen sulphide-releasing agents, prodrugs, lipoxygenase (LOX) inhibitors and dual COX/LOX inhibitors are presented. Their mechanism of action, as well as their advantages and disadvantages are discussed. Conclusion: Efforts, aiming to the development of safe non-steroidal anti-inflammatory agents, are evolving, however there are still several problems concerning gastro-protection to be efficiently solved, thus, design of effective and safe agents for the treatment of inflammatory conditions still remains a major challenge.

Objectives: A series of esters and amides, incorporating an antioxidant residue, such as trolox or caffeic acid, and various moieties with different biological activities, were synthesised. The obtained compounds demonstrated considerable anti-inflammatory, radical scavenging and antioxidant action. Thus, they could reduce carrageenan-induced rat paw oedema by 31-60% at 150 μ mol/kg and inhibit rat microsomal membrane lipid peroxidation with IC50 values as low as 1.4 μ M, which is much lower than that of trolox. Most of them could also inhibit soybean lipoxygenase. The thiomorpholine derivatives decreased significantly all lipidemic indices of Triton-induced hyperlipidemia in rats. The most active, the caffeic acid derivative (6), decreases triglycerides, total cholesterol and low density lipoprotein, in the plasma of hyperlipidemic rats, by 70%, 67%, and 73%, respectively, at 150 μ mol/kg (i.p.). Conclusion: The synthesised compounds, designed to exhibit two or more pharmacological actions, may be considered useful in the study of agents addressed to conditions involving inflammation and oxidative stress.

Background: Considering that inflammation is involved in many degenerative conditions, some derivatives of tolfenamic acid, naproxen and indomethacin were synthesised and evaluated biologically. They were found to possess increased anti-inflammatory activity, being more potent than the parent drugs. Method: Thus, compound 4, the ester of naproxen with di-tert-butyl-4-(hydroxymethyl)phenol, caused about 80% reduction of carrageenan-induced rat paw oedema, much higher than that of the starting drug. The antioxidant structure containing compounds 1-4 could inhibit soybean lipoxygenase, as well as rat microsomal membrane lipid peroxidation, both effects attributed to the presence of SH or phenolic groups. The effect of compound 1, the amide of tolfenamic acid with L-cysteine ethyl ester, on paracetamol-induced oxidative liver injury and on brain oxidative stress caused by ischemia– reperfusion was examined. Results: It was found that 1 could protect rat liver from glutathione depletion, being comparable to Nacetylcysteine, the classical antidote against paracetamol overdose, and restore hepatic function, as judged by the levels of hepatic enzymes in plasma and the microscopic examination of multiple liver slices. After cerebral ischemia, 1 reduced caspase-3 by 60% and significantly decreased the number of apoptotic cells, especially in hippocampus and cerebellum.

Reactive oxygen species, oxidative stress, and oxidative damage are increasingly assigned important roles as harmful factors in pathological conditions and ageing. ROS are potentially reactive molecules derived from the reduction of molecular oxygen in the course of aerobic metabolism. ROS can also be produced through a variety of enzymes. Under normal circumstances, ROS concentrations are tightly controlled by physiological antioxidants. When excessively produced, or when antioxidants are depleted, ROS can impose oxidative damage to lipids, proteins, sugars and DNA. This reduction-oxidation imbalance, called oxidative stress, can subsequently contribute to the development and progression of tissue damage and play a role in the pathology of various diseases. An antioxidant is defined as “any substance that, when present at low concentrations compared with those of a substrate, significantly delays, prevents or removes oxidative damage to this target molecule”. Despite evidence that oxidative damage contributes to a wide range of clinically important conditions, few antioxidants act as effective drugs in vivo. Inter alia, the difficulty of measuring antioxidant efficacy in vivo makes the interpretation of results from clinical trials difficult. A large number of synthetic compounds have been reported to possess antioxidant activity. Several of them derive from natural antioxidants, others have various structures. In this review, some of the most often reported classes of heterocyclic antioxidant compounds, as well as methods for evaluation of their antioxidant activity are discussed.

We have designed a number of 2-hydroxy (alkoxy)-2-aryl-4-alkyl-(5,6-alkyl)-morpholines with interesting biological activities, i.e. sympathomimetic, analgesic, drug metabolizing enzyme modulating ability, antioxidant potential, anti-inflammatory and anti-dyslipidemic properties. They are synthesised by reaction of the proper 2-aminoethanol with aryl-bromomethyl-ketone. The intermediate hydroxyaminoketone is spontaneously cyclised to form the tetrahydro-1,4-oxazine ring. The produced 2-hydroxy substituted morpholines form the 2-alkoxy derivatives. The 2-hydroxy or 2-alkoxy-1,4-oxazine derivatives can lose water or alcohol, to give styrene-type products. The conditions for oxazine ring formation and water or alcohol abstraction are investigated. Ionisation constants and partition coefficients have been determined and related to structure and activity. The biological activities of these compounds are quite interesting: The 2-phenyl analogues acquire the structural requirements for sympathomimetic amines, and present a structure related to the pethidine-type analgesics. Indeed, they show central dopaminergic and analgesic, antagonized by naloxone, activities. They also affect drug metabolising enzymes. The 2- phenyl and especially the 2-biphenyl derivatives are good antioxidants, also possessing anti-inflammatory and immunomodulating action. The later class of compounds reduces remarkably plasma triglycerides, total cholesterol and LDL-cholesterol in hyperlipidemic rats. Since NO plays a multiple role in atheromatosis and inflammation, some 2- nitroxy-alkoxy derivatives are synthesized and their NO-liberating ability assessed. These nitric esters are also found to be potent hypolipidemic-hypocholesterolemic agents. In a mechanism elucidation attempt, it is indicated that these derivatives may act as squalene synthase inhibitors.

Recently recognized as a distinct CD4+T helper (Th) lineage, Th17 cells have been implicated in host responses to infections and in pathogenesis associated with autoimmune diseases. This cytokine is implicated in primary Sjögren’s syndrome (pSS) immunopathology because of the increased levels of circulating interleukin (IL)-17 in pSS. Plasma and minor salivary glands (MSGs) from patients with pSS were therefore evaluated for CD4+T cells, T regulatory cells, IL-17, and supporting cytokines by immunohistochemistry, RT-PCR, and microbead assays. MSGs from pSS patients contain IL-17-expressing cells as a dominant population within inflammatory lesions. IL-17 protein expression progressively increased with higher biopsy focus scores (P< 0.0001), in parallel with detection by RT-PCR. Transforming growth factor-β, IL-6 and IL-23, which are requisite promoters of Th17 differentiation, were found in abundance compared with the amounts in control tissues. Although transforming growth factor-β is also a pivotal differentiation factor for immunosuppressive Foxp3+T regulatory cells (Tregs), an increase in Foxp3+Tregs was evident in biopsy specimens with mild and moderate inflammation but this increase was disproportionate to escalating pro-inflammatory Th17 populations in advanced disease. Furthermore, the Th17-centric cytokines IL-17, IL-6, IL-23, and IL-12 were significantly elevated in pSS plasma. These data identify a profusion of IL-17-generating cells and supporting cytokines within diseased pSS MSGs without a compensatory increase in immunomodulatory Tregs; this imbalance seems to foster a pathogenic milieu that may be causative and predictive of infiltrative injury and amenable to therapeutic intervention.

EP2302 is a novel nitric oxide donor compound that inhibits squalene synthase. We hypothesized that EP2302 can reduce atherosclerosis in the cholesterol-fed rabbit atherosclerosis model. Animals were fed a high-cholesterol (HC) diet for 4 weeks. Animals subsequently received drug or placebo for 4 (n = 15) or 12 weeks (n = 15) while on HC diet. A third group (n = 16) received drug or placebo for 4 weeks while on regular diet (regression group). No significant differences were observed in circulating lipids among any of the treatment groups at each time point during HC intake. The perimeter and area of the ascending aorta covered by lesions were significantly decreased in animals treated with 2 mg/kg EP2302 for 4 weeks (44% and 42% reduction, respectively). Moreover, a significant decrease in the perimeter of the ascending and descending aorta covered by lesions was observed in animals treated with 2 mg/kg EP2302 for 12 weeks (73% and 44% reduction, respectively) as well as in the regression group (61% and 65% reduction, respectively). Treatment with EP2302 did not cause any toxicity in animal vital organs. We have shown that EP2302 inhibits atherosclerosis in the cholesterol-fed rabbit and therefore may serve as a candidate drug to be tested in humans for atherosclerosis-related disorders.

EP2306 [2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide] inhibits squalene synthase and lipid biosynthesis and possesses antioxidant properties. We hypothesized that EP2306 can effectively modify circulating lipids and reduce atherosclerosis in the cholesterol-fed rabbit. Animals were fed a high-cholesterol diet for 4 weeks followed by 4 (phase 1 and 2) or 12 weeks (phase 3) of drug treatment while on high-cholesterol diet. In phase 1, the dose-effect relationship of EP2306 on lipids and atherosclerosis was established, and its most effective dose was determined (2 mg/kg). This dose reduced significantly total cholesterol (512 +/- 96 mg/dl before versus 320 +/- 124 mg/dl after treatment, p < 0.05) and atherosclerotic lesions compared with control animals. In phase 2, the effects of 2 mg/kg EP2306, 2.5 mg/kg simvastatin, and their combination were assessed. Although no significant effect on lipid parameters was observed, there was a significant reduction (35 +/- 5%, p < 0.05) of atherosclerotic lesions in animals treated with EP2306, a similar reduction with simvastatin, and a further reduction (48 +/- 7%, p < 0.05) when the two agents were combined. In animals treated for 12 weeks with the drugs (phase 3), only EP2306 significantly reduced atherosclerotic lesions by more than 50%, whereas simvastatin alone or in combination with EP2306 had no effect. Treatment with EP2306 did not adversely affect liver transaminases or cause any histopathological changes on various organs of the animals. In conclusion, we have shown that EP2306 inhibits atherosclerosis in vivo, indicating potential as a novel therapeutic agent for coronary artery disease and other atherosclerosis-related disorders.

Mycobacterium aviumis an opportunistic pathogen that commonly infects individuals colonized with HIV‐1, although it is less frequent in the post‐HAART era. These microorganisms invade macrophages after interacting with TLR2 and/or CD14 co‐receptors, but signaling pathways promoting survival in macrophages are not well defined. Although IFN‐γ plays an important role in protective immunity against bacterial infections, IFN‐γ responses are compromised in AIDS patients and evidence suggests that exogenous IFN‐γ is inadequate to clear the mycobacteria. To determine the mechanism by which M. aviumsurvives intracellularly, even in the presence of IFN‐γ, we studied the effect of mycobacteria infection in macrophages during early IFN‐γ signaling events. M. aviuminfected cells exhibited a reduced response to IFN‐γ, with suppressed phosphorylation of STAT‐1 compared with uninfected cells. Interaction of M. aviumwith macrophage receptors increased gene expression of the suppressors of cytokine signaling (SOCS) to diminish IFN responsiveness. Specifically, we observed an increase in mRNA for both SOCS‐3 and SOCS‐1, which correlates with elevated levels of SOCS protein and positive immunostaining in M. avium/HIV‐1 co‐infected tissues. We also linked the p38 MAPK signaling pathway to mycobacterial‐induced SOCS gene transcription. The induction of SOCS may be part of the strategy that allows the invader to render the macrophages unresponsive to IFN‐γ, which otherwise promotes clearance of the infection. Our data provide new insights into the manipulation of the host response by this opportunistic pathogen and the potential for modulating SOCS to influence the outcome of M. aviuminfection in immunocompromised hosts.

The effect on hepatic drug metabolising enzymes was evaluated for three representative structures (1, 2 and 3) that were selected from a series of substituted oxazine derivatives designed to possess particular pharmacological properties such as analgesic, antioxidant and hypolipidemic activity. In addition, since xenobiotic metabolism, reactive oxygen and nitrogen species, atherosclerosis and inflammation are interrelated and mutually affected, the effects of (2) and (3) on acute inflammation in vivo and lipoxygenase activity in vitro were also investigated. It was found that treatment of rats with (1) caused induction of cytochrome P450, enhancement of the metabolism of aminopyrine in vitro and of zoxazolamine and hexobarbital in vivo. Compound (2) appeared to induce particularly erythromycin N-demethylation, while (3), a nitric ester, reduced the catalytically active cytochrome P450, although it increased the metabolism of specific cytochrome P450 substrates, i.e. 4-nitrophenol and erythromycin. Compounds (2) and (3), with strong hypolipidemic and antioxidant properties, reduced acute inflammatory response in two inflammation models and inhibited lipoxygenase activity in vitro. These results are helpful in optimising the biological profile as well as the potential applications of substituted oxazines.

NO is produced endogenously from L-arginine by NOSs. Among its multiple activities, the homeostatic control of the vascular endothelium is crucial for atherosclerosis, a pathogenic condition connected with elevated levels of LDL, the main plasma cholesterol carrier. Oxidised LDL is proatheromatic, and toxic peroxidation products contribute to further endothelial damage. .NO controls vascular tone, inhibits LDL oxidation and has hypocholesterolaemic activity. This review is referred to the chemistry, biology and role of .NO on atherosclerosis and its treatment by .NO donors or modulators.

The synthesis and evaluation of activity of some nitric acid esters of substituted morpholines are presented. All compounds inhibit lipid peroxidation and reduce cholesterol (20−63%) and triglyceride (37−85%) plasma levels. The more potent NO donors 14 and 17 specifically reduce low-density lipoprotein (LDL). These data indicate that proper structural modifications to the hypolipidemic and antioxidant morpholines enabling NO production, besides preserving or enhancing the above activities, offer a remarkable reduction of LDL, considered advantageous for antiatheromatic agents.

Cultured rat precision-cut liver slices (PCLS) were used to study the influence of hypothermic preservation and reoxygenation at 37°C on cellular metabolism and drug biotransformation. Cold hypoxic storage caused a depressed metabolism in rat liver slices, but reoxygenation for 8 h at 37°C partially restored the levels of both ATP and GSH and totally restored the capacity to synthesize proteins. Metabolism of midazolam (CYP3A-dependent oxidation) by cold preserved liver slices was decreased by 30% but no further affected by reoxygenation, showing the same profile as freshly cut slices. Such a reoxygenation at 37°C is accompanied by a dramatic loss of CYP3A2 protein while CYP3A1 protein was unaffected. These results suggest that CYP3A2 did not play a major role in midazolam oxidation. Such results are not consistent with a putative reoxygenation injury but rather with cold hypoxic damage. Since cold preserved liver slices did not respond to bacterial endotoxin stimulation (lipopolysaccharides), a minor role of non-parenchymal cells is suggested as mediators for deleterious effects developed during the cold storage.

Cardiovascular diseases constitute the major cause of death in Western societies. Atherosclerosis is the most common disorder and the pathogenesis of this condition is related to oxidative modifications, leading to the induction of inflammatory mechanisms and finally to the formation of atheromatic plaques. Furthermore, radical mediated destruction of sarcoplasmic membranes is involved in arrhythmias and myocardial ischaemia - reoxygenation. Several recent studies, considering the participation of free radicals in the development of heart disorders, propose the use of antioxidant compounds or preparations in order to prevent the progression of the disease. This article focuses on the patents dated from 1998 through to the fist quarter of 2000, which are related to the therapeutic approaches to the major cardiovascular diseases.

In this investigation, we study the synthesis and the evaluation of antioxidant and hypocholesterolemic activity of a number of 2-biphenylyl morpholine derivatives, which are structurally similar to some substituted morpholines possessing antioxidant activity, as well as to hypocholesterolemic 3-biaryl-quinuclidines. The novel derivatives are found to inhibit the ferrous/ascorbate induced lipid peroxidation of microsomal membrane lipids, the most potent derivative, 2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol (compound 7), having an IC50 value of 250 μM. In addition, these compounds demonstrate hypocholesterolemic and hypolipidemic action. The most active compound (7) decreases total cholesterol, low density lipoprotein, and triglycerides in plasma of Triton WR-1339 induced hyperlipidemic rats by 54%, 51%, and 49%, respectively, at 28 μmol/kg (ip). The above results indicate that the new molecules may be proven useful as leads for the design of novel compounds as potentially antiatherogenic factors.

The role of reactive oxygen species in inflammatory processes has been well documented, while several antioxidant compounds have been shown to exhibit anti-inflammatory activity. We designed novel compounds as potential agents that combine enhanced antioxidant and anti-inflammatory activities. Derivatives of indomethacin, diclofenac, tolfenamic acid, and ibuprofen, four widely used nonsteroidal anti-inflammatory drugs, with cysteamine, a polar antioxidant molecule, were synthesized. The compounds were evaluated for their effect on free radical processes (protection against rat hepatic microsomal lipid-peroxidation and interaction with the stable free radical 1,1-diphenyl-2-picrylhydrazyl), as well as on carrageenan-induced inflammation (mouse paw edema inhibition). Furthermore, ulcerogenicity tests in rats were performed in order to evaluate the gastrointestinal irritation of the novel indomentacin derivative. It was found that all compounds were very potent antioxidants in vitro; they could inhibit lipid peroxidation very significantly, having IC50 values ranging from 55 to 510 μM, while they could also interact ~90% with DPPH at equimolar concentrations. We attribute these activities to their sulfhydryl group, as well as to their increased lipophilicity compared to cysteamine. Furthermore, the derivatives demonstrated significant anti-inflammatory activity, comparable to that of the parent molecules, while they showed significantly reduced ulcerogenic potency. Our results indicate that the combined pharmacological properties of these new derivatives may prove useful for the design and development of novel cytoprotective/anti-inflammatory molecules with potentially important therapeutic applications. Drug Dev. Res. 47:9–16, 1999. © 1999 Wiley-Liss, Inc.

A series of novel piperidine derivatives was prepared and their lipophilicity was determined (as RMvalues). These compounds as well as two intermediate α-keto-esters were tested for antioxidant activity.It was found that the cysteamine derivatives were efficient antioxidants, i.e. they could inhibit lipid peroxidation, act as hydroxyl radical scavengers and interact with 2,2-diphenyl-l-picrylhydrazyl radicals. This interaction could be attributed to the free SH group and this activity seemed to be favoured by increased lipophilicity.Replacement of SH by NH2or OH resulted in a decreased antioxidant activity of the compounds. However, the described activities seem not to be connected with any O−2· scavenging ability, at least under the experimental conditions applied. Furthermore, cysteamine derivatives seem to induce O−2· generation, a phenomenon often observed with thiol compounds.The antioxidant activity of the intermediate α-keto-esters varied and is probably mediated by different mechanisms.

Nine 3-(2-aminoethyl)pyrrole derivatives were investigated as anti-inflammatory agents in the carrageenan-induced rat paw oedema model and as antioxidants in the non-enzymatic lipid peroxidation assay. It was found that the derivatives which were substituted with a p-toluenesulphonyl group exhibited considerable anti-inflammatory activity and some also showed antioxidant properties. However, the presence of a p-toluenesulphonyl group did not invariably lead to activity. A structural feature which was essential for both activities was the aminoethyl side chain. Although a relationship between the antiinflammatory and the antioxidant activities was not apparent, the combination of these properties could be useful.

Four hydroxyethyl rutosides, 7,3′,4′-trihydroxyethyl quercetin, quercetin and a commercial standardized mixture of hydroxyethyl rutosides were investigated on non-enzymatic lipid peroxidation, for hydroxyl radical scavenging activity and interaction with 1,1-diphenyl-2-picrylhydrazyl stable free radical (DPPH). It was found that the tested compounds exhibited a considerable inhibition of microsomal lipid peroxidation. They were less active than the reference compound quercetin, and this was attributed to their structural characteristics. They were also found to be potent hydroxyl radical scavengers and to interact with DPPH. As hydroxyl radical scavengers, they were more potent than the known hydroxyl radical scavengers mannitol and dimethyl sulphoxide. These properties could be considered as a useful and exploitable combination.

The anti-inflammatory activity of two novel opioids PM and PO as well as of pethidine was studied. The mouse paw edema, induced by various phlogistic agents, was significantly inhibited after the administration of opioids, fact that was independent of their antioxidant properties. The anti-inflammatory action of the above opioids was not reversed by naloxone. These results suggest that a variety of complex regulatory activities may be performed by opioid agonists via naloxone-sensitive or naloxone insensitive receptors on inflammatory cells, directly or indirectly by the inhibition of cytokines and mediators involved in inflammation.