Anti-inflammatory property in vivo

McQuibban GA, Gong JH, Wong JP, Wallace JL, Clark-Lewis I, Overall CM. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 2002 100(4) 1160-1167. 

Hydroxycinnamic acid derivatives have shown antioxidant and anti-inflammatory properties in vivo and in vitro. They contribute to DNA protection and help to prevent Alzheimer s disease [64, 65]. However, data are still too limited for an informed assessment of hydroxycinnamics [49]. 

De Esch HP, Hanzer A, Leurs R, Lim HD, Smits RA, Zuiderveld OP, Adami M, Coruzzi G, Guaita E (2008) Fragment based design of new H4 receptor-ligands with anti-inflammatory properties in vivo. J Med Chem 51 2457-2467... 

Milk thistle may have anti-inflammatory properties. In vitro, silybin strongly and noncompetitively inhibits lipoxygenase and leukotriene formation. On the other hand, concentrations required to inhibit thromboxane and prostaglandin formation in vivo probably exceed dosing capabilities. Inhibition of leukocyte migration has also been observed in vivo and may be a factor when acute inflammation is present. 

The new second-generation antihistamines are more selective Hi histamine receptor antagonists, and many of them have additional anti-aUergic properties in vivo, for example they reduce the release of inflammatory mediators or inhibit the recruitment of inflammatory cells (3-7). They also enter the brain less well and are therefore less likely to cause central adverse effects. 

Researchers (Nuijens et al., 1997) at the Leiden University (the Netherlands) in collaboration with Pharming, NV (Leiden, the Netherlands) compared recombinant human lactoferrin (rhLF) expressed in the milk of transgenic mice with natural human milk-derived lactoferrin (hLF). They concluded that the unsaturated rhLF and natural hLF had comparable properties, indicating that hLF produced in bovine milk will exert similar, if not identical, antibacterial and anti-inflammatory activities in vivo. Pharming also developed the first transgenic bull in the late... 

Further, these newly synthesized products were evaluated as antioxidants and lipid peroxidation (LPO) inhibitors in vitro. One compound from both the groups, benzoxazepine and benzodiazepine, (R = Me) were found to be the most potent inhibitors of lipoxygenase and LPO, respectively. The amino substituent containing benzoxazepine derivative showed most encouraging antioxidant property. Benzodiazepine (R = R = 4-CIC6H4) derivative was also evaluated as anti-inflammatory agent in vivo. 

It was initially argued that the best potential PTK inhibitors would be compounds that compete for the substrate in the kinase binding domain. It was argued that such compounds would be less toxic than ATP mimics since they bind to those domains at the kinase site that are less conserved than the substrate binding domains. Indeed tyrphostins like AG 490 which blocks Jak-2 [10] and AG 556 which possesses anti-inflammatory properties have been shown to be highly non-toxic in vivo [34-37]. 

The histamine H4-receptor which was discovered in 2001 has been shown to have a role in chemo-taxis and mediator release in various types of immune cells including mast cells, eosinophils, dendritic cells and T cells. H4-receptor antagonists have been shown to have anti-inflammatory properties and efficacy in a number of disease models, such as those for asthma and colitis in vivo. Cinnarizine has a high affinity for the H4-receptor. Recently other H4-receptor antagonists have been developed with high receptor affinity and specificity. The first few studies into the function of H4-receptors suggested... 

Melanocortin peptides display anti-oxidant and anti-inflammatory properties and may be beneficial in the context of ischemia and reperfusion. Administration of ACTH-1-24, a melanocyte-stimulating hormone before ischemia prevented reperfusion arrhythmias in an in vivo model of regional ischemia and reperfiision. Furthermore, administration of long acting melanocortin peptide NDP MSH resulted in infarct size reduction in rats subjected to permanent coronary occlusion.29 Work in this area is not very extensive and awaits further exploration. 

Recently, researchers at Bristol Myers Squibb reported their discovery of inda-zole carboxamides (e.g., 42, Fig. 10), a new class of cannabimimetics, in which the C-2 carbon of 3-amido AAIs (e.g., 38, Fig. 9) is replaced by nitrogen. The indazole analog 42 exhibits high affinity for the CB2 receptor (Ki = 2.0 nM) compared to the corresponding AAl analogs 38 (Wrobleski et al. 2003). Indolopyridones (e.g., 43, Fig. 10), which are conformationally restricted C-3 amido AAIs, exhibit increased affinities for the CB2 receptor (Ki = 1.0 nM) and possess anti-inflammatory properties when administered orally in an in vivo murine inflammation model (Wrobleski et al. 2003). 

Antithrombin is a complex protein with multiple biologically important activities. It is the most critical modulator of coagulation, and has potent anti-inflammatory properties independent of its effects on coagulation [35, 70-73]. Several in vitro and in vivo animal studies, some of which used hpAT as a direct comparator, were undertaken to evaluate the potency of rhAT. 

It should be noted that when evaluating in vivo experiments with orally administered NAEs, NAE bioavailability and pharmacokinetics are rarely taken into consideration. It is known that intestinal mucosa, liver (Schmid et al., 1985), and small intestine (Katayama et al., 1997) have a high level of FAAH activity. Thus, it is likely that dietary NAEs are readily degraded in the intestinal tract. In this context, it is interesting to note that the original paper about the anti-inflammatory properties of NAEs attributed them to the ethanolamine moiety of the molecule (Kuehl et al., 1957). Mazzari et al. (1996), however, did not find any anti-inflammatory effect of orally administered ethanolamine and palmitic acid in a model of substance-P-induced extravasation. Thus, there are... 

Manzamines have shown a variety of bioactivities ineluding cytotoxicity, antimicrobial, pesticidal, and anti-inflammatory properties [2] some of them demonstrated effects on HTV and AIDS opportunistic infections [2], To date, the greatest potential for the manzamine alkaloids appears to be against malaria with manzamine A showing improved aetivity over the elinieally used drugs chloroquine and artemisinin both in vitro and in vivo [2]. 

Also other members of the profen-family, among them naproxen, flurbiprofen, ketoprofen and tiaprofenic acid, are of great importance today. In general, these are 2-aryl- or 2-heteroaryl-propionic acids, of which in vitro only the (S)-(+)-enantiomer inhibits cyclooxygenase-1 (Fig. 5.84). In vivo, depending on the particular animal species, and also in humans, the (U)-(-)-enantiomer is converted to various degrees into its (S)-enantiomer with the aid of -methylacyl-CoA-racemase, via the Coenzyme A-thioester. In addition, more recent investigations could show that (R)-ibuprofen and (R)-flurbiprofen themselves have also anti-inflammatory properties. Many of the profens, with the exception of naproxen, are therefore marketed as racemates. 

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