Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 13, Issue 1, 2014

Diabetes is a chronic metabolic problem closely related to cardiovascular disease leading to premature death. Dyslipidemia is an important risk factor responsible for cardiovascular disease in patients with diabetes. This paper is based on review of articles published to observe the effect of N. Sativa (black seed) on lipid levels in patients suffering from Diabetes Mellitus. A search of indexed papers and clinical trials was done using MEDLINE and PubMed and Cochrane search engine. All studies assessing the effect of N. Sativa ingestion on lipid levels among diabetics (animal or human) were included. A total of 12 trials (6 human studies and 6 animal studies) fulfilling the inclusion criteria were reviewed. Majority of human and animal trials done among humans and animals with diabetes or metabolic syndrome demonstrated reduction in weight and improvement in serum lipid levels including decrease total lipids, triglycerides, LDL levels. However, increase in HDL level showed questionable results. N. Sativa L and its different preparations can be used as an adjuvant with lipid lowering drugs for control of lipids however its role as a main therapeutic agent cannot be recommended and more metanalysis using standardized preparations with a close watch on methodological short falls is suggested to prove its role.

Cutaneous fibrosis seen in systemic sclerosis (SSc) is a generalized connective tissue disorder, characterized by a wide spectrum of microvascular and immunological abnormalities. Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter and immune modulator, is also an important mediator of bidirectional interactions between the vasoactive amines and the skin.5-HT, a commonly secreted amine, is a known inducer of fibrosis, although the mechanistic basis for it and growth factors regulating fibrosis and proliferation in the microenvironment are unclear. We review that as serotonin has powerful vasodilator, immunomodulator, and growth factor actions, this pathway could be involved in skin fibrotic. Since serotoninergic system play a role in skin fibrotic, and 5-HTs drugs, an usual treatment for this type of patients. These provides a future perspective for research and drug development.

The medicinal activity of COX-2 inhibitors are sufficiently beneficial to urge the search for new drug designs. This study presents 16 analogs of lumiracoxib and 10 analogs to valdecoxib having properties suitable as COX-2 inhibitors. For lumiracoxib analogs the mean Log P, polar surface area, and formula weight are 3.00, 70.46 A2, and 276.60, respectively. For valdecoxib analogs the mean Log P, polar surface area, and formula weight are 3.65, 68.46 A2, and 322.32, respectively. Grubb’s test analysis of seven properties for seven known COX-2 selective inhibitors and those of 26 analog compounds indicated no outliers. The unpaired t-test compared Log P and polar surface area of seven known COX-2 inhibitors to all 26 analogs and found no difference. All 26 analogs showed no violation of the Rule of 5, this being an indicator of favorable bioavailability. Hierarchical cluster analysis by single linkage indicated lumiracoxib is most similar to analogs 2, 4, 5, 6, 7, 9, 10, 11, 14, 15, 16, and 17. Valdecoxib has highest similarity to analogs 8, 19, 21, 22, 23, 26, 27, and 28. Multiple regression analysis successfully produced equations for prediction of similar compounds to lumiracoxib and valdecoxib. Path analysis indicated that number of atoms, oxygen & nitrogen atoms, and Log P are the greatest determinants for formula weight for known COX-2 inhibitors. Criteria for molecular properties is established for identifying COX-2 inhibitors. These 26 analogs show much potential for active COX-2 inhibition.

The orange-peel derived terpene d-Limonene, probably through its metabolite, perillyl alcohol (POH), has been reported to have tissue-repair properties. Two murine models of respectively 12-O-Tetradecanoylphorbol-13-Acetate (TPA)-induced dermatitis and mechanical skin lesion were used here to assess the efficacy of d-Limonene or POH applied topically. Macroscopic and microscopic evaluation of skin lesions was performed as well as that of P-selectin expression, together with measurements of serum concentrations of IL-1β, IL-6 and TNF-α in the first model. Healing and angiogenesis around the scar were examined in the second model. Because differences in angiogenesis were noted, the effect of both d-Limonene and POH was further tested on an in vitro model of endothelial microtubules formation. Both d-Limonene and POH reduced the severity and extension of TPA-induced skin lesions with significantly lowered macroscopic and microscopic scores (p<0.04 in both cases). Moreover, the expression of P-selectin induced by TPA was abrogated by POH and significantly lower serum concentrations of IL-6 and TNF-α were observed in d-Limonene- and POH-treated mice (p<0.04 and 0.03). In the second model, tissue regeneration was improved, especially by POH, and was clearly associated with reduced neovascularization. This surprising anti-angiogenic effect was confirmed in the matrigel model of endothelial microtubules formation. These studies show that d-Limonene and POH demonstrate significant anti-inflammatory effects in murine dermal inflammation and wound-healing. The decreased systemic cytokine production as well as a consistent inhibition of endothelial P-selectin expression and neo-vascularization induced by these terpenic compounds contribute to their healing effects on the epidermal barrier.

Aceclofenac, a nonsteroidal anti-inflammatory drug, has a propensity to cause gastric ulcers, while zinc ions are known to possess anti-ulcer and anti-inflammatory activities. With a view to reduce the gastroenteropathies associated with aceclofenac, its zinc complex was prepared and characterized using spectroscopy and differential scanning calorimetry. In vitro hydrolysis study showed that zinc complex of aceclofenac is more stable in HCl buffer (pH 1.2) than in phosphate buffer (pH 7.4) indicating the stability of the complex in stomach. In silico testing of the aceclofenac and its complex using PASS (Prediction of activity spectra of substances) software revealed that the complex might possess antiinflammatory activity which was confirmed by carrageenan-induced rat paw edema test. It has been found that antiinflammatory activity of this complex is comparable with that of parent drug along with reduction in ulcer index. Thus, the use of complex is suggested to be more preferable than aceclofenac alone.

Aegle marmelos (Indian Bael) is a tree which belongs to the family of Rutaceae. It holds a prominent position in both Indian medicine and Indian culture. We have screened various fractions of Aegle marmelos extracts for their anticancer properties using in vitro cell models. Gas chromatography-Mass spectrometry (GC-MS) was employed to analyze the biomolecules present in the Aegle marmelos extract. Jurkat and human neuroblastoma (IMR-32) cells were treated with different concentrations of the fractionated Aegle marmelos extracts. Flow cytometric analysis revealed that optimal concentration (50μg/ml) of beta caryophyllene and caryophyllene oxide fractions of Aegle marmelos extract can induce apoptosis in Jurkat cell line. cDNA expression profiling of pro-apoptotic and anti-apoptotic genes was carried out using real time PCR (RT-PCR). Down-regulation of anti-apoptotic genes (bcl-2, mdm2, cox2 and cmyb) and up-regulation of pro-apoptotic genes (bax, bak1, caspase-8, caspase-9 and ATM) in Jurkat and IMR-32 cells treated with the beta caryophyllene and caryophyllene oxide fractions of Aegle marmelos extract revealed the insights of the downstream apoptotic mechanism. Furthermore, in-silico approach was employed to understand the upstream target involved in the induction of apoptosis by the beta caryophyllene and caryophyllene oxide fractions of Aegle marmelos extract. Herein, we report that beta caryophyllene and caryophyllene oxide isolated from Aegle marmelos can act as potent anti-inflammatory agents and modulators of a newly established therapeutic target, 15-lipoxygenase (15-LOX). Beta caryophyllene and caryophyllene oxide can induce apoptosis in lymphoma and neuroblastoma cells via modulation of 15-LOX (up-stream target) followed by the down-regulation of anti-apoptotic and up-regulation of pro-apoptotic genes.

Inflammation is one of the pathophysiological pathways suggested for the development of cardiovascular disease in obstructive sleep apnea (OSA). The recurrent nocturnal episodes of hypoxia/reoxygenation observed in patients with OSA appear to be partly responsible for the systemic inflammatory response. The aim of this study was to investigate the role of inflammation by measuring the C-reactive protein (CRP) and fibrinogen levels, and erythrocyte sedimentation rate (ESR) in the OSA according to gender. This study included 139 apparently healthy subjects with newly diagnosed OSA and 27 control subjects who underwent overnight polysomnography and routine blood tests. Levels of inflammatory markers (CRP, fibrinogen, and ESR) were determined from the blood samples taken in the morning. The levels of CRP and fibrinogen were significantly higher in patients than in controls (p<0.0001 and p=0.001, respectively). Fibrinogen and ESR were significantly higher in the female patients than in the male patients (p<0.0001). In female patients, CRP and ESR correlated with time spent at oxygen saturation (T%SaO2)<90 (R=0.327, p=0.029 and R=0.301, p=0.05, respectively), T%SaO2<85 (R=0.482, p=0.001 and R=0.409, p=0.006, respectively), oxygen desaturation index (ODI) (R=0.298, p=0.047 and R=0.340, p=0.026, respectively), lowest oxygen saturation (SaO2) (R=-0.293, p=0.051 and R=-0.374, p=0.013, respectively), mean SaO2 (R=-0.408, p=0.005 and R=-0.385, p=0.011, respectively). In male patients, CRP correlated with T%SaO2<90 (R=0.267, p=0.009), T%SaO2<85 (R=0.279, p=0.006), mean SaO2 (R=-0.284, p=0.006) and fibrinogen correlated with T%SaO2<90 (R=0.282, p=0.028), and mean SaO2 (R=-0.252, p=0.05). In conclusion, increased values of systemic inflammatory markers and their correlations with sleep data observed in our study support other studies suggesting the possible involvement of inflammation in OSA. As this correlation is more apparent in female patients then the males, it suggests that there may be a stronger relation between OSA development and inflammation in females. Higher levels of CRP, fibrinogen, and ESR may result from the combined interactions of obesity, metabolic syndrome (MetS) and nocturnal hypoxia.

Objective: To study the role of serum Monoamine oxidase (MAO) in Lichen planus(LP). Methods: 82 cases of Lichen planus patients and 35 healthy controls were selected in the investigation. The total serum MAO levels were measured. Results: The levels of serum MAO in Lichen planus patients were significantly higher than those in healthy controls (P<0.01). The severity of Lichen planus was not correlated with serum MAO levels (r =0.4873, t=0.73, p>0.05). Conclusion: According to the findings, there might be a coincidence of MAO and lichen planus. However, further studies are required to clarify the immunological mechanisms which are responsible for MAO synthesis during immunoreaction.

Dyslipidemia plays an important role in the provocation of cardiovascular disease. Psoriasis was associated with metabolic disorder and therefore the present study was performed to evaluate the therapeutic effect of combination of blackseed with garlic as a treatment for dyslipidemia. A randomized, double-blind, placebo controlled, two arms parallel study consisted of 4 week diet stabilization period that included a 4 week base line evaluation phase, followed by an 8 week treatment period. The study comprised men (n=127) and women (n=131) aged 24 to 57 years, who met the NCEP ATP III criteria for drug treatment of hyperlipidemia and dietary intervention. Three hundred patients were randomized to treatment and 258 completed the study. The lipid profile included total cholesterol, HDL-C, Non-HDL-C, LDL-C, and Triglyceride. There were no significant differences between the two treatment groups at the baseline for triglyceride, HDL, Non-HDL, LDL and total cholesterol. Following 8 weeks treatment with simvastatin plus placebo the reduction in Non-HDL, triglyceride, LDL and total cholesterol following treatment course was statistically highly significant (P= <0.01). However, the increase in HDL was significant (P=0.02). Patients who received simvastatin, plus black seed and garlic for 8 weeks of treatment show significant differences between baseline and after treatment course for all tested profiles (P=<0.01). This comparison of mean values reveals a high significant difference (P=<0.01) for cholesterol, triglyceride, Non-HDL, and LDL, and significant difference (P=0.03) for HDL between the two treatment groups. This study suggests that the evaluated combination was effective in correction of dyslipidemia. Large scale clinical trials comparing different doses are warranted.

Background: Allergic rhinitis (AR) is the most common manifestation of atopic reaction to inhaled allergens. It is a chronic inflammatory disease which may first appear at any age, but the onset is usually during childhood or adolescence. Up to date there is no curative treatment for this disorder and most of the drugs that were used for treatment only can induce symptomatic relief and some of them have side effect and can cause withdrawal symptoms. Objective: To evaluate the therapeutic efficacy of the Nigella sativa (NS) extract as treatment approach for allergic rhinitis. Patients & Methods: A total of 68 patients with AR were included in the study, of them 19 patients were with mild symptoms, 28 patients were with moderate symptoms and 21 patients were with severe symptoms. Each group was subdivided into active and control subgroups. To prove that the patient's symptoms were allergic in nature, skin test was performed for all patients. Any individual with negative skin test was excluded. The individuals in the active group received N. sativa oil and the control group individuals received ordinary food oil in the form of nasal drops for 6 weeks. Results: After the 6 weeks treatment course, 100% of the patients in the mild active group became symptoms free; while in moderate active group 68.7% became symptoms free and 25% were improved; while in severe active group 58.3% became symptoms free and 25% were improved. In addition, 92.1% of total patients in the active group demonstrated improvement in their symptoms or were symptoms free, while the corresponding value was 30.1% in the control group (P=0.000). At the end of 6 weeks of treatment with topical use, the improvement in tolerability of allergen exposure in active group became 55.2% which was significant (P=0.006) as compared with control group which was accounted for 20% at the same time. Conclusion: Topical application of black seed oil was effective in the treatment of allergic rhinitis, with minimal side effects.